|
Inhibitory activity in mice bearing L1210 leukemia
|
Mus musculus
|
18.0
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 of human colon tumor (LS174T) xenograft in nude mice
|
Mus musculus
|
36.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selective phenolic acylation of 10-hydroxycamptothecin using poly (ethylene glycol) carboxylic acid.
Year : 2003
Volume : 13
Issue : 3
First Page : 577
Last Page : 580
Authors : Greenwald RB, Choe YH, Wu D.
Abstract : Selective acylation of the phenolic hydroxyl group of 10-hydroxycamptothecin has been accomplished using phenyl dichlorophosphate. Additional modification of the 10-OH as an ether permits a 20-acyl derivative to be synthesized. This result along with data from a 6-hydroxyquinoline model strongly suggests that powerful intermolecular hydrogen bonding exists in the parent molecule.
|
Inhibitory activity against P388 Leukemia cells
|
Mus musculus
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selective phenolic acylation of 10-hydroxycamptothecin using poly (ethylene glycol) carboxylic acid.
Year : 2003
Volume : 13
Issue : 3
First Page : 577
Last Page : 580
Authors : Greenwald RB, Choe YH, Wu D.
Abstract : Selective acylation of the phenolic hydroxyl group of 10-hydroxycamptothecin has been accomplished using phenyl dichlorophosphate. Additional modification of the 10-OH as an ether permits a 20-acyl derivative to be synthesized. This result along with data from a 6-hydroxyquinoline model strongly suggests that powerful intermolecular hydrogen bonding exists in the parent molecule.
|
Inhibition of Topoisomerase I by cleavage complex formation in human HL-60 cells
|
None
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Plant antitumor agents. 30. Synthesis and structure activity of novel camptothecin analogs.
Year : 1993
Volume : 36
Issue : 18
First Page : 2689
Last Page : 2700
Authors : Wall ME, Wani MC, Nicholas AW, Manikumar G, Tele C, Moore L, Truesdale A, Leitner P, Besterman JM.
Abstract : A large number of camptothecin (CPT) analogs have been prepared in the 20S, 20RS, and 20R configurations with a number of ring A substituents. Topoisomerase I (T-I) inhibition data (IC50) have been obtained by standard procedures. In general, substitution at the 9 or 10 positions with amino, halogeno, or hydroxyl groups in compounds with 20S configuration results in compounds with enhanced T-I inhibition. Compounds in the 20RS configuration were less active in vitro and in vivo and those in the 20R configuration were inactive. Compounds with 10,11-methylenedioxy substitution on ring A displayed a marked increase in potency in the T-I inhibition assay. The activities of some of the analogs as determined in a variety of in vivo assays including the L-1210 mouse leukemia assay were, in general, in accord with T-I inhibition. A number of water-soluble analogs such as 20-glycinate esters, 9-glycinamides, or hydrolyzed lactone salts were prepared and tested in in vitro and in vivo assays. In general, these compounds were less active than CPT both in terms of T-I inhibition and life prolongation in the L-1210 assay. However, certain 20-glycinate esters showed good in vivo activity after iv administration.
|
Inhibitory concentration against human HCT116 colon cancer cell line
|
Homo sapiens
|
148.0
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.
|
Cytotoxicity against human HepG2 cells assessed as inhibition of [3H]thymidine after 48 hrs
|
Homo sapiens
|
5.4
nM
|
|
Journal : J. Med. Chem.
Title : Benzyl ether-linked glucuronide derivative of 10-hydroxycamptothecin designed for selective camptothecin-based anticancer therapy.
Year : 2008
Volume : 51
Issue : 6
First Page : 1740
Last Page : 1746
Authors : Leu YL, Chen CS, Wu YJ, Chern JW.
