|
Percent inhibition of acetylcholinesterase using ATCh1 as a substrate
|
Homo sapiens
|
13.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues.
Year : 2001
Volume : 44
Issue : 10
First Page : 1594
Last Page : 1602
Authors : Kim DK, Ryu DH, Lee JY, Lee N, Kim YW, Kim JS, Chang K, Im GJ, Kim TK, Choi WS.
Abstract : Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development.
|
Antiproliferative activity against human DU145 prostate cell line
|
Homo sapiens
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : BN 80927: a novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II.
Year : 1999
Volume : 9
Issue : 17
First Page : 2599
Last Page : 2602
Authors : Lavergne O, Harnett J, Rolland A, Lanco C, Lesueur-Ginot L, Demarquay D, Huchet M, Coulomb H, Bigg DC.
Abstract : BN 80927, a novel homocamptothecin derivative, inhibits both topoisomerase I and topoisomerase II mediated DNA relaxation and shows pronounced cytotoxicity against HT29, SKOV-3, DU145 and MCF7 human tumor cell lines.
|
In vitro antitumor activity against HOC-21 (human ovarian cancer) cells.
|
Homo sapiens
|
0.0412
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antitumor activity of ring A- and F-modified hexacyclic camptothecin analogues.
Year : 1998
Volume : 41
Issue : 13
First Page : 2308
Last Page : 2318
Authors : Sugimori M, Ejima A, Ohsuki S, Uoto K, Mitsui I, Kawato Y, Hirota Y, Sato K, Terasawa H.
Abstract : Nineteen ring A- and F-modified hexacyclic analogues of camptothecin were synthesized by Friedländer condensation of appropriately substituted bicyclic amino ketones with tricyclic ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory activity. Seventeen of the compounds showed cytotoxic effects comparable or superior to those of 7-ethyl-10-hydroxycamptothecin (SN-38) against mouse leukemia P388 and human tumor cell lines HOC-21 and QG-56. Introduction of a compact and inductively electron-withdrawing substituent such as a hydroxy, methoxy, chloro, or fluoro group into position 5 of ring A of the hexacyclic compound remarkably increased the antitumor activity. The potency of topoisomerase I inhibition of these compounds showed good correlation with their cytotoxicity. Among them, the 4-methyl-5-fluoro hexacyclic compound was the most potent of all and was 10 times as active as SN-38 in in vitro antitumor activity.
|
Tested in vitro for the inhibition of HOC-21(human ovarian cancer) cell line by MTT assay
|
Homo sapiens
|
0.1231
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Antitumor agents. 7. Synthesis and antitumor activity of novel hexacyclic camptothecin analogues.
Year : 1994
Volume : 37
Issue : 19
First Page : 3033
Last Page : 3039
Authors : Sugimori M, Ejima A, Ohsuki S, Uoto K, Mitsui I, Matsumoto K, Kawato Y, Yasuoka M, Sato K, Tagawa H.
Abstract : Eleven novel hexacyclic and three 7,9-disubstituted pentacyclic derivatives of camptothecin were synthesized and evaluated for in vitro cytotoxic activity against P388, HOC-21, and QG-56 and in vivo antileukemic activity against P388 in mice. Hexacyclic compounds which have an additional 5-, 6-, or 7-membered ring cyclized at positions 7 and 9 of camptothecin were prepared by intramolecular cyclization of pentacyclic camptothecin derivatives or Friedländer condensation of the appropriate bicyclic amino ketone and tricyclic ketone. All of the hexacyclic compounds exhibited compatible or superior activity of 7-ethyl-10-hydroxycamptothecin (SN-38) in in vitro assays without regard to the size or type of the additional ring, and three of six compounds showed more than 300% T/C on in vivo assay. These results suggest that the potency of the hexacyclic ring system is higher than that of the original pentacyclic ring system of camptothecin and that the conformational rigidity of substituents at positions 7 and 9 is favorable for antitumor activity.
|
In vitro inhibitory concentration required against HT-29 human colon cancer cells
|
Homo sapiens
|
27.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cancer chemotherapy: a SN-38 (7-ethyl-10-hydroxycamptothecin) glucuronide prodrug for treatment by a PMT (Prodrug MonoTherapy) strategy.
Year : 2003
Volume : 13
Issue : 5
First Page : 947
Last Page : 950
Authors : Angenault S, Thirot S, Schmidt F, Monneret C, Pfeiffer B, Renard P.
Abstract : A glucuronide-based prodrug of SN-38 (7-ethyl-10-hydroxycamptothecin) has been synthesized for use in a Prodrug MonoTherapy Strategy (PMT). Since this prodrug is significantly less cytotoxic than SN-38 itself and efficiently releases the drug in vitro in the presence of beta-D-glucuronidase, it can be considered as an appropriate candidate for cancer treatment by a PMT strategy.
|
Antiproliferative activity against human HT-29 colon cell line
|
Homo sapiens
|
22.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : BN 80927: a novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II.
Year : 1999
Volume : 9
Issue : 17
First Page : 2599
Last Page : 2602
Authors : Lavergne O, Harnett J, Rolland A, Lanco C, Lesueur-Ginot L, Demarquay D, Huchet M, Coulomb H, Bigg DC.
Abstract : BN 80927, a novel homocamptothecin derivative, inhibits both topoisomerase I and topoisomerase II mediated DNA relaxation and shows pronounced cytotoxicity against HT29, SKOV-3, DU145 and MCF7 human tumor cell lines.
|
Inhibitory activity in mice bearing L1210 leukemia
|
Mus musculus
|
8.9
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I and antitumor activity.
Year : 1991
Volume : 34
Issue : 1
First Page : 98
Last Page : 107
Authors : Kingsbury WD, Boehm JC, Jakas DR, Holden KG, Hecht SM, Gallagher G, Caranfa MJ, McCabe FL, Faucette LF, Johnson RK.
Abstract : Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxycamptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25,26) or by total synthesis (35,42,43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK&F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.
|
Inhibition against MDA-MB-435 S human breast cancer cells in the absence of albumin
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity.
Year : 2000
Volume : 43
Issue : 21
First Page : 3970
Last Page : 3980
Authors : Bom D, Curran DP, Kruszewski S, Zimmer SG, Thompson Strode J, Kohlhagen G, Du W, Chavan AJ, Fraley KA, Bingcang AL, Latus LJ, Pommier Y, Burke TG.
Abstract : We describe the rational design and synthesis of B- and A, B-ring-modified camptothecins. The key alpha-hydroxy-delta-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant camptothecin analogues. In human blood 14 displayed a t(1/2) of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to camptothecin and 10-hydroxycamptothecin, as well as the FDA-approved camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.
|
Inhibition against MDA-MB-435 S human breast cancer cells in the presence of 30 mg/mL HSA
|
Homo sapiens
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity.
Year : 2000
Volume : 43
Issue : 21
First Page : 3970
Last Page : 3980
Authors : Bom D, Curran DP, Kruszewski S, Zimmer SG, Thompson Strode J, Kohlhagen G, Du W, Chavan AJ, Fraley KA, Bingcang AL, Latus LJ, Pommier Y, Burke TG.
Abstract : We describe the rational design and synthesis of B- and A, B-ring-modified camptothecins. The key alpha-hydroxy-delta-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant camptothecin analogues. In human blood 14 displayed a t(1/2) of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to camptothecin and 10-hydroxycamptothecin, as well as the FDA-approved camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.
|
Antiproliferative activity against human MCF-7 breast cell line
|
Homo sapiens
|
370.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : BN 80927: a novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II.
Year : 1999
Volume : 9
Issue : 17
First Page : 2599
Last Page : 2602
Authors : Lavergne O, Harnett J, Rolland A, Lanco C, Lesueur-Ginot L, Demarquay D, Huchet M, Coulomb H, Bigg DC.
Abstract : BN 80927, a novel homocamptothecin derivative, inhibits both topoisomerase I and topoisomerase II mediated DNA relaxation and shows pronounced cytotoxicity against HT29, SKOV-3, DU145 and MCF7 human tumor cell lines.
|
Cytotoxicity against human non-small-cell lung carcinoma cell line H460 (NSCLC-H460)
|
Homo sapiens
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity.
Year : 2001
Volume : 44
Issue : 20
First Page : 3264
Last Page : 3274
Authors : Dallavalle S, Ferrari A, Biasotti B, Merlini L, Penco S, Gallo G, Marzi M, Tinti MO, Martinelli R, Pisano C, Carminati P, Carenini N, Beretta G, Perego P, De Cesare M, Pratesi G, Zunino F.
Abstract : In an attempt to synthesize potential anticancer agents acting by inhibition of topoisomerase I (Topo I) a new series of oxyiminomethyl derivatives in position 7 of camptothecin (CPT) was prepared. The synthesis relied on the condensation of 20S-CPT-7-aldehyde or 20S-CPT-7-ketones with alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl O-substituted hydroxylamines. The compounds were tested for their cytotoxic activity in vitro against H460 non-small lung carcinoma cell line, the activity being for 24 out of 37 compounds in the 0.01-0.3 microM range. A QSAR analysis indicated that lipophilicity is the main parameter correlated with cytotoxicity. Investigation of the DNA-Topo I-drug cleavable complex showed a rough parallelism between cytotoxicity and inhibition of Topo I. Persistence of the DNA cleavage after NaCl-mediated disruption of the ternary complex suggests that for the most potent compounds, e.g., 15, the cytotoxicity was at least in part related to stabilization of the complex, as also supported by the persistence of the DNA-enzyme complex in drug-treated cells. The in vivo antitumor efficacy of the most potent analogue (15) was evaluated in direct comparison with topotecan using human lung tumor xenograft models. In the range of optimal doses (2-3 mg/kg), the improved efficacy of 15 was documented in terms of inhibition of tumor growth and rate of complete response.
|
In vitro antitumor activity against P388 (murine leukemia) cells.
|
Mus musculus
|
0.00144
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antitumor activity of ring A- and F-modified hexacyclic camptothecin analogues.
Year : 1998
Volume : 41
Issue : 13
First Page : 2308
Last Page : 2318
Authors : Sugimori M, Ejima A, Ohsuki S, Uoto K, Mitsui I, Kawato Y, Hirota Y, Sato K, Terasawa H.
Abstract : Nineteen ring A- and F-modified hexacyclic analogues of camptothecin were synthesized by Friedländer condensation of appropriately substituted bicyclic amino ketones with tricyclic ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory activity. Seventeen of the compounds showed cytotoxic effects comparable or superior to those of 7-ethyl-10-hydroxycamptothecin (SN-38) against mouse leukemia P388 and human tumor cell lines HOC-21 and QG-56. Introduction of a compact and inductively electron-withdrawing substituent such as a hydroxy, methoxy, chloro, or fluoro group into position 5 of ring A of the hexacyclic compound remarkably increased the antitumor activity. The potency of topoisomerase I inhibition of these compounds showed good correlation with their cytotoxicity. Among them, the 4-methyl-5-fluoro hexacyclic compound was the most potent of all and was 10 times as active as SN-38 in in vitro antitumor activity.
|
Tested in vitro for the inhibition of P388 (mouse leukemia) cell line by MTT assay; 1.95-6.93 ng/mL
|
Mus musculus
|
0.00693
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Antitumor agents. 7. Synthesis and antitumor activity of novel hexacyclic camptothecin analogues.
Year : 1994
Volume : 37
Issue : 19
First Page : 3033
Last Page : 3039
Authors : Sugimori M, Ejima A, Ohsuki S, Uoto K, Mitsui I, Matsumoto K, Kawato Y, Yasuoka M, Sato K, Tagawa H.
Abstract : Eleven novel hexacyclic and three 7,9-disubstituted pentacyclic derivatives of camptothecin were synthesized and evaluated for in vitro cytotoxic activity against P388, HOC-21, and QG-56 and in vivo antileukemic activity against P388 in mice. Hexacyclic compounds which have an additional 5-, 6-, or 7-membered ring cyclized at positions 7 and 9 of camptothecin were prepared by intramolecular cyclization of pentacyclic camptothecin derivatives or Friedländer condensation of the appropriate bicyclic amino ketone and tricyclic ketone. All of the hexacyclic compounds exhibited compatible or superior activity of 7-ethyl-10-hydroxycamptothecin (SN-38) in in vitro assays without regard to the size or type of the additional ring, and three of six compounds showed more than 300% T/C on in vivo assay. These results suggest that the potency of the hexacyclic ring system is higher than that of the original pentacyclic ring system of camptothecin and that the conformational rigidity of substituents at positions 7 and 9 is favorable for antitumor activity.
|
In vitro antitumor activity against QG-56 (human lung cancer) cells.
|
Homo sapiens
|
0.0009
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antitumor activity of ring A- and F-modified hexacyclic camptothecin analogues.