Abstract : A beta-glucuronidase-activated prodrug approach was applied to 10-hydroxycamptothecin, a Camptotheca alkaloid with promising antitumor activity but poor water solubility. We synthesized a glucuronide prodrug of 10-hydroxycamptothecin ( 7) in which glucuronic acid is connected via a self-immolative 3-nitrobenzyl ether linker to the 10-OH group of 10-hydroxycamptothecin. Compound 7 was 80 times more soluble than 10-hydroxycamptothecin in aqueous solution at pH 4.0 and was stable in human plasma. Prodrug 7 was 10- to 15-fold less toxic than the parent drug to four human tumor cell lines. In the presence of beta-glucuronidase, prodrug 7 could be activated to elicit similar cytotoxicity to the parent drug in tumor cells. Enzyme kinetic studies showed that Escherichia coli beta-glucuronidase had a quite low K m of 0.18 microM for compound 7 and exhibited 520 times higher catalytic efficiency for 7 than for 6 (a glucuronide prodrug of 9-aminocamptothecin). Molecular modeling studies predicted that compound 7 would have a higher binding affinity to human beta-glucuronidase than compound 6. Prodrug 7 may be useful for selective cancer chemotherapy by a prodrug monotherapy (PMT) or antibody-directed enzyme prodrug therapy (ADEPT) strategy.
|
Cytotoxicity against human Colo 205 cells assessed as inhibition of [3H]thymidine after 48 hrs
|
Homo sapiens
|
9.1
nM
|
|
Journal : J. Med. Chem.
Title : Benzyl ether-linked glucuronide derivative of 10-hydroxycamptothecin designed for selective camptothecin-based anticancer therapy.
Year : 2008
Volume : 51
Issue : 6
First Page : 1740
Last Page : 1746
Authors : Leu YL, Chen CS, Wu YJ, Chern JW.
Abstract : A beta-glucuronidase-activated prodrug approach was applied to 10-hydroxycamptothecin, a Camptotheca alkaloid with promising antitumor activity but poor water solubility. We synthesized a glucuronide prodrug of 10-hydroxycamptothecin ( 7) in which glucuronic acid is connected via a self-immolative 3-nitrobenzyl ether linker to the 10-OH group of 10-hydroxycamptothecin. Compound 7 was 80 times more soluble than 10-hydroxycamptothecin in aqueous solution at pH 4.0 and was stable in human plasma. Prodrug 7 was 10- to 15-fold less toxic than the parent drug to four human tumor cell lines. In the presence of beta-glucuronidase, prodrug 7 could be activated to elicit similar cytotoxicity to the parent drug in tumor cells. Enzyme kinetic studies showed that Escherichia coli beta-glucuronidase had a quite low K m of 0.18 microM for compound 7 and exhibited 520 times higher catalytic efficiency for 7 than for 6 (a glucuronide prodrug of 9-aminocamptothecin). Molecular modeling studies predicted that compound 7 would have a higher binding affinity to human beta-glucuronidase than compound 6. Prodrug 7 may be useful for selective cancer chemotherapy by a prodrug monotherapy (PMT) or antibody-directed enzyme prodrug therapy (ADEPT) strategy.
|
Cytotoxicity against human HT29 cells assessed as inhibition of [3H]thymidine after 48 hrs
|
Homo sapiens
|
8.8
nM
|
|
Journal : J. Med. Chem.
Title : Benzyl ether-linked glucuronide derivative of 10-hydroxycamptothecin designed for selective camptothecin-based anticancer therapy.
Year : 2008
Volume : 51
Issue : 6
First Page : 1740
Last Page : 1746
Authors : Leu YL, Chen CS, Wu YJ, Chern JW.
Abstract : A beta-glucuronidase-activated prodrug approach was applied to 10-hydroxycamptothecin, a Camptotheca alkaloid with promising antitumor activity but poor water solubility. We synthesized a glucuronide prodrug of 10-hydroxycamptothecin ( 7) in which glucuronic acid is connected via a self-immolative 3-nitrobenzyl ether linker to the 10-OH group of 10-hydroxycamptothecin. Compound 7 was 80 times more soluble than 10-hydroxycamptothecin in aqueous solution at pH 4.0 and was stable in human plasma. Prodrug 7 was 10- to 15-fold less toxic than the parent drug to four human tumor cell lines. In the presence of beta-glucuronidase, prodrug 7 could be activated to elicit similar cytotoxicity to the parent drug in tumor cells. Enzyme kinetic studies showed that Escherichia coli beta-glucuronidase had a quite low K m of 0.18 microM for compound 7 and exhibited 520 times higher catalytic efficiency for 7 than for 6 (a glucuronide prodrug of 9-aminocamptothecin). Molecular modeling studies predicted that compound 7 would have a higher binding affinity to human beta-glucuronidase than compound 6. Prodrug 7 may be useful for selective cancer chemotherapy by a prodrug monotherapy (PMT) or antibody-directed enzyme prodrug therapy (ADEPT) strategy.
|
Cytotoxicity against human H298 cells assessed as inhibition of [3H]thymidine after 48 hrs
|
Homo sapiens
|
6.9
nM
|
|
Journal : J. Med. Chem.
Title : Benzyl ether-linked glucuronide derivative of 10-hydroxycamptothecin designed for selective camptothecin-based anticancer therapy.
Year : 2008
Volume : 51
Issue : 6
First Page : 1740
Last Page : 1746
Authors : Leu YL, Chen CS, Wu YJ, Chern JW.
Abstract : A beta-glucuronidase-activated prodrug approach was applied to 10-hydroxycamptothecin, a Camptotheca alkaloid with promising antitumor activity but poor water solubility. We synthesized a glucuronide prodrug of 10-hydroxycamptothecin ( 7) in which glucuronic acid is connected via a self-immolative 3-nitrobenzyl ether linker to the 10-OH group of 10-hydroxycamptothecin. Compound 7 was 80 times more soluble than 10-hydroxycamptothecin in aqueous solution at pH 4.0 and was stable in human plasma. Prodrug 7 was 10- to 15-fold less toxic than the parent drug to four human tumor cell lines. In the presence of beta-glucuronidase, prodrug 7 could be activated to elicit similar cytotoxicity to the parent drug in tumor cells. Enzyme kinetic studies showed that Escherichia coli beta-glucuronidase had a quite low K m of 0.18 microM for compound 7 and exhibited 520 times higher catalytic efficiency for 7 than for 6 (a glucuronide prodrug of 9-aminocamptothecin). Molecular modeling studies predicted that compound 7 would have a higher binding affinity to human beta-glucuronidase than compound 6. Prodrug 7 may be useful for selective cancer chemotherapy by a prodrug monotherapy (PMT) or antibody-directed enzyme prodrug therapy (ADEPT) strategy.
|
Cytotoxicity against human HL-60 cells after 72 hrs by MTT assay
|
Homo sapiens
|
410.0
nM
|
|
Journal : J. Nat. Prod.
Title : Bioactive triterpene glycosides from the sea cucumber Holothuria fuscocinerea.
Year : 2006
Volume : 69
Issue : 10
First Page : 1492
Last Page : 1495
Authors : Zhang SY, Yi YH, Tang HF.
Abstract : Bioassay-guided fractionation of the active n-BuOH extract of the sea cucumber Holothuria fuscocinerea resulted in the isolation of three new triterpene glycosides, fuscocinerosides A (1), B (2), and C (3), along with two known glycosides, pervicoside C (4) and holothurin A (5), as active compounds causing morphological abnormality of Pyricularia oryzae mycelia. Compounds 1-5 possess the same tetrasaccharide moiety, 3-O-methyl-beta-D-glucopyranosyl-(1-->3)-beta-D- glucopyranosyl-(1-->4)-beta-D-quinovopyranosyl-(1-->2)-4-O-sodiumsulfato-beta-D-xylopyranosyl, linked to C-3 of holostane triterpene aglycones that differ in their side chains and 17-substituents. Their structures were elucidated by extensive spectral studies as well as chemical evidence. All the glycosides showed in vitro cytotoxicity against two human tumor cell lines.
|
Cytotoxicity against human Bel-7402 cells after 72 hrs by sulforhodamine B assay
|
Homo sapiens
|
280.0
nM
|
|
Journal : J. Nat. Prod.
Title : Bioactive triterpene glycosides from the sea cucumber Holothuria fuscocinerea.
Year : 2006
Volume : 69
Issue : 10
First Page : 1492
Last Page : 1495
Authors : Zhang SY, Yi YH, Tang HF.