Year : 1998
Volume : 41
Issue : 13
First Page : 2308
Last Page : 2318
Authors : Sugimori M, Ejima A, Ohsuki S, Uoto K, Mitsui I, Kawato Y, Hirota Y, Sato K, Terasawa H.
Abstract : Nineteen ring A- and F-modified hexacyclic analogues of camptothecin were synthesized by Friedländer condensation of appropriately substituted bicyclic amino ketones with tricyclic ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory activity. Seventeen of the compounds showed cytotoxic effects comparable or superior to those of 7-ethyl-10-hydroxycamptothecin (SN-38) against mouse leukemia P388 and human tumor cell lines HOC-21 and QG-56. Introduction of a compact and inductively electron-withdrawing substituent such as a hydroxy, methoxy, chloro, or fluoro group into position 5 of ring A of the hexacyclic compound remarkably increased the antitumor activity. The potency of topoisomerase I inhibition of these compounds showed good correlation with their cytotoxicity. Among them, the 4-methyl-5-fluoro hexacyclic compound was the most potent of all and was 10 times as active as SN-38 in in vitro antitumor activity.
|
Tested in vitro for the inhibition of QG-56 (human lung squamous cell carcinoma) cell line by MTT assay
|
Homo sapiens
|
0.00317
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Antitumor agents. 7. Synthesis and antitumor activity of novel hexacyclic camptothecin analogues.
Year : 1994
Volume : 37
Issue : 19
First Page : 3033
Last Page : 3039
Authors : Sugimori M, Ejima A, Ohsuki S, Uoto K, Mitsui I, Matsumoto K, Kawato Y, Yasuoka M, Sato K, Tagawa H.
Abstract : Eleven novel hexacyclic and three 7,9-disubstituted pentacyclic derivatives of camptothecin were synthesized and evaluated for in vitro cytotoxic activity against P388, HOC-21, and QG-56 and in vivo antileukemic activity against P388 in mice. Hexacyclic compounds which have an additional 5-, 6-, or 7-membered ring cyclized at positions 7 and 9 of camptothecin were prepared by intramolecular cyclization of pentacyclic camptothecin derivatives or Friedländer condensation of the appropriate bicyclic amino ketone and tricyclic ketone. All of the hexacyclic compounds exhibited compatible or superior activity of 7-ethyl-10-hydroxycamptothecin (SN-38) in in vitro assays without regard to the size or type of the additional ring, and three of six compounds showed more than 300% T/C on in vivo assay. These results suggest that the potency of the hexacyclic ring system is higher than that of the original pentacyclic ring system of camptothecin and that the conformational rigidity of substituents at positions 7 and 9 is favorable for antitumor activity.
|
Antiproliferative activity against human SKOV-3 ovarian cell line
|
Homo sapiens
|
720.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : BN 80927: a novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II.
Year : 1999
Volume : 9
Issue : 17
First Page : 2599
Last Page : 2602
Authors : Lavergne O, Harnett J, Rolland A, Lanco C, Lesueur-Ginot L, Demarquay D, Huchet M, Coulomb H, Bigg DC.
Abstract : BN 80927, a novel homocamptothecin derivative, inhibits both topoisomerase I and topoisomerase II mediated DNA relaxation and shows pronounced cytotoxicity against HT29, SKOV-3, DU145 and MCF7 human tumor cell lines.
|
In Vitro cytotoxicity against human breast cancer cell line (SK-BR-3)
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues.
Year : 2001
Volume : 44
Issue : 10
First Page : 1594
Last Page : 1602
Authors : Kim DK, Ryu DH, Lee JY, Lee N, Kim YW, Kim JS, Chang K, Im GJ, Kim TK, Choi WS.
Abstract : Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development.
|
In Vitro cytotoxicity against human colon cancer cell line (WiDr)
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues.
Year : 2001
Volume : 44
Issue : 10
First Page : 1594
Last Page : 1602
Authors : Kim DK, Ryu DH, Lee JY, Lee N, Kim YW, Kim JS, Chang K, Im GJ, Kim TK, Choi WS.
Abstract : Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development.
|
In Vitro cytotoxicity against human lung cancer cell line (A549)
|
Homo sapiens
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues.
Year : 2001
Volume : 44
Issue : 10
First Page : 1594
Last Page : 1602
Authors : Kim DK, Ryu DH, Lee JY, Lee N, Kim YW, Kim JS, Chang K, Im GJ, Kim TK, Choi WS.
Abstract : Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development.
|
In Vitro cytotoxicity against human lung cancer cell line (H128)
|
Homo sapiens
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues.
Year : 2001
Volume : 44
Issue : 10
First Page : 1594
Last Page : 1602
Authors : Kim DK, Ryu DH, Lee JY, Lee N, Kim YW, Kim JS, Chang K, Im GJ, Kim TK, Choi WS.
Abstract : Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development.
|
In Vitro cytotoxicity against human ovarian cancer cell line (SK-OV-3)
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues.
Year : 2001
Volume : 44
Issue : 10
First Page : 1594
Last Page : 1602
Authors : Kim DK, Ryu DH, Lee JY, Lee N, Kim YW, Kim JS, Chang K, Im GJ, Kim TK, Choi WS.
Abstract : Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development.
|
In Vitro cytotoxicity against human stomach cancer cell line (MKN45)
|
Homo sapiens
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues.
Year : 2001
Volume : 44
Issue : 10
First Page : 1594
Last Page : 1602
Authors : Kim DK, Ryu DH, Lee JY, Lee N, Kim YW, Kim JS, Chang K, Im GJ, Kim TK, Choi WS.
Abstract : Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development.
|
Effective concentration against DNA topoisomerase I
|
Homo sapiens
|
320.0
nM
|
|
Effective concentration against DNA topoisomerase I
|
Homo sapiens
|
70.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Camptothecin analogs with bulky, hydrophobic substituents at the 7-position via a Grignard reaction.
Year : 2004
Volume : 14
Issue : 21
First Page : 5377
Last Page : 5381
Authors : Manikumar G, Wadkins RM, Bearss D, Von Hoff DD, Wani MC, Wall ME.
Abstract : By developing a new synthetic procedure for introduction of side chains onto the camptothecin ring system, we were able to achieve the preparation of a number of analogs bearing bulky, hydrophobic groups directly attached to the 7-position. These include 7-tert-butylcamptothecin, 7-benzylcamptothecin and the corresponding 10,11-methylenedioxycamptothecins. This method involves the reaction of an appropriate orthoaminobenzonitrile with various Grignard reagents to give the corresponding orthoaminoketones. Friedlander condensation of the latter with the key tricyclic ketone leads to 7-substituted camptothecin analogs. We report the activity of these compounds as topoisomerase I poisons and their ability to inhibit growth of selected tumor cell lines.
|
Inhibitory concentration against human HCT116 colon cancer cell line
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antitumor activity of 7-ethyl-9-alkyl derivatives of camptothecin.
Year : 2005
Volume : 15
Issue : 8
First Page : 2003
Last Page : 2006
Authors : Gao H, Zhang X, Chen Y, Shen H, Sun J, Huang M, Ding J, Li C, Lu W.
Abstract : A series of new camptothecin derivatives, as topoisomerase I inhibitor, were synthesized to identify potent antitumor agents. The synthesis method was based on the Claisen rearrangement of 10-allyloxy-7-ethylcamptothecin. All of the compounds were assayed for cytotoxicity against two human tumor cell lines, Bel7402, HCT116, and showed good potency in vitro. Compounds 2, 4, 9, were assessed for the stability of lactone in human plasma. And then compound 2 was tested for antitumor activity in vitro against mouse tumor sarcoma-180. The results suggested that the small alkyl groups in the both 7- and 9-positions of camptothecin could promote liposolubility, antitumor activity in vitro and vivo, though did not bring much increase of the stability of lactone.
|
Concentration required to inhibit growth of human cervical HeLa carcinoma cell line
|
Homo sapiens
|
25.7
nM
|
|
Concentration required to inhibit growth of human cervical HeLa carcinoma cell line
|
Homo sapiens
|
38.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Camptothecin analogs with bulky, hydrophobic substituents at the 7-position via a Grignard reaction.
Year : 2004
Volume : 14
Issue : 21
First Page : 5377
Last Page : 5381
Authors : Manikumar G, Wadkins RM, Bearss D, Von Hoff DD, Wani MC, Wall ME.
Abstract : By developing a new synthetic procedure for introduction of side chains onto the camptothecin ring system, we were able to achieve the preparation of a number of analogs bearing bulky, hydrophobic groups directly attached to the 7-position. These include 7-tert-butylcamptothecin, 7-benzylcamptothecin and the corresponding 10,11-methylenedioxycamptothecins. This method involves the reaction of an appropriate orthoaminobenzonitrile with various Grignard reagents to give the corresponding orthoaminoketones. Friedlander condensation of the latter with the key tricyclic ketone leads to 7-substituted camptothecin analogs. We report the activity of these compounds as topoisomerase I poisons and their ability to inhibit growth of selected tumor cell lines.
|
Concentration required to inhibit growth of human prostate PC-3 carcinoma cell line
|
Homo sapiens
|
35.6
nM
|
|
Concentration required to inhibit growth of human prostate PC-3 carcinoma cell line
|
Homo sapiens
|
35.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Camptothecin analogs with bulky, hydrophobic substituents at the 7-position via a Grignard reaction.
Year : 2004
Volume : 14
Issue : 21
First Page : 5377
Last Page : 5381
Authors : Manikumar G, Wadkins RM, Bearss D, Von Hoff DD, Wani MC, Wall ME.
Abstract : By developing a new synthetic procedure for introduction of side chains onto the camptothecin ring system, we were able to achieve the preparation of a number of analogs bearing bulky, hydrophobic groups directly attached to the 7-position. These include 7-tert-butylcamptothecin, 7-benzylcamptothecin and the corresponding 10,11-methylenedioxycamptothecins. This method involves the reaction of an appropriate orthoaminobenzonitrile with various Grignard reagents to give the corresponding orthoaminoketones. Friedlander condensation of the latter with the key tricyclic ketone leads to 7-substituted camptothecin analogs. We report the activity of these compounds as topoisomerase I poisons and their ability to inhibit growth of selected tumor cell lines.
|
In-vitro inhibitory concentration for human tumor HELA cell-line was determined using MTT assay after 3 days of incubation
|
Homo sapiens
|
22.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antitumor activity of the hexacyclic camptothecin derivatives.
Year : 2005
Volume : 15
Issue : 13
First Page : 3233
Last Page : 3236
Authors : Gao H, Zhang X, Chen Y, Shen H, Pang T, Sun J, Xu C, Ding J, Li C, Lu W.
Abstract : A series of hexacyclic camptothecin derivatives were synthesized to test for antitumor activity as topoisomerase I inhibitor. The strategy of synthesis was used for the formation of additional furan and dihydrofuran rings fused with 9- and 10-positions of camptothecin. All of the hexacyclic camptothecins were assayed for cytotoxicity against four human tumor cell lines, HL60, BEL-7402, HCT-116, and HeLa, and showed very impressive cytotoxicity activity in vitro. Enzyme activity of the hexacyclic camptothecins was evaluated, being equal or superior to that of SN-38. The stability of four compounds was assessed in human plasma. Two of these compounds were chosen to test for antitumor activity in vivo against Sarcoma-180. The results suggested that additional furan and dihydrofuran rings could improve the antitumor activity in vitro and vivo, though the stability of the lactone ring did not increase.
|
In-vitro inhibitory concentration for human tumor HL60 cell-line was determined using SRB assay after 3 days of incubation
|
Homo sapiens
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antitumor activity of the hexacyclic camptothecin derivatives.
Year : 2005
Volume : 15
Issue : 13
First Page : 3233
Last Page : 3236
Authors : Gao H, Zhang X, Chen Y, Shen H, Pang T, Sun J, Xu C, Ding J, Li C, Lu W.
Abstract : A series of hexacyclic camptothecin derivatives were synthesized to test for antitumor activity as topoisomerase I inhibitor. The strategy of synthesis was used for the formation of additional furan and dihydrofuran rings fused with 9- and 10-positions of camptothecin. All of the hexacyclic camptothecins were assayed for cytotoxicity against four human tumor cell lines, HL60, BEL-7402, HCT-116, and HeLa, and showed very impressive cytotoxicity activity in vitro. Enzyme activity of the hexacyclic camptothecins was evaluated, being equal or superior to that of SN-38. The stability of four compounds was assessed in human plasma. Two of these compounds were chosen to test for antitumor activity in vivo against Sarcoma-180. The results suggested that additional furan and dihydrofuran rings could improve the antitumor activity in vitro and vivo, though the stability of the lactone ring did not increase.
|
In-vitro inhibitory concentration for human tumor HCT116 cell-line was determined using MTT assay after 3 days of incubation
|
Homo sapiens
|
3.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antitumor activity of the hexacyclic camptothecin derivatives.