Abstract : Bioassay-guided fractionation of the active n-BuOH extract of the sea cucumber Holothuria fuscocinerea resulted in the isolation of three new triterpene glycosides, fuscocinerosides A (1), B (2), and C (3), along with two known glycosides, pervicoside C (4) and holothurin A (5), as active compounds causing morphological abnormality of Pyricularia oryzae mycelia. Compounds 1-5 possess the same tetrasaccharide moiety, 3-O-methyl-beta-D-glucopyranosyl-(1-->3)-beta-D- glucopyranosyl-(1-->4)-beta-D-quinovopyranosyl-(1-->2)-4-O-sodiumsulfato-beta-D-xylopyranosyl, linked to C-3 of holostane triterpene aglycones that differ in their side chains and 17-substituents. Their structures were elucidated by extensive spectral studies as well as chemical evidence. All the glycosides showed in vitro cytotoxicity against two human tumor cell lines.
|
Cytotoxicity against human HL60 cells
|
Homo sapiens
|
0.024
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Cytotoxic sesquiterpenoids from Eupatorium chinense.
Year : 2004
Volume : 67
Issue : 4
First Page : 638
Last Page : 643
Authors : Yang SP, Huo J, Wang Y, Lou LG, Yue JM.
Abstract : Ten new sesquiterpenoids, namely, eupachinilides A-J (1-10), together with seven known sesquiterpenoids, eupachifolin D (11), budlein B (12), 8 beta-(4'-hydroxytiglyloxy)-2 beta-hydroxy-1 alpha H,5 alpha H,6 beta H,7 alpha H-guai-3,10(14),11(13)-trien-6,12-olide (13), 1,10-hydrobahia (14), 2 alpha-hydroxyeupatolide (15), eupaserrin (16), and mollisorin B (17), were isolated from the whole plant of Eupatorium chinense. Their structures were elucidated mainly by spectral methods, especially 2D NMR techniques. Eupachinilides A (1), E (5), F (6), and I (9) exhibited moderate cytotoxic activities against several tumor cell lines. The structures assigned previously for eupachifolins B (11a), C (13a), and D (11) were revised by spectral analysis and 2D NMR techniques.
|
Cytotoxicity against human Bel7402 cells
|
Homo sapiens
|
0.62
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Cytotoxic sesquiterpenoids from Eupatorium chinense.
Year : 2004
Volume : 67
Issue : 4
First Page : 638
Last Page : 643
Authors : Yang SP, Huo J, Wang Y, Lou LG, Yue JM.
Abstract : Ten new sesquiterpenoids, namely, eupachinilides A-J (1-10), together with seven known sesquiterpenoids, eupachifolin D (11), budlein B (12), 8 beta-(4'-hydroxytiglyloxy)-2 beta-hydroxy-1 alpha H,5 alpha H,6 beta H,7 alpha H-guai-3,10(14),11(13)-trien-6,12-olide (13), 1,10-hydrobahia (14), 2 alpha-hydroxyeupatolide (15), eupaserrin (16), and mollisorin B (17), were isolated from the whole plant of Eupatorium chinense. Their structures were elucidated mainly by spectral methods, especially 2D NMR techniques. Eupachinilides A (1), E (5), F (6), and I (9) exhibited moderate cytotoxic activities against several tumor cell lines. The structures assigned previously for eupachifolins B (11a), C (13a), and D (11) were revised by spectral analysis and 2D NMR techniques.
|
Cytotoxicity against human Bel7402 cells after 72 hrs by SRB assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : J. Nat. Prod.
Title : Cytotoxic asterosaponins capable of promoting polymerization of tubulin from the starfish Culcita novaeguineae.
Year : 2009
Volume : 72
Issue : 2
First Page : 284
Last Page : 289
Authors : Tang HF, Cheng G, Wu J, Chen XL, Zhang SY, Wen AD, Lin HW.
Abstract : Four new asterosaponins, novaeguinosides A (1), B (2), C (3), and D (4), were isolated from the bioactive fraction of the starfish Culcita novaeguineae, as active compounds capable of promoting polymerization of tubulin. Their structures were elucidated by extensive spectroscopic studies and chemical evidence. Compounds 1 and 3 are characterized by sulfated side chains not previously found in asterosaponins, and 1 is the first example of a trisulfated asterosaponin. In the side chains of 2 and 4, the 26-carboxylic acid function is found as an amide derivative of taurine, which is a rare feature and first encountered among asterosaponins. All the asterosaponins showed cytotoxicity against two human tumor cell lines.
|
Antitumor activity against human A549/ATCC cells by SRB method
|
Homo sapiens
|
110.0
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
|
210.0
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 KB cells after 48 hrs by MTT assay
|
Homo sapiens
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of quinolone and naphthyridine derivatives as potential topoisomerase I inhibitors by scaffold modification.
Year : 2009
Volume : 52
Issue : 18
First Page : 5649
Last Page : 5661
Authors : You QD, Li ZY, Huang CH, Yang Q, Wang XJ, Guo QL, Chen XG, He XG, Li TK, Chern JW.
Abstract : A novel series of topoisomerase I (Top I) inhibitors were designed on the basis of camptothecin using scaffold modification strategy. Thirty-one new compounds were synthesized and evaluated for anticell proliferation activity. The most potent compound 26 presented a significant inhibitory effect on Top I, leading to Top I-mediated cleavage and influences on Top I expression at the cellular level. Moreover, 26 was proved to induce cell death via apoptosis and accelerated DNA strand breaks without significant alteration in cell cycle populations. All of the experimental results herein indicated that 26 could interact with DNA-Top I complex and induce cancer cell apoptosis to produce antitumor effects. The in vivo evaluation of 26 on the growth of HT-29 tumor xenografts in nude mice suggested its therapeutic potential for further development.
|
Cytotoxicity against human A2780 cells after 48 hrs by MTT assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of quinolone and naphthyridine derivatives as potential topoisomerase I inhibitors by scaffold modification.
Year : 2009
Volume : 52
Issue : 18
First Page : 5649
Last Page : 5661
Authors : You QD, Li ZY, Huang CH, Yang Q, Wang XJ, Guo QL, Chen XG, He XG, Li TK, Chern JW.
Abstract : A novel series of topoisomerase I (Top I) inhibitors were designed on the basis of camptothecin using scaffold modification strategy. Thirty-one new compounds were synthesized and evaluated for anticell proliferation activity. The most potent compound 26 presented a significant inhibitory effect on Top I, leading to Top I-mediated cleavage and influences on Top I expression at the cellular level. Moreover, 26 was proved to induce cell death via apoptosis and accelerated DNA strand breaks without significant alteration in cell cycle populations. All of the experimental results herein indicated that 26 could interact with DNA-Top I complex and induce cancer cell apoptosis to produce antitumor effects. The in vivo evaluation of 26 on the growth of HT-29 tumor xenografts in nude mice suggested its therapeutic potential for further development.
|
Cytotoxicity against human Bel7402 cells after 48 hrs by MTT assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of quinolone and naphthyridine derivatives as potential topoisomerase I inhibitors by scaffold modification.
Year : 2009
Volume : 52
Issue : 18
First Page : 5649
Last Page : 5661
Authors : You QD, Li ZY, Huang CH, Yang Q, Wang XJ, Guo QL, Chen XG, He XG, Li TK, Chern JW.
Abstract : A novel series of topoisomerase I (Top I) inhibitors were designed on the basis of camptothecin using scaffold modification strategy. Thirty-one new compounds were synthesized and evaluated for anticell proliferation activity. The most potent compound 26 presented a significant inhibitory effect on Top I, leading to Top I-mediated cleavage and influences on Top I expression at the cellular level. Moreover, 26 was proved to induce cell death via apoptosis and accelerated DNA strand breaks without significant alteration in cell cycle populations. All of the experimental results herein indicated that 26 could interact with DNA-Top I complex and induce cancer cell apoptosis to produce antitumor effects. The in vivo evaluation of 26 on the growth of HT-29 tumor xenografts in nude mice suggested its therapeutic potential for further development.
|
Cytotoxicity against human CNE2 cells after 48 hrs by MTT assay
|
Homo sapiens
|
370.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Natural tanshinone-like heterocyclic-fused ortho-quinones from regioselective Diels-Alder reaction: synthesis and cytotoxicity evaluation.