Year : 2005
Volume : 15
Issue : 13
First Page : 3233
Last Page : 3236
Authors : Gao H, Zhang X, Chen Y, Shen H, Pang T, Sun J, Xu C, Ding J, Li C, Lu W.
Abstract : A series of hexacyclic camptothecin derivatives were synthesized to test for antitumor activity as topoisomerase I inhibitor. The strategy of synthesis was used for the formation of additional furan and dihydrofuran rings fused with 9- and 10-positions of camptothecin. All of the hexacyclic camptothecins were assayed for cytotoxicity against four human tumor cell lines, HL60, BEL-7402, HCT-116, and HeLa, and showed very impressive cytotoxicity activity in vitro. Enzyme activity of the hexacyclic camptothecins was evaluated, being equal or superior to that of SN-38. The stability of four compounds was assessed in human plasma. Two of these compounds were chosen to test for antitumor activity in vivo against Sarcoma-180. The results suggested that additional furan and dihydrofuran rings could improve the antitumor activity in vitro and vivo, though the stability of the lactone ring did not increase.
|
In-vitro inhibitory concentration for human tumor BEL-7402 cell-line was determined using MTT assay after 3 days of incubation
|
Homo sapiens
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antitumor activity of the hexacyclic camptothecin derivatives.
Year : 2005
Volume : 15
Issue : 13
First Page : 3233
Last Page : 3236
Authors : Gao H, Zhang X, Chen Y, Shen H, Pang T, Sun J, Xu C, Ding J, Li C, Lu W.
Abstract : A series of hexacyclic camptothecin derivatives were synthesized to test for antitumor activity as topoisomerase I inhibitor. The strategy of synthesis was used for the formation of additional furan and dihydrofuran rings fused with 9- and 10-positions of camptothecin. All of the hexacyclic camptothecins were assayed for cytotoxicity against four human tumor cell lines, HL60, BEL-7402, HCT-116, and HeLa, and showed very impressive cytotoxicity activity in vitro. Enzyme activity of the hexacyclic camptothecins was evaluated, being equal or superior to that of SN-38. The stability of four compounds was assessed in human plasma. Two of these compounds were chosen to test for antitumor activity in vivo against Sarcoma-180. The results suggested that additional furan and dihydrofuran rings could improve the antitumor activity in vitro and vivo, though the stability of the lactone ring did not increase.
|
In vitro inhibitory concentration against human lung large cell carcinoma cell line, H460 (after 1 hour exposure)
|
Homo sapiens
|
210.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and cytotoxic activity of substituted luotonin A derivatives.
Year : 2004
Volume : 14
Issue : 23
First Page : 5757
Last Page : 5761
Authors : Dallavalle S, Merlini L, Beretta GL, Tinelli S, Zunino F.
Abstract : Luotonin A is a cytotoxic alkaloid that has been shown to inhibit topoisomerase I via stabilization of the binary complex topoisomerase-DNA in the same fashion as camptothecin. The synthesis and the cytotoxic activity on the lung carcinoma cell line H460 of a series of derivatives of Luotonin A is reported. The compounds inhibit topoisomerase I but show weak cytotoxic activity, thus confirming the peculiarity of ring E of camptothecin for antitumor activity.
|
Inhibition of human H460 cell growth
|
Homo sapiens
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cytotoxic activity of polyamine analogues of camptothecin.
Year : 2006
Volume : 49
Issue : 17
First Page : 5177
Last Page : 5186
Authors : Dallavalle S, Giannini G, Alloatti D, Casati A, Marastoni E, Musso L, Merlini L, Morini G, Penco S, Pisano C, Tinelli S, De Cesare M, Beretta GL, Zunino F.
Abstract : A number of derivatives of camptothecin with a polyamine chain linked to position 7 of camptothecin via an amino, imino, or oxyiminomethyl group were synthesized and tested for their biological activity. All compounds showed marked growth inhibitory activity against the H460 human lung carcinoma cell line. In particular, the iminomethyl derivatives where the amino groups of the chain were protected with Boc groups exhibited a high potency, with IC50 values of approximately 10(-8) M. The pattern of DNA cleavage in vitro and the persistence of the cleavable ternary complex drug-DNA-topoisomerase I observed with polyamine conjugates containing free amino groups support a contribution of specific drug interaction with DNA as a determinant of activity. Modeling of compound 7c in the complex with topoisomerase 1 and DNA is consistent with this hypothesis. The lack of a specific correlation between stabilization of the cleavable complex and growth inhibition likely reflects multiple factors including the cellular pharmacokinetic behavior related to the variable lipophilicity of the conjugate, and the nature and linkage of the polyamine moiety.
|
Antiproliferative activity against human DU145 cells after 96 hrs
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and bioevaluation of 22-hydroxyacuminatine analogs.
Year : 2008
Volume : 18
Issue : 6
First Page : 2143
Last Page : 2146
Authors : Grillet F, Baumlová B, Prévost G, Constant JF, Chaumeron S, Bigg DC, Greene AE, Kanazawa A.
Abstract : A series of 22-hydroxyacuminatine analogs was prepared by using different Friedländer condensations. Several of the new compounds were tested for antiproliferative activity on cancer cell lines and for topoisomerase I inhibitory activity.
|
Antiproliferative activity against human MIA PaCa cells after 96 hrs
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and bioevaluation of 22-hydroxyacuminatine analogs.
Year : 2008
Volume : 18
Issue : 6
First Page : 2143
Last Page : 2146
Authors : Grillet F, Baumlová B, Prévost G, Constant JF, Chaumeron S, Bigg DC, Greene AE, Kanazawa A.
Abstract : A series of 22-hydroxyacuminatine analogs was prepared by using different Friedländer condensations. Several of the new compounds were tested for antiproliferative activity on cancer cell lines and for topoisomerase I inhibitory activity.
|
Antiproliferative activity against human HT29 cells after 96 hrs
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and bioevaluation of 22-hydroxyacuminatine analogs.
Year : 2008
Volume : 18
Issue : 6
First Page : 2143
Last Page : 2146
Authors : Grillet F, Baumlová B, Prévost G, Constant JF, Chaumeron S, Bigg DC, Greene AE, Kanazawa A.
Abstract : A series of 22-hydroxyacuminatine analogs was prepared by using different Friedländer condensations. Several of the new compounds were tested for antiproliferative activity on cancer cell lines and for topoisomerase I inhibitory activity.
|
Antiproliferative activity against human H460 cells after 1 hr of drug exposure measured after 72 hrs
|
Homo sapiens
|
220.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : E-ring-modified 7-oxyiminomethyl camptothecins: Synthesis and preliminary in vitro and in vivo biological evaluation.
Year : 2008
Volume : 18
Issue : 9
First Page : 2910
Last Page : 2915
Authors : Giannini G, Marzi M, Cabri W, Marastoni E, Battistuzzi G, Vesci L, Pisano C, Beretta GL, De Cesare M, Zunino F.
Abstract : In contrast to five-membered E-ring analogues, 7-oxyiminomethyl derivatives of homocamptothecins showed ability to form stable ternary complexes with DNA and topoisomerase I. The 7-oxyiminomethyl derivatives of homocamptothecins were evaluated as a racemic mixture. Following the isolation of the two enantiomers, the 20 (R)-hydroxy isomer confirms the best activity. By using a panel of human tumor cells, all tested homocamptothecins showed a potent antiproliferative activity, correlating to the persistence of the cleavable complex. No significant difference was observed between the natural scaffold and the corresponding homocamptothecin homologue. A selected compound of this series exhibited an excellent antitumor activity against human gastrointestinal tumor xenografts.
|
Antiproliferative activity against human HT29 cells after 1 hr of drug exposure measured after 72 hrs
|
Homo sapiens
|
670.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : E-ring-modified 7-oxyiminomethyl camptothecins: Synthesis and preliminary in vitro and in vivo biological evaluation.
Year : 2008
Volume : 18
Issue : 9
First Page : 2910
Last Page : 2915
Authors : Giannini G, Marzi M, Cabri W, Marastoni E, Battistuzzi G, Vesci L, Pisano C, Beretta GL, De Cesare M, Zunino F.
Abstract : In contrast to five-membered E-ring analogues, 7-oxyiminomethyl derivatives of homocamptothecins showed ability to form stable ternary complexes with DNA and topoisomerase I. The 7-oxyiminomethyl derivatives of homocamptothecins were evaluated as a racemic mixture. Following the isolation of the two enantiomers, the 20 (R)-hydroxy isomer confirms the best activity. By using a panel of human tumor cells, all tested homocamptothecins showed a potent antiproliferative activity, correlating to the persistence of the cleavable complex. No significant difference was observed between the natural scaffold and the corresponding homocamptothecin homologue. A selected compound of this series exhibited an excellent antitumor activity against human gastrointestinal tumor xenografts.
|
Cytotoxicity against human H460 cells
|
Homo sapiens
|
220.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and cytotoxic activity of new 9-substituted camptothecins.
Year : 2008
Volume : 18
Issue : 9
First Page : 2781
Last Page : 2787
Authors : Dallavalle S, Rocchetta DG, Musso L, Merlini L, Morini G, Penco S, Tinelli S, Beretta GL, Zunino F.
Abstract : A series of novel 9-substituted camptothecins derived from 9-formylcamptothecin were synthesized. The aldehyde was obtained from 10-hydroxycamptothecin or, better, by total synthesis. The compounds showed antiproliferative activity higher than that of the reference compound topotecan. Modelling suggested the possibility of a favourable interaction of small and polar 9-substituents with the topoisomerase I-DNA complex, which is consistent with the higher activity of these derivatives with respect to the corresponding 7-substituted camptothecins.
|
Antiproliferative activity against human NCI-H460 cells after short term exposure for 1 hr measured after 72 hrs in drug-free medium
|
Homo sapiens
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Semisynthesis, biological activity, and molecular modeling studies of C-ring-modified camptothecins.
Year : 2009
Volume : 52
Issue : 4
First Page : 1029
Last Page : 1039
Authors : Samorì C, Guerrini A, Varchi G, Fontana G, Bombardelli E, Tinelli S, Beretta GL, Basili S, Moro S, Zunino F, Battaglia A.
Abstract : The synthesis, biological activity, and molecular modeling studies of C-ring-modified camptothecins are reported. A general synthetic protocol, based on "C-5 camptothecin (C-5-CPT) enolate chemistry", allows one to obtain various C5-substituted analogues. All new compounds, obtained as 1:1 epimeric mixtures, were tested for their antiproliferative activity. Experimental data showed that all novel derivatives are less active than the reference compounds and that one of the two epimers is more active than the other. Molecular docking simulations were performed to achieve more insight into the interactions between the new C5-modified CPTs and Topo I. A good correlation was observed when the data of cytotoxicity and the values calculated for the free binding energy were combined.
|
Cytotoxicity against human A549 cells by SRB method
|
Homo sapiens
|
80.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Semi-synthesis and biological activity of gamma-lactones analogs of camptothecin.
Year : 2008
Volume : 18
Issue : 24
First Page : 6441
Last Page : 6443
Authors : Li M, Tang W, Zeng F, Lou L, You T.
Abstract : A series of E-ring gamma-lactone camptothecin derivatives were synthesized by semi-synthesis via a three-step domino reaction. Their biological activity was evaluated on two types of human tumor cell lines A549 and HT-29 with sulforhodamine-B (SRB) method. The antitumor activity of these compounds was lower than SN-38, only compound 12c was found to be close to the activity of Topotecan. The structure-activity relationship (SAR) of these analogs was studied and discussed.
|
Cytotoxicity against human HT-29 cells by SRB method
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Semi-synthesis and biological activity of gamma-lactones analogs of camptothecin.
Year : 2008
Volume : 18
Issue : 24
First Page : 6441
Last Page : 6443
Authors : Li M, Tang W, Zeng F, Lou L, You T.
Abstract : A series of E-ring gamma-lactone camptothecin derivatives were synthesized by semi-synthesis via a three-step domino reaction. Their biological activity was evaluated on two types of human tumor cell lines A549 and HT-29 with sulforhodamine-B (SRB) method. The antitumor activity of these compounds was lower than SN-38, only compound 12c was found to be close to the activity of Topotecan. The structure-activity relationship (SAR) of these analogs was studied and discussed.
|
Cytotoxicity against human KB3-1 cells after 4 days by MTT method
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 12-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridines as novel topoisomerase I-targeting antitumor agents.