Year : 2009
Volume : 44
Issue : 10
First Page : 3915
Last Page : 3921
Authors : Shen YD, Tian YX, Bu XZ, Gu LQ.
Abstract : A series of new natural tanshinone-like oxoheterocyclic-fused ortho-quinone derivatives were synthesized from readily available benzofuranol and N-substituted dienes via IBX oxidation-cycloaddition-aromatization procedure. The regiospecific Diels-Alder cycloaddition reactions of N-dienes were achieved efficiently with a variety of dienophiles. It is found that the amide moiety in the molecular could be preserved or eliminated by control of the aromatization conditions. Selected oxoheterocyclic-fused ortho-quinones as well as several thioheterocyclic-fused ortho-quinones we obtained before were evaluated for their cytotoxicities on different cancer cell lines and the Structure-Activity Relationship (SAR) was discussed.
|
Growth inhibition of human SMMC7721 cells after 48 hrs by MTT assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : J. Nat. Prod.
Title : Steroidal sapogenins and glycosides from the rhizomes of Dioscorea bulbifera.
Year : 2009
Volume : 72
Issue : 11
First Page : 1964
Last Page : 1968
Authors : Liu H, Chou GX, Wu T, Guo YL, Wang SC, Wang CH, Wang ZT.
Abstract : Four new steroidal sapogenins (1-4), named diosbulbisins A-D, two new spirostane glycosides, diosbulbisides A (5) and B (6), one new cholestane glycoside, diosbulbiside C (7), and the known compounds 8-10 were isolated from rhizomes of Dioscorea bulbifera. Their structures were elucidated by 1D and 2D NMR techniques, HRFTMS, and chemical methods. The unusual furospirostanol sapogenin skeletons, as found in compounds 3 and 4, are reported in the family Dioscoreaceae for the first time. Cytotoxicity of compounds 1-10 was evaluated using two human hepatocellular carcinoma cell lines (Bel-7402 and SMMC7721).
|
Cytotoxicity against human K562 cells after 72 hrs by MTT assay
|
Homo sapiens
|
160.0
nM
|
|
Journal : J. Nat. Prod.
Title : Polyhydroxysteroidal glycosides from the starfish Anthenea chinensis.
Year : 2010
Volume : 73
Issue : 4
First Page : 590
Last Page : 597
Authors : Ma N, Tang HF, Qiu F, Lin HW, Tian XR, Yao MN.
Abstract : Ten new polyhydroxysteroidal glycosides, anthenosides B-K (2-11), were isolated from the ethanol extract of the starfish Anthenea chinensis. Their structures were elucidated by extensive spectroscopic studies and chemical evidence. The unprecedented carbohydrate chain 6-O-methyl-beta-d-galactofuranosyl-(1-->3)-(6-O-methyl-beta-d-galactofuranose) was present in all the compounds except compounds 10 and 11. Compounds 5, 7, a mixture of 8 and 9, and a mixture of 10 and 11 showed inhibitory activity against human tumor K-562 and BEL-7402 cells. Furthermore, the mixture of 10 and 11 also exhibited cytotoxicity against human tumor U87MG cells and promoted tubulin polymerization.
|
Cytotoxicity against human Bel7402 cells after 72 hrs by SRB assay
|
Homo sapiens
|
360.0
nM
|
|
Journal : J. Nat. Prod.
Title : Polyhydroxysteroidal glycosides from the starfish Anthenea chinensis.
Year : 2010
Volume : 73
Issue : 4
First Page : 590
Last Page : 597
Authors : Ma N, Tang HF, Qiu F, Lin HW, Tian XR, Yao MN.
Abstract : Ten new polyhydroxysteroidal glycosides, anthenosides B-K (2-11), were isolated from the ethanol extract of the starfish Anthenea chinensis. Their structures were elucidated by extensive spectroscopic studies and chemical evidence. The unprecedented carbohydrate chain 6-O-methyl-beta-d-galactofuranosyl-(1-->3)-(6-O-methyl-beta-d-galactofuranose) was present in all the compounds except compounds 10 and 11. Compounds 5, 7, a mixture of 8 and 9, and a mixture of 10 and 11 showed inhibitory activity against human tumor K-562 and BEL-7402 cells. Furthermore, the mixture of 10 and 11 also exhibited cytotoxicity against human tumor U87MG cells and promoted tubulin polymerization.
|
Cytotoxicity against human HL60 cells after 48 hrs by MTT assay
|
Homo sapiens
|
40.0
nM
|
|
Journal : J. Nat. Prod.