Year : 2009
Volume : 17
Issue : 7
First Page : 2877
Last Page : 2885
Authors : Feng W, Satyanarayana M, Tsai YC, Liu AA, Liu LF, LaVoie EJ.
Abstract : 2,3-Dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine and a few of its 12-substituted analogs are active as TOP1-targeting agents. Studies were performed to further evaluate the potential of this series of non-camptothecin TOP1-targeting agents. The influence of a hydroxymethyl, formyl, N,N-dimethylaminomethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl), and 4-(N,N-dimethylamino)butyl substituent at the 12-position on TOP1-targeting activity and tumor cell growth was evaluated. In addition, the relative pharmacologic activities of the 12-carboxamide analog, as well as its N-methyl and N,N-dimethyl derivatives were assessed.
|
Cytotoxicity against MDR1 overexpressing human KBV1 cells after 4 days by MTT method
|
Homo sapiens
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 12-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridines as novel topoisomerase I-targeting antitumor agents.
Year : 2009
Volume : 17
Issue : 7
First Page : 2877
Last Page : 2885
Authors : Feng W, Satyanarayana M, Tsai YC, Liu AA, Liu LF, LaVoie EJ.
Abstract : 2,3-Dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine and a few of its 12-substituted analogs are active as TOP1-targeting agents. Studies were performed to further evaluate the potential of this series of non-camptothecin TOP1-targeting agents. The influence of a hydroxymethyl, formyl, N,N-dimethylaminomethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl), and 4-(N,N-dimethylamino)butyl substituent at the 12-position on TOP1-targeting activity and tumor cell growth was evaluated. In addition, the relative pharmacologic activities of the 12-carboxamide analog, as well as its N-methyl and N,N-dimethyl derivatives were assessed.
|
Cytotoxicity against BCRP overexpressing human KBH5.0 cells after 4 days by MTT method
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 12-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridines as novel topoisomerase I-targeting antitumor agents.
Year : 2009
Volume : 17
Issue : 7
First Page : 2877
Last Page : 2885
Authors : Feng W, Satyanarayana M, Tsai YC, Liu AA, Liu LF, LaVoie EJ.
Abstract : 2,3-Dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine and a few of its 12-substituted analogs are active as TOP1-targeting agents. Studies were performed to further evaluate the potential of this series of non-camptothecin TOP1-targeting agents. The influence of a hydroxymethyl, formyl, N,N-dimethylaminomethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl), and 4-(N,N-dimethylamino)butyl substituent at the 12-position on TOP1-targeting activity and tumor cell growth was evaluated. In addition, the relative pharmacologic activities of the 12-carboxamide analog, as well as its N-methyl and N,N-dimethyl derivatives were assessed.
|
Antiproliferative activity against human HCT116 cells after 3 days
|
Homo sapiens
|
0.55
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new camptothecin analogs with improved antitumor activities.
Year : 2009
Volume : 19
Issue : 7
First Page : 2018
Last Page : 2021
Authors : Niizuma S, Tsukazaki M, Suda H, Murata T, Ohwada J, Ozawa S, Fukuda H, Murasaki C, Kohchi M, Morikami K, Yoshinari K, Endo M, Ura M, Tanimura H, Miyazaki Y, Takasuka T, Kawashima A, Nanba E, Nakano K, Ogawa K, Kobayashi K, Okabe H, Umeda I, Shimma N.
Abstract : Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
|
Antiproliferative activity against human QG56 cells after 3 days
|
Homo sapiens
|
2.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new camptothecin analogs with improved antitumor activities.
Year : 2009
Volume : 19
Issue : 7
First Page : 2018
Last Page : 2021
Authors : Niizuma S, Tsukazaki M, Suda H, Murata T, Ohwada J, Ozawa S, Fukuda H, Murasaki C, Kohchi M, Morikami K, Yoshinari K, Endo M, Ura M, Tanimura H, Miyazaki Y, Takasuka T, Kawashima A, Nanba E, Nakano K, Ogawa K, Kobayashi K, Okabe H, Umeda I, Shimma N.
Abstract : Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
|
Antiproliferative activity against human NCI-H460 cells after 3 days
|
Homo sapiens
|
3.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new camptothecin analogs with improved antitumor activities.
Year : 2009
Volume : 19
Issue : 7
First Page : 2018
Last Page : 2021
Authors : Niizuma S, Tsukazaki M, Suda H, Murata T, Ohwada J, Ozawa S, Fukuda H, Murasaki C, Kohchi M, Morikami K, Yoshinari K, Endo M, Ura M, Tanimura H, Miyazaki Y, Takasuka T, Kawashima A, Nanba E, Nakano K, Ogawa K, Kobayashi K, Okabe H, Umeda I, Shimma N.
Abstract : Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
|
Antiproliferative activity against human PC6 expressing BCRP cells after 6 days
|
Homo sapiens
|
5.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new camptothecin analogs with improved antitumor activities.
Year : 2009
Volume : 19
Issue : 7
First Page : 2018
Last Page : 2021
Authors : Niizuma S, Tsukazaki M, Suda H, Murata T, Ohwada J, Ozawa S, Fukuda H, Murasaki C, Kohchi M, Morikami K, Yoshinari K, Endo M, Ura M, Tanimura H, Miyazaki Y, Takasuka T, Kawashima A, Nanba E, Nakano K, Ogawa K, Kobayashi K, Okabe H, Umeda I, Shimma N.
Abstract : Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
|
Antiproliferative activity against human PC6 cells carrying pRC after 6 days
|
Homo sapiens
|
0.43
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new camptothecin analogs with improved antitumor activities.
Year : 2009
Volume : 19
Issue : 7
First Page : 2018
Last Page : 2021
Authors : Niizuma S, Tsukazaki M, Suda H, Murata T, Ohwada J, Ozawa S, Fukuda H, Murasaki C, Kohchi M, Morikami K, Yoshinari K, Endo M, Ura M, Tanimura H, Miyazaki Y, Takasuka T, Kawashima A, Nanba E, Nakano K, Ogawa K, Kobayashi K, Okabe H, Umeda I, Shimma N.
Abstract : Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
|
Antitumor activity against human A549/ATCC cells by SRB method
|
Homo sapiens
|
88.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 7-Cycloalkylcamptothecin derivatives: Preparation and biological evaluation.
Year : 2009
Volume : 19
Issue : 15
First Page : 4107
Last Page : 4109
Authors : Li M, Jin W, Jiang C, Zheng C, Tang W, You T, Lou L.
Abstract : A series of 7-cycloalkylcamptothecin derivatives were synthesized from camptothecin with two methods. Their biological activities in vitro were evaluated with sulforhodamine-B (SRB) method on four types of human tumor cell lines A549/ATCC, HT29, NCI-H460 and HL60. Most of these camptothecin analogues show higher antitumor activity than the reference compounds SN-38 and Topotecan, with the IC(50) values low to nM level. Structure-activity relationship studies of these compounds mostly match the conclusion we achieved before from quantitative structure-activity relationship (QSAR) research.
|
Antitumor activity against human HT-29 cells by SRB method
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 7-Cycloalkylcamptothecin derivatives: Preparation and biological evaluation.
Year : 2009
Volume : 19
Issue : 15
First Page : 4107
Last Page : 4109
Authors : Li M, Jin W, Jiang C, Zheng C, Tang W, You T, Lou L.
Abstract : A series of 7-cycloalkylcamptothecin derivatives were synthesized from camptothecin with two methods. Their biological activities in vitro were evaluated with sulforhodamine-B (SRB) method on four types of human tumor cell lines A549/ATCC, HT29, NCI-H460 and HL60. Most of these camptothecin analogues show higher antitumor activity than the reference compounds SN-38 and Topotecan, with the IC(50) values low to nM level. Structure-activity relationship studies of these compounds mostly match the conclusion we achieved before from quantitative structure-activity relationship (QSAR) research.
|
Cytotoxicity against human A549 cells
|
Homo sapiens
|
47.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Semisynthesis of triptolide analogues: effect of γ-lactone and C-14 substituents on cytotoxic activities.
Year : 2011
Volume : 21
Issue : 10
First Page : 3046
Last Page : 3049
Authors : Aoyagi Y, Hitotsuyanagi Y, Hasuda T, Fukaya H, Takeya K, Aiyama R, Matsuzaki T, Hashimoto S.
Abstract : Triptolide γ-lactone and C-14 analogues were prepared and evaluated cytotoxity against human lung adenocarcinoma epithelial A549 cells and human colon adenocarcinoma HT-29 cells. γ-Lactone substructure and C-14 substituents affected the biological activities significantly.
|
Cytotoxicity against human HT-29 cells
|
Homo sapiens
|
5.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Semisynthesis of triptolide analogues: effect of γ-lactone and C-14 substituents on cytotoxic activities.
Year : 2011
Volume : 21
Issue : 10
First Page : 3046
Last Page : 3049
Authors : Aoyagi Y, Hitotsuyanagi Y, Hasuda T, Fukaya H, Takeya K, Aiyama R, Matsuzaki T, Hashimoto S.
Abstract : Triptolide γ-lactone and C-14 analogues were prepared and evaluated cytotoxity against human lung adenocarcinoma epithelial A549 cells and human colon adenocarcinoma HT-29 cells. γ-Lactone substructure and C-14 substituents affected the biological activities significantly.
|
TP_TRANSPORTER: drug resistance(Imatinib mesylate) in BCRP-expressing SaoS2 cells
|
None
|
176.0
nM
|
|
Journal : Cancer Res.
Title : Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro.
Year : 2004
Volume : 64
Issue : 1
First Page : 2333
Last Page : 2337
Authors : Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, Traxler P.
Abstract : Imatinib mesylate (Gleevec, STI571) is a kinase inhibitor selective for Bcr-Abl, activated c-Kit kinases, and platelet-derived growth factor receptor tyrosine kinase. Imatinib mesylate, similar to many other tyrosine kinase inhibitors (TKIs), such as members of the 4-anilinoquinazoline class, competes for ATP binding. Previously, 4-anilinoquinazoline TKIs have been shown to inhibit the function of the breast cancer resistance-associated drug transporter (ABCG2), reversing resistance to camptothecin derivatives topotecan and SN-38. However, the potential to inhibit ABCG2 for the 2-phenylamino-pyrimidine class of TKIs, exemplified by imatinib mesylate, has not been examined. Here, we show that imatinib mesylate potently reverses ABCG2-mediated resistance to topotecan and SN-38 and significantly increases accumulation of topotecan only in cells expressing functional ABCG2. However, overexpression of ABCG2 does not confer resistance to imatinib mesylate. Furthermore, accumulation and efflux of [(14)C]imatinib mesylate are unaltered between ABCG2-expressing and non-ABCG2-expressing cells or by ATP depletion. These results suggest that imatinib mesylate inhibits the function of ABCG2 but is not a substrate for this transporter.
|
Cytotoxicity against human PC3 cells expressing alpha5beta3 integrin assessed as cell survival after 72 hrs by SRB assay
|
Homo sapiens
|
2.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Camptothecins in tumor homing via an RGD sequence mimetic.
Year : 2012
Volume : 22
Issue : 20
First Page : 6509
Last Page : 6512
Authors : Alloatti D, Giannini G, Vesci L, Castorina M, Pisano C, Badaloni E, Cabri W.
Abstract : A RGD peptide mimetic was conjugated to four camptothecins, with the purpose to improve their therapeutic index. The conjugate derivatives were evaluated against two tumor cell lines, one overexpressing integrins (human ovarian carcinoma, A2780) and a second one with a low integrin expression (human prostate cancer, PC3). The in vitro screening was completed with the adhesion behavior to vitronectin. Compound 8 (ST7456CL1) was selected for the in vivo investigation after stability tests over 24h, in PBS solution and in rat plasma, and compared to irinotecan. The former showed a prolonged half-life.
|
Cytotoxicity against human A2780 cells overexpressing alpha5beta3 integrin assessed as cell survival after 72 hrs by SRB assay
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Camptothecins in tumor homing via an RGD sequence mimetic.
Year : 2012
Volume : 22
Issue : 20
First Page : 6509
Last Page : 6512
Authors : Alloatti D, Giannini G, Vesci L, Castorina M, Pisano C, Badaloni E, Cabri W.
Abstract : A RGD peptide mimetic was conjugated to four camptothecins, with the purpose to improve their therapeutic index. The conjugate derivatives were evaluated against two tumor cell lines, one overexpressing integrins (human ovarian carcinoma, A2780) and a second one with a low integrin expression (human prostate cancer, PC3). The in vitro screening was completed with the adhesion behavior to vitronectin. Compound 8 (ST7456CL1) was selected for the in vivo investigation after stability tests over 24h, in PBS solution and in rat plasma, and compared to irinotecan. The former showed a prolonged half-life.
|
Cytotoxicity against human DU145 cells
|
Homo sapiens
|
30.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Evolution in medicinal chemistry of E-ring-modified Camptothecin analogs as anticancer agents.
Year : 2013
Volume : 63
First Page : 746
Last Page : 757
Authors : Huang Q, Wang L, Lu W.
Abstract : Camptothecin (CPT), a natural topoisomerase (Topo) I inhibitor, exhibits powerful antineoplastic activity against colorectal, breast, lung and ovarian cancers. However, the poor solubility and the inherent instability of the lactone E-ring in physiological pH resulted in low therapeutic efficacy and severe toxicity. In the past several decades' substantial progress toward understanding its pharmacology, lots of analogs have been prepared to overcome its drawbacks. The review provides a detailed discussion of the evolution in medicinal chemistry of CPT analogs with modification of the E-ring lactone.
|
Cytotoxicity against human HT-29 cells
|
Homo sapiens
|
30.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Evolution in medicinal chemistry of E-ring-modified Camptothecin analogs as anticancer agents.
Year : 2013
Volume : 63
First Page : 746
Last Page : 757
Authors : Huang Q, Wang L, Lu W.
Abstract : Camptothecin (CPT), a natural topoisomerase (Topo) I inhibitor, exhibits powerful antineoplastic activity against colorectal, breast, lung and ovarian cancers. However, the poor solubility and the inherent instability of the lactone E-ring in physiological pH resulted in low therapeutic efficacy and severe toxicity. In the past several decades' substantial progress toward understanding its pharmacology, lots of analogs have been prepared to overcome its drawbacks. The review provides a detailed discussion of the evolution in medicinal chemistry of CPT analogs with modification of the E-ring lactone.
|
Inhibition of topoisomerase 1 (unknown origin)-mediated DNA cleavage at 1 uM relative to SN-38
|
Homo sapiens
|
1.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Evolution in medicinal chemistry of E-ring-modified Camptothecin analogs as anticancer agents.
Year : 2013
Volume : 63
First Page : 746
Last Page : 757
Authors : Huang Q, Wang L, Lu W.
Abstract : Camptothecin (CPT), a natural topoisomerase (Topo) I inhibitor, exhibits powerful antineoplastic activity against colorectal, breast, lung and ovarian cancers. However, the poor solubility and the inherent instability of the lactone E-ring in physiological pH resulted in low therapeutic efficacy and severe toxicity. In the past several decades' substantial progress toward understanding its pharmacology, lots of analogs have been prepared to overcome its drawbacks. The review provides a detailed discussion of the evolution in medicinal chemistry of CPT analogs with modification of the E-ring lactone.
|
Cytotoxicity against mouse L1210 cells
|
Mus musculus
|
40.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Evolution in medicinal chemistry of E-ring-modified Camptothecin analogs as anticancer agents.
Year : 2013
Volume : 63
First Page : 746
Last Page : 757
Authors : Huang Q, Wang L, Lu W.
Abstract : Camptothecin (CPT), a natural topoisomerase (Topo) I inhibitor, exhibits powerful antineoplastic activity against colorectal, breast, lung and ovarian cancers. However, the poor solubility and the inherent instability of the lactone E-ring in physiological pH resulted in low therapeutic efficacy and severe toxicity. In the past several decades' substantial progress toward understanding its pharmacology, lots of analogs have been prepared to overcome its drawbacks. The review provides a detailed discussion of the evolution in medicinal chemistry of CPT analogs with modification of the E-ring lactone.
|
Cytotoxicity against human DU145 cells assessed as inhibition of cell viability after 72 hrs by MTS assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dual-acting histone deacetylase-topoisomerase I inhibitors.
Year : 2013
Volume : 23
Issue : 11
First Page : 3283
Last Page : 3287
Authors : Guerrant W, Patil V, Canzoneri JC, Yao LP, Hood R, Oyelere AK.
Abstract : Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands that can modulate multiple targets while avoiding the toxicity of a single-targeted agent. Two attractive targets, histone deacetylase (HDAC) and topoisomerase I (Topo I), are cellular modulators that can broadly arrest cancer proliferation through a range of downstream effects. Both are clinically validated targets with multiple inhibitors in therapeutic use. We describe herein the design and synthesis of dual-acting histone deacetylase-topoisomerase I inhibitors. We also show that these dual-acting agents retain activity against HDAC and Topo I, and potently arrest cancer proliferation.
|
Cytotoxicity against human HT-29 cells assessed as growth inhibition after 3 days by SRB assay
|
Homo sapiens
|
106.67
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Suzuki coupling based synthesis and in vitro cytotoxic evaluation of 7-heteroaryl-substituted camptothecin analogs.
Year : 2014
Volume : 24
Issue : 6
First Page : 1597
Last Page : 1599
Authors : Wang L, Huang Y, Zhang J, Tong L, Chen Y, Lu W, Huang Q.
Abstract : In an effort to discover potent antitumor agents, a series of novel C-7-heteroaryl-substituted camptothecin derivatives were designed and synthesized via microwave-promoted Suzuki coupling reaction. These analogs were then assessed for cytotoxicity against three human tumor cell lines, A549, HCT116, HT-29, and inhibitory effects on topoisomerase I. All of the new compounds showed potent inhibition of human tumor cell growth, among which compound 10a showed higher cytotoxic activity than that of SN-38. Furthermore, this series of compounds retained or enhanced Topo I inhibition.
|
Cytotoxicity against human HCT116 cells assessed as growth inhibition after 3 days by SRB assay
|
Homo sapiens
|
31.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Suzuki coupling based synthesis and in vitro cytotoxic evaluation of 7-heteroaryl-substituted camptothecin analogs.
Year : 2014
Volume : 24
Issue : 6
First Page : 1597
Last Page : 1599
Authors : Wang L, Huang Y, Zhang J, Tong L, Chen Y, Lu W, Huang Q.
Abstract : In an effort to discover potent antitumor agents, a series of novel C-7-heteroaryl-substituted camptothecin derivatives were designed and synthesized via microwave-promoted Suzuki coupling reaction. These analogs were then assessed for cytotoxicity against three human tumor cell lines, A549, HCT116, HT-29, and inhibitory effects on topoisomerase I. All of the new compounds showed potent inhibition of human tumor cell growth, among which compound 10a showed higher cytotoxic activity than that of SN-38. Furthermore, this series of compounds retained or enhanced Topo I inhibition.
|
Cytotoxicity against human A549 cells assessed as growth inhibition after 3 days by SRB assay
|
Homo sapiens
|
2.72
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Suzuki coupling based synthesis and in vitro cytotoxic evaluation of 7-heteroaryl-substituted camptothecin analogs.
Year : 2014
Volume : 24
Issue : 6
First Page : 1597
Last Page : 1599
Authors : Wang L, Huang Y, Zhang J, Tong L, Chen Y, Lu W, Huang Q.
Abstract : In an effort to discover potent antitumor agents, a series of novel C-7-heteroaryl-substituted camptothecin derivatives were designed and synthesized via microwave-promoted Suzuki coupling reaction. These analogs were then assessed for cytotoxicity against three human tumor cell lines, A549, HCT116, HT-29, and inhibitory effects on topoisomerase I. All of the new compounds showed potent inhibition of human tumor cell growth, among which compound 10a showed higher cytotoxic activity than that of SN-38. Furthermore, this series of compounds retained or enhanced Topo I inhibition.
|
Cytotoxicity against human A549 cells
|
Homo sapiens
|
259.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Suzuki coupling based synthesis and in vitro cytotoxic evaluation of 7-heteroaryl-substituted camptothecin analogs.
Year : 2014
Volume : 24
Issue : 6
First Page : 1597
Last Page : 1599
Authors : Wang L, Huang Y, Zhang J, Tong L, Chen Y, Lu W, Huang Q.
Abstract : In an effort to discover potent antitumor agents, a series of novel C-7-heteroaryl-substituted camptothecin derivatives were designed and synthesized via microwave-promoted Suzuki coupling reaction. These analogs were then assessed for cytotoxicity against three human tumor cell lines, A549, HCT116, HT-29, and inhibitory effects on topoisomerase I. All of the new compounds showed potent inhibition of human tumor cell growth, among which compound 10a showed higher cytotoxic activity than that of SN-38. Furthermore, this series of compounds retained or enhanced Topo I inhibition.
|
Cytotoxicity against human HCT116 cells
|
Homo sapiens
|
166.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Suzuki coupling based synthesis and in vitro cytotoxic evaluation of 7-heteroaryl-substituted camptothecin analogs.
Year : 2014
Volume : 24
Issue : 6
First Page : 1597
Last Page : 1599
Authors : Wang L, Huang Y, Zhang J, Tong L, Chen Y, Lu W, Huang Q.
Abstract : In an effort to discover potent antitumor agents, a series of novel C-7-heteroaryl-substituted camptothecin derivatives were designed and synthesized via microwave-promoted Suzuki coupling reaction. These analogs were then assessed for cytotoxicity against three human tumor cell lines, A549, HCT116, HT-29, and inhibitory effects on topoisomerase I. All of the new compounds showed potent inhibition of human tumor cell growth, among which compound 10a showed higher cytotoxic activity than that of SN-38. Furthermore, this series of compounds retained or enhanced Topo I inhibition.
|
Cytotoxicity against human MDA-MB-231 cells
|
Homo sapiens
|
176.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Suzuki coupling based synthesis and in vitro cytotoxic evaluation of 7-heteroaryl-substituted camptothecin analogs.
Year : 2014
Volume : 24
Issue : 6
First Page : 1597
Last Page : 1599
Authors : Wang L, Huang Y, Zhang J, Tong L, Chen Y, Lu W, Huang Q.
Abstract : In an effort to discover potent antitumor agents, a series of novel C-7-heteroaryl-substituted camptothecin derivatives were designed and synthesized via microwave-promoted Suzuki coupling reaction. These analogs were then assessed for cytotoxicity against three human tumor cell lines, A549, HCT116, HT-29, and inhibitory effects on topoisomerase I. All of the new compounds showed potent inhibition of human tumor cell growth, among which compound 10a showed higher cytotoxic activity than that of SN-38. Furthermore, this series of compounds retained or enhanced Topo I inhibition.
|
Cytotoxicity against human HCT116 cells after 72 hrs by sulforhodamine B assay
|
Homo sapiens
|
4.28
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents.
Year : 2015
Volume : 23
Issue : 9
First Page : 1950
Last Page : 1962
Authors : Wang L, Xie S, Ma L, Chen Y, Lu W.
Abstract : Fifteen novel homocamptothecin derivatives with α-OMe substituted E-rings were designed and synthesized. All of the derivatives exhibited similar or superior cytotoxicities compared with that of SN-38, and they inhibited Topo I activity in a cell-free assay in a manner similar to that of SN-38, confirming that they represent a new class of Topo I inhibitors. Notably, the water soluble compound 36o (1.2 mg/mL) exhibited increased lactone stability, and at 0.5 mg/kg and 3.0 mg/kg, it demonstrated significant antitumor activity in mice bearing a xenograft model using human colon cancer cell line HT-29. On the basis of these positive results, further development of 36o-related compounds as potential anticancer clinical trial candidates is definitely warranted.
|
Cytotoxicity against human HT-29 cells after 72 hrs by sulforhodamine B assay
|
Homo sapiens
|
18.54
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents.
Year : 2015
Volume : 23
Issue : 9
First Page : 1950
Last Page : 1962
Authors : Wang L, Xie S, Ma L, Chen Y, Lu W.
Abstract : Fifteen novel homocamptothecin derivatives with α-OMe substituted E-rings were designed and synthesized. All of the derivatives exhibited similar or superior cytotoxicities compared with that of SN-38, and they inhibited Topo I activity in a cell-free assay in a manner similar to that of SN-38, confirming that they represent a new class of Topo I inhibitors. Notably, the water soluble compound 36o (1.2 mg/mL) exhibited increased lactone stability, and at 0.5 mg/kg and 3.0 mg/kg, it demonstrated significant antitumor activity in mice bearing a xenograft model using human colon cancer cell line HT-29. On the basis of these positive results, further development of 36o-related compounds as potential anticancer clinical trial candidates is definitely warranted.
|
Inhibition of human recombinant UGT1A1 expressed in HEK293 cells assessed as reduction in estradiol 3-glucuronidation using 4 to 75 uM estradiol by LC-MS/MS method
|
Homo sapiens
|
40.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Correlation between bilirubin glucuronidation and estradiol-3-gluronidation in the presence of model UDP-glucuronosyltransferase 1A1 substrates/inhibitors.