Title : Diterpenoids from the feces of Trogopterus xanthipes.
Year : 2010
Volume : 73
Issue : 5
First Page : 865
Last Page : 869
Authors : Zhao J, Zhu HJ, Zhou XJ, Yang TH, Wang YY, Su J, Li Y, Cheng YX.
Abstract : Three new isopimarane diterpenoids, trogopteroids A-C (1-3), four new aromatic diterpenoids, trogopteroids D-G (4-7), and 12 known diterpenoids were isolated from the feces of Trogopterus xanthipes. Their structures were identified using spectroscopic methods. The relative configuration of 1 was confirmed by quantum calculations. Compound 1 represents the first example of a norisopimarane diterpenoid with an 8alpha,15alpha-olide ring. With the exception of compound 14, all diterpenoids were evaluated for cytotoxicity against seven human tumor cell lines.
|
Cytotoxicity against human Jurkat cells after 48 hrs by MTT assay
|
Homo sapiens
|
30.0
nM
|
|
Journal : J. Nat. Prod.
Title : Diterpenoids from the feces of Trogopterus xanthipes.
Year : 2010
Volume : 73
Issue : 5
First Page : 865
Last Page : 869
Authors : Zhao J, Zhu HJ, Zhou XJ, Yang TH, Wang YY, Su J, Li Y, Cheng YX.
Abstract : Three new isopimarane diterpenoids, trogopteroids A-C (1-3), four new aromatic diterpenoids, trogopteroids D-G (4-7), and 12 known diterpenoids were isolated from the feces of Trogopterus xanthipes. Their structures were identified using spectroscopic methods. The relative configuration of 1 was confirmed by quantum calculations. Compound 1 represents the first example of a norisopimarane diterpenoid with an 8alpha,15alpha-olide ring. With the exception of compound 14, all diterpenoids were evaluated for cytotoxicity against seven human tumor cell lines.
|
Cytotoxicity against human U937 cells after 48 hrs by MTT assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : J. Nat. Prod.
Title : Diterpenoids from the feces of Trogopterus xanthipes.
Year : 2010
Volume : 73
Issue : 5
First Page : 865
Last Page : 869
Authors : Zhao J, Zhu HJ, Zhou XJ, Yang TH, Wang YY, Su J, Li Y, Cheng YX.
Abstract : Three new isopimarane diterpenoids, trogopteroids A-C (1-3), four new aromatic diterpenoids, trogopteroids D-G (4-7), and 12 known diterpenoids were isolated from the feces of Trogopterus xanthipes. Their structures were identified using spectroscopic methods. The relative configuration of 1 was confirmed by quantum calculations. Compound 1 represents the first example of a norisopimarane diterpenoid with an 8alpha,15alpha-olide ring. With the exception of compound 14, all diterpenoids were evaluated for cytotoxicity against seven human tumor cell lines.
|
Antitumor activity against human KB cells by WST-1 assay
|
Homo sapiens
|
829.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The solvolysis of topotecan in alcohols and acetic anhydride.
Year : 2011
Volume : 21
Issue : 8
First Page : 2324
Last Page : 2326
Authors : Li J, Wang G, Dong M, Zhang Q.
Abstract : Six derivatives of 10-hydroxycamptothecin were prepared via solvolysis of topotecan in corresponding alcohols and acetic anhydride. We attributed the specific reactivity of topotecan to the internal hydrogen-bonding between 10-hydroxy and the nitrogen atom in position 9. As a result the reaction underwent through an intermediate ortho-quionomethlide species to reach equilibrium. Bioactivity screening data showed all products could potentially inhibit the proliferation of several cancer cell lines in vitro and a bigger size group in 9-position would be favorable for the anti-tumor activities observably.
|
Antitumor activity against human HepG2 cells by WST-1 assay
|
Homo sapiens
|
981.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The solvolysis of topotecan in alcohols and acetic anhydride.