Year : 2011
Volume : 39
Issue : 2
First Page : 322
Last Page : 329
Authors : Zhou J, Tracy TS, Remmel RP.
Abstract : Inhibition of UDP-glucuronosyltransferase (UGT) 1A1-catalyzed bilirubin glucuronidation by drug compounds may potentially be of clinical concern. However, in drug discovery and development settings, bilirubin is less than an ideal in vitro probe for assessing the potential of a chemical entity to inhibit bilirubin glucuronidation. In part, this is due to the propensity of bilirubin to photodegrade and to the instability of its metabolites. To this end, the utility of estradiol-3-glucuronidation as a surrogate in vitro predictor for interactions with bilirubin was evaluated. The glucuronidation kinetics of bilirubin and estradiol were carefully characterized with recombinant UGT1A1 expressed in human embryonic kidney 293 cells. Consistent with previous reports, estradiol-3-glucuronidation displayed sigmoidal kinetics, whereas bilirubin glucuronidation exhibited typical hyperbolic kinetics. The two compounds also mutually inhibited the metabolism of the other. Sixteen UGT1A1 substrates/inhibitors were evaluated as effectors of each reaction. Fourteen compounds inhibited both bilirubin and estradiol glucuronidation. However, two compounds (ethinylestradiol and daidzein) exhibited mixed effects (concentration-dependent activation and inhibition) on estradiol-3-glucuronidation, whereas bilirubin glucuronidation was inhibited by both compounds. In addition, 7-ethyl-10-hydroxycamptothecin, a substrate of UGT1A1 (reported K(m) = 24 μM) seemed to be a weak inhibitor of bilirubin glucuronidation (IC(50) = 356.4 μM) but a partial inhibitor of estradiol-3-glucuronidation. The IC(50) values of the inhibitors against estradiol-3-glucuronidation were strongly correlated with IC(50) values against bilirubin glucuronidation, resulting in an R(2) value of 0.9604 (activator excluded) or 0.8287 (activator included). Thus, estradiol-3-glucuronidation can serve as a good surrogate for predicting inhibition of bilirubin glucuronidation with the caveat that occasionally compounds may demonstrate activation of estradiol-3-glucuronidation.
|
Cytotoxicity against human HCT15 cells assessed as growth inhibition after 72 hrs by SRB assay
|
Homo sapiens
|
8.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 10-Boronic acid substituted camptothecin as prodrug of SN-38.
Year : 2016
Volume : 116
First Page : 84
Last Page : 89
Authors : Wang L, Xie S, Ma L, Chen Y, Lu W.
Abstract : Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon-boron bond to the SN-38. Prodrug B1 selectively activated by H2O2, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H2O2. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.0 mg/kg in a xenograft model using human brain star glioblastoma cell lines U87MG.
|
Cytotoxicity against human HT-29 cells assessed as growth inhibition after 72 hrs by SRB assay
|
Homo sapiens
|
54.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 10-Boronic acid substituted camptothecin as prodrug of SN-38.
Year : 2016
Volume : 116
First Page : 84
Last Page : 89
Authors : Wang L, Xie S, Ma L, Chen Y, Lu W.
Abstract : Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon-boron bond to the SN-38. Prodrug B1 selectively activated by H2O2, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H2O2. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.0 mg/kg in a xenograft model using human brain star glioblastoma cell lines U87MG.
|
Cytotoxicity against human MCF7 cells assessed as growth inhibition after 72 hrs by SRB assay
|
Homo sapiens
|
515.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 10-Boronic acid substituted camptothecin as prodrug of SN-38.
Year : 2016
Volume : 116
First Page : 84
Last Page : 89
Authors : Wang L, Xie S, Ma L, Chen Y, Lu W.
Abstract : Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon-boron bond to the SN-38. Prodrug B1 selectively activated by H2O2, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H2O2. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.0 mg/kg in a xenograft model using human brain star glioblastoma cell lines U87MG.
|
Cytotoxicity against human U87MG cells assessed as growth inhibition after 72 hrs by SRB assay
|
Homo sapiens
|
30.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 10-Boronic acid substituted camptothecin as prodrug of SN-38.
Year : 2016
Volume : 116
First Page : 84
Last Page : 89
Authors : Wang L, Xie S, Ma L, Chen Y, Lu W.
Abstract : Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon-boron bond to the SN-38. Prodrug B1 selectively activated by H2O2, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H2O2. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.0 mg/kg in a xenograft model using human brain star glioblastoma cell lines U87MG.
|
Cytotoxicity against human U251 cells assessed as growth inhibition after 72 hrs by SRB assay
|
Homo sapiens
|
21.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 10-Boronic acid substituted camptothecin as prodrug of SN-38.
Year : 2016
Volume : 116
First Page : 84
Last Page : 89
Authors : Wang L, Xie S, Ma L, Chen Y, Lu W.
Abstract : Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon-boron bond to the SN-38. Prodrug B1 selectively activated by H2O2, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H2O2. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.0 mg/kg in a xenograft model using human brain star glioblastoma cell lines U87MG.
|
Antiproliferative activity against human PANC1 cells after 96 hrs by CellTiter-Glo luminescence assay
|
Homo sapiens
|
82.5
nM
|
|
Title : Multikinase inhibitors for use in the treatment of cancer
Year : 2009
|
Cytotoxicity against human NCI-H460 cells pretreated for 24 hrs under hypoxic condition followed by compound washout measured after 72 hrs by MTT assay
|
Homo sapiens
|
60.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of hypoxia-activated prodrugs of SN-38.
Year : 2017
Volume : 132
First Page : 135
Last Page : 141
Authors : Jin C, Zhang Q, Lu W.
Abstract : We designed new hypoxia-activated prodrugs by conjugating (1-methyl-2-nitro-1H-imidazol-5-yl)methanol with 7-ethyl-10-hydroxy camptothecin (SN-38). Initially, we improved the method of multi-gram scale synthesis of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol, which increased the yield to 42% compared to 8% by the original synthesis method. The improved method was used to synthesize evofosfamide (TH-302) and hypoxia-activated prodrugs of SN-38. Two different linkages between (1-methyl-2-nitro-1H-imidazol-5-yl)methanol and SN-38 were evaluated that afforded different hypoxia-selectivity and toxicity. Compound 16 (IOS), containing an ether linkage, was considered to be a promising hypoxia-selective antitumor agent.
|
Cytotoxicity against human NCI-H460 cells pretreated for 24 hrs under normoxic condition followed by compound washout measured after 72 hrs by MTT assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of hypoxia-activated prodrugs of SN-38.
Year : 2017
Volume : 132
First Page : 135
Last Page : 141
Authors : Jin C, Zhang Q, Lu W.
Abstract : We designed new hypoxia-activated prodrugs by conjugating (1-methyl-2-nitro-1H-imidazol-5-yl)methanol with 7-ethyl-10-hydroxy camptothecin (SN-38). Initially, we improved the method of multi-gram scale synthesis of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol, which increased the yield to 42% compared to 8% by the original synthesis method. The improved method was used to synthesize evofosfamide (TH-302) and hypoxia-activated prodrugs of SN-38. Two different linkages between (1-methyl-2-nitro-1H-imidazol-5-yl)methanol and SN-38 were evaluated that afforded different hypoxia-selectivity and toxicity. Compound 16 (IOS), containing an ether linkage, was considered to be a promising hypoxia-selective antitumor agent.
|
Cytotoxicity against human NCI-H460 cells assessed as growth reduction under normoxic condition after 72 hrs by MTT assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Synthesis and Biological Evaluation of Paclitaxel and Camptothecin Prodrugs on the Basis of 2-Nitroimidazole.
Year : 2017
Volume : 8
Issue : 7
First Page : 762
Last Page : 765
Authors : Jin C, Wen S, Zhang Q, Zhu Q, Yu J, Lu W.
Abstract : Due to the low esterase activity in human plasma, many ester and carbonate prodrugs tested in humans may be less effective than that in preclinical animals. In this letter, PTX and SN-38 were attached to the N-1 position of 2-nitroimidazole via a carbonate linker. Presumably, 2-aminoimidazole may help promote the intramolecular hydrolysis of the carbonate bond. The prodrugs exhibited a considerable stability in buffers at different pH values as well as in human plasma. Furthermore, a rapid reduction was exhibited in the presence of nitroreductase. An in vitro cytotoxicity assay demonstrated that hypoxic conditions could increase the toxicity of prodrugs. Potentially, the compound species may form a new class of promising antitumor agents.
|
Cytotoxicity against human NCI-H460 cells assessed as growth reduction under hypoxic condition after 72 hrs by MTT assay
|
Homo sapiens
|
47.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Synthesis and Biological Evaluation of Paclitaxel and Camptothecin Prodrugs on the Basis of 2-Nitroimidazole.
Year : 2017
Volume : 8
Issue : 7
First Page : 762
Last Page : 765
Authors : Jin C, Wen S, Zhang Q, Zhu Q, Yu J, Lu W.
Abstract : Due to the low esterase activity in human plasma, many ester and carbonate prodrugs tested in humans may be less effective than that in preclinical animals. In this letter, PTX and SN-38 were attached to the N-1 position of 2-nitroimidazole via a carbonate linker. Presumably, 2-aminoimidazole may help promote the intramolecular hydrolysis of the carbonate bond. The prodrugs exhibited a considerable stability in buffers at different pH values as well as in human plasma. Furthermore, a rapid reduction was exhibited in the presence of nitroreductase. An in vitro cytotoxicity assay demonstrated that hypoxic conditions could increase the toxicity of prodrugs. Potentially, the compound species may form a new class of promising antitumor agents.
|
Cytotoxicity against human HT-29 cells assessed as growth reduction under normoxic condition after 72 hrs by MTT assay
|
Homo sapiens
|
96.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Synthesis and Biological Evaluation of Paclitaxel and Camptothecin Prodrugs on the Basis of 2-Nitroimidazole.
Year : 2017
Volume : 8
Issue : 7
First Page : 762
Last Page : 765
Authors : Jin C, Wen S, Zhang Q, Zhu Q, Yu J, Lu W.
Abstract : Due to the low esterase activity in human plasma, many ester and carbonate prodrugs tested in humans may be less effective than that in preclinical animals. In this letter, PTX and SN-38 were attached to the N-1 position of 2-nitroimidazole via a carbonate linker. Presumably, 2-aminoimidazole may help promote the intramolecular hydrolysis of the carbonate bond. The prodrugs exhibited a considerable stability in buffers at different pH values as well as in human plasma. Furthermore, a rapid reduction was exhibited in the presence of nitroreductase. An in vitro cytotoxicity assay demonstrated that hypoxic conditions could increase the toxicity of prodrugs. Potentially, the compound species may form a new class of promising antitumor agents.
|
Cytotoxicity against human HT-29 cells assessed as growth reduction under hypoxic condition after 72 hrs by MTT assay
|
Homo sapiens
|
119.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Synthesis and Biological Evaluation of Paclitaxel and Camptothecin Prodrugs on the Basis of 2-Nitroimidazole.
Year : 2017
Volume : 8
Issue : 7
First Page : 762
Last Page : 765
Authors : Jin C, Wen S, Zhang Q, Zhu Q, Yu J, Lu W.
Abstract : Due to the low esterase activity in human plasma, many ester and carbonate prodrugs tested in humans may be less effective than that in preclinical animals. In this letter, PTX and SN-38 were attached to the N-1 position of 2-nitroimidazole via a carbonate linker. Presumably, 2-aminoimidazole may help promote the intramolecular hydrolysis of the carbonate bond. The prodrugs exhibited a considerable stability in buffers at different pH values as well as in human plasma. Furthermore, a rapid reduction was exhibited in the presence of nitroreductase. An in vitro cytotoxicity assay demonstrated that hypoxic conditions could increase the toxicity of prodrugs. Potentially, the compound species may form a new class of promising antitumor agents.
|
Cytotoxicity against human MCF7 cells after 72 hrs by sulforhodamine B assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : J Nat Prod
Title : Flabellipparicine, a Flabelliformide-Apparicine-Type Bisindole Alkaloid from Tabernaemontana divaricata.
Year : 2018
Volume : 81
Issue : 9
First Page : 1976
Last Page : 1983
Authors : Cai YS, Sarotti AM, Zhou TL, Huang R, Qiu G, Tian C, Miao ZH, Mándi A, Kurtán T, Cao S, Yang SP.
Abstract : Four new monoterpenoid bisindole alkaloids, flabellipparicine (1), 19,20-dihydrovobparicine (2), 10'-demethoxy-19,20-dihydrovobatensine D (3), and 3'-(2-oxopropyl)ervahanine A (4), and 10 known monoterpenoid indole alkaloids were isolated from the stems of Tabernaemontana divaricata. All structures were elucidated based on spectroscopic methods, and the absolute configuration of 1 was established using conformational analysis and TDDFT-ECD calculation of selected stereoisomers. Compound 1 represents the first flabelliformide-apparicine-type bisindole alkaloid, in which the flabelliformide-like unit connects to the apparicine-like unit with a C-3-C-22' bond and an N-1-C-16' bond to form an uncommon five-membered ring between the two monomers. All alkaloids were evaluated for their cytotoxicity against two human cancer cell lines, MCF-7 and A-549. Compounds 2, 4, and 14 exhibited cytotoxicity against MCF-7 and A-549 with IC50 values in the range of 2 nM to 8 μM.
|
Cytotoxicity against human A549 cells after 72 hrs by sulforhodamine B assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J Nat Prod
Title : Flabellipparicine, a Flabelliformide-Apparicine-Type Bisindole Alkaloid from Tabernaemontana divaricata.
Year : 2018
Volume : 81
Issue : 9
First Page : 1976
Last Page : 1983
Authors : Cai YS, Sarotti AM, Zhou TL, Huang R, Qiu G, Tian C, Miao ZH, Mándi A, Kurtán T, Cao S, Yang SP.
Abstract : Four new monoterpenoid bisindole alkaloids, flabellipparicine (1), 19,20-dihydrovobparicine (2), 10'-demethoxy-19,20-dihydrovobatensine D (3), and 3'-(2-oxopropyl)ervahanine A (4), and 10 known monoterpenoid indole alkaloids were isolated from the stems of Tabernaemontana divaricata. All structures were elucidated based on spectroscopic methods, and the absolute configuration of 1 was established using conformational analysis and TDDFT-ECD calculation of selected stereoisomers. Compound 1 represents the first flabelliformide-apparicine-type bisindole alkaloid, in which the flabelliformide-like unit connects to the apparicine-like unit with a C-3-C-22' bond and an N-1-C-16' bond to form an uncommon five-membered ring between the two monomers. All alkaloids were evaluated for their cytotoxicity against two human cancer cell lines, MCF-7 and A-549. Compounds 2, 4, and 14 exhibited cytotoxicity against MCF-7 and A-549 with IC50 values in the range of 2 nM to 8 μM.
|
Antiproliferative activity against human A549 cells after 72 hrs by SRB assay
|
Homo sapiens
|
1.62
nM
|
|
Journal : Bioorg Med Chem
Title : A series of camptothecin prodrugs exhibit HDAC inhibition activity.
Year : 2018
Volume : 26
Issue : 16
First Page : 4706
Last Page : 4715
Authors : Zhu Q, Yu X, Shen Q, Zhang Q, Su M, Zhou Y, Li J, Chen Y, Lu W.
Abstract : Camptothecin plays an important role in clinical cancer treatment, and its derivatives are a favorite of pharmaceutical chemists. Herein, we have designed a series of camptothecin prodrugs that exhibit histone deacetylase (HDAC) inhibition activity based on the synergy effect between HDAC inhibitors and camptothecin derivatives. With the evaluation of stability in buffers or plasma from human or mouse model, an appropriate linker was found, so the active drug can be released efficiently and compound 21a exhibited strong antiproliferative activity in A549 and HCT-116 cell lines. These results indicated that the well-designed prodrug can be promising in cancer treatment.
|
Antiproliferative activity against human HCT116 cells after 72 hrs by SRB assay
|
Homo sapiens
|
0.78
nM
|
|
Journal : Bioorg Med Chem
Title : A series of camptothecin prodrugs exhibit HDAC inhibition activity.
Year : 2018
Volume : 26
Issue : 16
First Page : 4706
Last Page : 4715
Authors : Zhu Q, Yu X, Shen Q, Zhang Q, Su M, Zhou Y, Li J, Chen Y, Lu W.
Abstract : Camptothecin plays an important role in clinical cancer treatment, and its derivatives are a favorite of pharmaceutical chemists. Herein, we have designed a series of camptothecin prodrugs that exhibit histone deacetylase (HDAC) inhibition activity based on the synergy effect between HDAC inhibitors and camptothecin derivatives. With the evaluation of stability in buffers or plasma from human or mouse model, an appropriate linker was found, so the active drug can be released efficiently and compound 21a exhibited strong antiproliferative activity in A549 and HCT-116 cell lines. These results indicated that the well-designed prodrug can be promising in cancer treatment.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-28.1
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Cytotoxicity against human HepG2 cells after 72 hrs by MTT assay
|
Homo sapiens
|
480.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Monodisperse oligoethylene glycols modified Camptothecin, 10-Hydroxycamptothecin and SN38 prodrugs.
Year : 2019
Volume : 29
Issue : 4
First Page : 581
Last Page : 584
Authors : Deng T, Mao X, Xiao Y, Yang Z, Zheng X, Jiang ZX.
Abstract : Camptothecin, which represents a class of natural products with high anticancer activity, suffers low water solubility which hampers its clinic application. To address this issue, monodisperse polyethylene glycols were employed to modify this class of natural products, including Camptothecin, 10-Hydroxycamptothecin, and SN38. Through selective modification with a series of monodisperse polyethylene glycols, 31 Camptothecin derivatives, including 9 ethers and 22 carbonates, were prepared using a macrocyclic sulfate-based strategy with high efficacy. Monodisperse polyethylene glycols modification provided the Camptothecin derivatives with high purity and fine-tunable water solubility. Through the physicochemical and biological assays, a few novel prodrugs with good solubility, cytotoxicity, and valuable drug release profile were identified as promising anticancer drug candidates.
|
Antiproliferative activity against human A549 cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
11.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation.
Year : 2020
Volume : 63
Issue : 10
First Page : 5421
Last Page : 5441
Authors : Zhu S, Shen Q, Gao Y, Wang L, Fang Y, Chen Y, Lu W.
Abstract : Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including acceptable HSP90α affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chemical and biological evaluation.
|
Antiproliferative activity against human HCT116 cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation.
Year : 2020
Volume : 63
Issue : 10
First Page : 5421
Last Page : 5441
Authors : Zhu S, Shen Q, Gao Y, Wang L, Fang Y, Chen Y, Lu W.
Abstract : Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including acceptable HSP90α affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chemical and biological evaluation.
|
Antiproliferative activity against human MIAPaCa2 cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation.
Year : 2020
Volume : 63
Issue : 10
First Page : 5421
Last Page : 5441
Authors : Zhu S, Shen Q, Gao Y, Wang L, Fang Y, Chen Y, Lu W.
Abstract : Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including acceptable HSP90α affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chemical and biological evaluation.
|
Antiproliferative activity against human Capan1 cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
8.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation.
Year : 2020
Volume : 63
Issue : 10
First Page : 5421
Last Page : 5441
Authors : Zhu S, Shen Q, Gao Y, Wang L, Fang Y, Chen Y, Lu W.
Abstract : Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including acceptable HSP90α affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chemical and biological evaluation.
|
Cytotoxicity agains human HL7702 cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation.
Year : 2020
Volume : 63
Issue : 10
First Page : 5421
Last Page : 5441
Authors : Zhu S, Shen Q, Gao Y, Wang L, Fang Y, Chen Y, Lu W.
Abstract : Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including acceptable HSP90α affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chemical and biological evaluation.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
25.05
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.29
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-0.04081
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.02
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.12
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.08
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.02
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.08
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.12
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Cytotoxicity against human C3PV cells assessed as reduction in cell viability measured after 24 hrs by MTT assay
|
Homo sapiens
|
510.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Artemisinin Derivatives with Antimelanoma Activity Show Inhibitory Effect against Human DNA Topoisomerase 1.
Year : 2020
Volume : 11
Issue : 5
First Page : 1035
Last Page : 1040
Authors : Botta L, Filippi S, Zippilli C, Cesarini S, Bizzarri BM, Cirigliano A, Rinaldi T, Paiardini A, Fiorucci D, Saladino R, Negri R, Benedetti P.
Abstract : Artesunic acid and artemisinin are natural substances with promiscuous anticancer activity against different types of cancer cell lines. The mechanism of action of these compounds is associated with the formation of reactive radical species by cleavage of the sesquiterpene pharmacophore endoperoxide bridge. Here we suggested topoisomerase 1 as a possible molecular target for the improvement of the anticancer activity of these compounds. In this context, we report that novel hybrid and dimer derivatives of artesunic acid and artemisinin, bearing camptothecin and SN38 as side-chain biological effectors, can inhibit growth of yeast cells overexpressing human topoisomerase 1 and its enzymatic activity <i>in vitro</i>. These derivatives showed also anticancer activity in melanoma cell lines higher than camptothecin and paclitaxel. <i>In silico</i> molecular docking calculations highlighted a common binding mode for the novel derivatives, with the sesquiterpene lactone scaffold being located near the traditional recognition site for camptothecin, while the bioactive side-chain effector laid in the camptothecin cleft.
|
Cytotoxicity against human RPMI7951 cells assessed as reduction in cell viability measured after 24 hrs by MTT assay
|
Homo sapiens
|
260.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Artemisinin Derivatives with Antimelanoma Activity Show Inhibitory Effect against Human DNA Topoisomerase 1.
Year : 2020
Volume : 11
Issue : 5
First Page : 1035
Last Page : 1040
Authors : Botta L, Filippi S, Zippilli C, Cesarini S, Bizzarri BM, Cirigliano A, Rinaldi T, Paiardini A, Fiorucci D, Saladino R, Negri R, Benedetti P.
Abstract : Artesunic acid and artemisinin are natural substances with promiscuous anticancer activity against different types of cancer cell lines. The mechanism of action of these compounds is associated with the formation of reactive radical species by cleavage of the sesquiterpene pharmacophore endoperoxide bridge. Here we suggested topoisomerase 1 as a possible molecular target for the improvement of the anticancer activity of these compounds. In this context, we report that novel hybrid and dimer derivatives of artesunic acid and artemisinin, bearing camptothecin and SN38 as side-chain biological effectors, can inhibit growth of yeast cells overexpressing human topoisomerase 1 and its enzymatic activity <i>in vitro</i>. These derivatives showed also anticancer activity in melanoma cell lines higher than camptothecin and paclitaxel. <i>In silico</i> molecular docking calculations highlighted a common binding mode for the novel derivatives, with the sesquiterpene lactone scaffold being located near the traditional recognition site for camptothecin, while the bioactive side-chain effector laid in the camptothecin cleft.
|
Cytotoxicity against human SK-MEL-24 cells assessed as reduction in cell viability measured after 24 hrs by MTT assay
|
Homo sapiens
|
480.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Artemisinin Derivatives with Antimelanoma Activity Show Inhibitory Effect against Human DNA Topoisomerase 1.
Year : 2020
Volume : 11
Issue : 5
First Page : 1035
Last Page : 1040
Authors : Botta L, Filippi S, Zippilli C, Cesarini S, Bizzarri BM, Cirigliano A, Rinaldi T, Paiardini A, Fiorucci D, Saladino R, Negri R, Benedetti P.
Abstract : Artesunic acid and artemisinin are natural substances with promiscuous anticancer activity against different types of cancer cell lines. The mechanism of action of these compounds is associated with the formation of reactive radical species by cleavage of the sesquiterpene pharmacophore endoperoxide bridge. Here we suggested topoisomerase 1 as a possible molecular target for the improvement of the anticancer activity of these compounds. In this context, we report that novel hybrid and dimer derivatives of artesunic acid and artemisinin, bearing camptothecin and SN38 as side-chain biological effectors, can inhibit growth of yeast cells overexpressing human topoisomerase 1 and its enzymatic activity <i>in vitro</i>. These derivatives showed also anticancer activity in melanoma cell lines higher than camptothecin and paclitaxel. <i>In silico</i> molecular docking calculations highlighted a common binding mode for the novel derivatives, with the sesquiterpene lactone scaffold being located near the traditional recognition site for camptothecin, while the bioactive side-chain effector laid in the camptothecin cleft.
|
Cytotoxicity against FR-positive human SKHEP1 cells assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Folate Receptor Targeting and Cathepsin B-Sensitive Drug Delivery System for Selective Cancer Cell Death and Imaging.
Year : 2020
Volume : 11
Issue : 8
First Page : 1514
Last Page : 1520
Authors : Jin X, Zhang J, Jin X, Liu L, Tian X.
Abstract : In this work, a folate receptor (FR)-mediated dual-targeting drug delivery system was synthesized to improve the tumor-killing efficiency and inhibit the side effects of anticancer drugs. We designed and synthesized an FR-mediated fluorescence probe (FA-Rho) and FR-mediated cathepsin B-sensitive drug delivery system (FA-GFLG-SN38). FA-GFLG-SN38 is composed of the FR ligand (folic acid, FA), the tetrapeptide substrate for cathepsin B (GFLG), and an anticancer drug (SN38). The rhodamine B (Rho)-labeled probe FA-Rho is suitable for specific fluorescence imaging of SK-Hep-1 cells overexpressing FR and inactive in FR-negative A549 and 16-HBE cells. FA-GFLG-SN38 exhibited strong cytotoxicity against FR-overexpressing SK-Hep-1, HeLa, and Siha cells, with IC<sub>50</sub> values of 2-3 μM, but had no effect on FR-negative A549 and 16-HBE cells. The experimental results show that the FA-CFLG-SN38 drug delivery system proposed by us can effectively inhibit tumor proliferation in vitro, and it can be adopted for the diagnostics of tumor tissues and provide a basis for effective tumor therapy.
|
Cytotoxicity against FR-positive human HeLa cells assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Folate Receptor Targeting and Cathepsin B-Sensitive Drug Delivery System for Selective Cancer Cell Death and Imaging.
Year : 2020
Volume : 11
Issue : 8
First Page : 1514
Last Page : 1520
Authors : Jin X, Zhang J, Jin X, Liu L, Tian X.
Abstract : In this work, a folate receptor (FR)-mediated dual-targeting drug delivery system was synthesized to improve the tumor-killing efficiency and inhibit the side effects of anticancer drugs. We designed and synthesized an FR-mediated fluorescence probe (FA-Rho) and FR-mediated cathepsin B-sensitive drug delivery system (FA-GFLG-SN38). FA-GFLG-SN38 is composed of the FR ligand (folic acid, FA), the tetrapeptide substrate for cathepsin B (GFLG), and an anticancer drug (SN38). The rhodamine B (Rho)-labeled probe FA-Rho is suitable for specific fluorescence imaging of SK-Hep-1 cells overexpressing FR and inactive in FR-negative A549 and 16-HBE cells. FA-GFLG-SN38 exhibited strong cytotoxicity against FR-overexpressing SK-Hep-1, HeLa, and Siha cells, with IC<sub>50</sub> values of 2-3 μM, but had no effect on FR-negative A549 and 16-HBE cells. The experimental results show that the FA-CFLG-SN38 drug delivery system proposed by us can effectively inhibit tumor proliferation in vitro, and it can be adopted for the diagnostics of tumor tissues and provide a basis for effective tumor therapy.
|
Cytotoxicity against FR-positive human SiHa cells assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Folate Receptor Targeting and Cathepsin B-Sensitive Drug Delivery System for Selective Cancer Cell Death and Imaging.
Year : 2020
Volume : 11
Issue : 8
First Page : 1514
Last Page : 1520
Authors : Jin X, Zhang J, Jin X, Liu L, Tian X.
Abstract : In this work, a folate receptor (FR)-mediated dual-targeting drug delivery system was synthesized to improve the tumor-killing efficiency and inhibit the side effects of anticancer drugs. We designed and synthesized an FR-mediated fluorescence probe (FA-Rho) and FR-mediated cathepsin B-sensitive drug delivery system (FA-GFLG-SN38). FA-GFLG-SN38 is composed of the FR ligand (folic acid, FA), the tetrapeptide substrate for cathepsin B (GFLG), and an anticancer drug (SN38). The rhodamine B (Rho)-labeled probe FA-Rho is suitable for specific fluorescence imaging of SK-Hep-1 cells overexpressing FR and inactive in FR-negative A549 and 16-HBE cells. FA-GFLG-SN38 exhibited strong cytotoxicity against FR-overexpressing SK-Hep-1, HeLa, and Siha cells, with IC<sub>50</sub> values of 2-3 μM, but had no effect on FR-negative A549 and 16-HBE cells. The experimental results show that the FA-CFLG-SN38 drug delivery system proposed by us can effectively inhibit tumor proliferation in vitro, and it can be adopted for the diagnostics of tumor tissues and provide a basis for effective tumor therapy.
|
Cytotoxicity against human 16HBE cells assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Folate Receptor Targeting and Cathepsin B-Sensitive Drug Delivery System for Selective Cancer Cell Death and Imaging.
Year : 2020
Volume : 11
Issue : 8
First Page : 1514
Last Page : 1520
Authors : Jin X, Zhang J, Jin X, Liu L, Tian X.
Abstract : In this work, a folate receptor (FR)-mediated dual-targeting drug delivery system was synthesized to improve the tumor-killing efficiency and inhibit the side effects of anticancer drugs. We designed and synthesized an FR-mediated fluorescence probe (FA-Rho) and FR-mediated cathepsin B-sensitive drug delivery system (FA-GFLG-SN38). FA-GFLG-SN38 is composed of the FR ligand (folic acid, FA), the tetrapeptide substrate for cathepsin B (GFLG), and an anticancer drug (SN38). The rhodamine B (Rho)-labeled probe FA-Rho is suitable for specific fluorescence imaging of SK-Hep-1 cells overexpressing FR and inactive in FR-negative A549 and 16-HBE cells. FA-GFLG-SN38 exhibited strong cytotoxicity against FR-overexpressing SK-Hep-1, HeLa, and Siha cells, with IC<sub>50</sub> values of 2-3 μM, but had no effect on FR-negative A549 and 16-HBE cells. The experimental results show that the FA-CFLG-SN38 drug delivery system proposed by us can effectively inhibit tumor proliferation in vitro, and it can be adopted for the diagnostics of tumor tissues and provide a basis for effective tumor therapy.
|
Cytotoxicity against FR-negative human A549 cells assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Folate Receptor Targeting and Cathepsin B-Sensitive Drug Delivery System for Selective Cancer Cell Death and Imaging.
Year : 2020
Volume : 11
Issue : 8
First Page : 1514
Last Page : 1520
Authors : Jin X, Zhang J, Jin X, Liu L, Tian X.
Abstract : In this work, a folate receptor (FR)-mediated dual-targeting drug delivery system was synthesized to improve the tumor-killing efficiency and inhibit the side effects of anticancer drugs. We designed and synthesized an FR-mediated fluorescence probe (FA-Rho) and FR-mediated cathepsin B-sensitive drug delivery system (FA-GFLG-SN38). FA-GFLG-SN38 is composed of the FR ligand (folic acid, FA), the tetrapeptide substrate for cathepsin B (GFLG), and an anticancer drug (SN38). The rhodamine B (Rho)-labeled probe FA-Rho is suitable for specific fluorescence imaging of SK-Hep-1 cells overexpressing FR and inactive in FR-negative A549 and 16-HBE cells. FA-GFLG-SN38 exhibited strong cytotoxicity against FR-overexpressing SK-Hep-1, HeLa, and Siha cells, with IC<sub>50</sub> values of 2-3 μM, but had no effect on FR-negative A549 and 16-HBE cells. The experimental results show that the FA-CFLG-SN38 drug delivery system proposed by us can effectively inhibit tumor proliferation in vitro, and it can be adopted for the diagnostics of tumor tissues and provide a basis for effective tumor therapy.
|
Cytotoxicity against human A549 assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : Eur J Med Chem
Title : F10, a new camptothecin derivative, was identified as a new orally-bioavailable, potent antitumor agent.
Year : 2020
Volume : 202
First Page : 112528
Last Page : 112528
Authors : Fan S,Cao YX,Li GY,Lei H,Attiogbe MKI,Yao JC,Yang XY,Liu YJ,Hei YY,Zhang H,Cao L,Zhang XY,Du SS,Zhang GM,Zhang SQ
Abstract : Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited cancer cells growth with the IC of 0.002, 0.003, 0.011 and 0.081 μM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 μg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.
|
Cytotoxicity against human HCT-116 assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : F10, a new camptothecin derivative, was identified as a new orally-bioavailable, potent antitumor agent.
Year : 2020
Volume : 202
First Page : 112528
Last Page : 112528
Authors : Fan S,Cao YX,Li GY,Lei H,Attiogbe MKI,Yao JC,Yang XY,Liu YJ,Hei YY,Zhang H,Cao L,Zhang XY,Du SS,Zhang GM,Zhang SQ
Abstract : Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited cancer cells growth with the IC of 0.002, 0.003, 0.011 and 0.081 μM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 μg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.
|
Cytotoxicity against human LoVo assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
301.0
nM
|
|
Journal : Eur J Med Chem
Title : F10, a new camptothecin derivative, was identified as a new orally-bioavailable, potent antitumor agent.
Year : 2020
Volume : 202
First Page : 112528
Last Page : 112528
Authors : Fan S,Cao YX,Li GY,Lei H,Attiogbe MKI,Yao JC,Yang XY,Liu YJ,Hei YY,Zhang H,Cao L,Zhang XY,Du SS,Zhang GM,Zhang SQ
Abstract : Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited cancer cells growth with the IC of 0.002, 0.003, 0.011 and 0.081 μM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 μg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.
|
Cytotoxicity against human COLO 205 assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
220.0
nM
|
|
Journal : Eur J Med Chem
Title : F10, a new camptothecin derivative, was identified as a new orally-bioavailable, potent antitumor agent.
Year : 2020
Volume : 202
First Page : 112528
Last Page : 112528
Authors : Fan S,Cao YX,Li GY,Lei H,Attiogbe MKI,Yao JC,Yang XY,Liu YJ,Hei YY,Zhang H,Cao L,Zhang XY,Du SS,Zhang GM,Zhang SQ
Abstract : Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited cancer cells growth with the IC of 0.002, 0.003, 0.011 and 0.081 μM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 μg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.
|
Cytotoxicity against human Raji assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
5.0
nM
|
|
Journal : Eur J Med Chem
Title : F10, a new camptothecin derivative, was identified as a new orally-bioavailable, potent antitumor agent.
Year : 2020
Volume : 202
First Page : 112528
Last Page : 112528
Authors : Fan S,Cao YX,Li GY,Lei H,Attiogbe MKI,Yao JC,Yang XY,Liu YJ,Hei YY,Zhang H,Cao L,Zhang XY,Du SS,Zhang GM,Zhang SQ
Abstract : Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited cancer cells growth with the IC of 0.002, 0.003, 0.011 and 0.081 μM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 μg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.
|
Cytotoxicity against human Hela assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
145.0
nM
|
|
Journal : Eur J Med Chem
Title : F10, a new camptothecin derivative, was identified as a new orally-bioavailable, potent antitumor agent.
Year : 2020
Volume : 202
First Page : 112528
Last Page : 112528
Authors : Fan S,Cao YX,Li GY,Lei H,Attiogbe MKI,Yao JC,Yang XY,Liu YJ,Hei YY,Zhang H,Cao L,Zhang XY,Du SS,Zhang GM,Zhang SQ
Abstract : Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited cancer cells growth with the IC of 0.002, 0.003, 0.011 and 0.081 μM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 μg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.
|
Cytotoxicity against human NCI-H1975 assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
810.0
nM
|
|
Journal : Eur J Med Chem
Title : F10, a new camptothecin derivative, was identified as a new orally-bioavailable, potent antitumor agent.
Year : 2020
Volume : 202
First Page : 112528
Last Page : 112528
Authors : Fan S,Cao YX,Li GY,Lei H,Attiogbe MKI,Yao JC,Yang XY,Liu YJ,Hei YY,Zhang H,Cao L,Zhang XY,Du SS,Zhang GM,Zhang SQ
Abstract : Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited cancer cells growth with the IC of 0.002, 0.003, 0.011 and 0.081 μM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 μg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.
|
Cytotoxicity against human MCF7 cells assessed as inhibition of cell growth measured after 72 hrs
|
Homo sapiens
|
660.0
nM
|
|
|
Cytotoxicity against human HT-29 cells assessed as inhibition of cell growth measured after 72 hrs
|
Homo sapiens
|
20.0
nM
|
|
|
Cytotoxicity against human HL-60 cells assessed as inhibition of cell growth measured after 72 hrs
|
Homo sapiens
|
2.0
nM
|
|
|
Cytotoxicity against human A549 cells assessed as inhibition of cell growth measured after 72 hrs
|
Homo sapiens
|
28.0
nM
|
|
|
Cytotoxicity against human HeLa cells assessed as reduction in cell viability incubated for 24 hrs by MTT assay
|
Homo sapiens
|
349.0
nM
|
|