Year : 2011
Volume : 21
Issue : 8
First Page : 2324
Last Page : 2326
Authors : Li J, Wang G, Dong M, Zhang Q.
Abstract : Six derivatives of 10-hydroxycamptothecin were prepared via solvolysis of topotecan in corresponding alcohols and acetic anhydride. We attributed the specific reactivity of topotecan to the internal hydrogen-bonding between 10-hydroxy and the nitrogen atom in position 9. As a result the reaction underwent through an intermediate ortho-quionomethlide species to reach equilibrium. Bioactivity screening data showed all products could potentially inhibit the proliferation of several cancer cell lines in vitro and a bigger size group in 9-position would be favorable for the anti-tumor activities observably.
|
Antitumor activity against mouse C26 cells by WST-1 assay
|
Mus musculus
|
496.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The solvolysis of topotecan in alcohols and acetic anhydride.
Year : 2011
Volume : 21
Issue : 8
First Page : 2324
Last Page : 2326
Authors : Li J, Wang G, Dong M, Zhang Q.
Abstract : Six derivatives of 10-hydroxycamptothecin were prepared via solvolysis of topotecan in corresponding alcohols and acetic anhydride. We attributed the specific reactivity of topotecan to the internal hydrogen-bonding between 10-hydroxy and the nitrogen atom in position 9. As a result the reaction underwent through an intermediate ortho-quionomethlide species to reach equilibrium. Bioactivity screening data showed all products could potentially inhibit the proliferation of several cancer cell lines in vitro and a bigger size group in 9-position would be favorable for the anti-tumor activities observably.
|
Antitumor against human GLC82 cells assessed as cell survival after 48 hrs by MTT assay
|
Homo sapiens
|
230.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and evaluation of mansonone F derivatives as topoisomerase inhibitors.
Year : 2011
Volume : 46
Issue : 8
First Page : 3339
Last Page : 3347
Authors : Wu WB, Ou JB, Huang ZH, Chen SB, Ou TM, Tan JH, Li D, Shen LL, Huang SL, Gu LQ, Huang ZS.
Abstract : A series of mansonone F (MF) derivatives were designed and synthesized. These compounds were found to be strong inhibitors for topoisomerases, with much more significant inhibition for topoisomerase II rather than topoisomerase I. The best inhibitor showed 20 times stronger anti-topoisomerase II activity than a positive control Etoposide. The cytotoxic activity of these MF derivatives was evaluated against human cancer cell lines CNE-2 and Glc-82, which showed that these compounds were potent antitumor agents. The structure-activity relationships (SARs) study revealed that o-quinone group and pyran ring are important for their cytotoxic activity.
|
Inhibition of cell proliferation of human HepG2 cells at 30 ug/mL after 48 hrs by Sulforhodamine B assay
|
Homo sapiens
|
92.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, structure-activity relationship and biological evaluation of anticancer activity for novel N-substituted sophoridinic acid derivatives.
Year : 2011
Volume : 21
Issue : 18
First Page : 5251
Last Page : 5254
Authors : Li X, Zhao WL, Jiang JD, Ren KH, Du NN, Li YB, Wang YX, Bi CW, Shao RG, Song DQ.
Abstract : Sophoridine (1), a natural anticancer drug, has been used in China for decades. A series of novel N-substituted sophoridinic acid derivatives were synthesized and evaluated for their cytotoxicity with 1 as the lead. The structure-activity relationship indicated that introduction of an aliphatic acyl on the nitrogen atom might significantly enhance the anticancer activity. Among the compounds, 6b bearing bromoacetyl side-chain afforded a potential effect against four human tumor cell lines (liver, colon, breast, and lung). The mechanism of action of 6b is to inhibit the activity of DNA topoisomerase I, followed by the S-phase arrest and then cause apoptotic cell death, similar to that of its parent 1. We consider 6b promising for further anticancer investigation.
|
Cytotoxicity against human HCT116 after 72 hrs by SRB assay
|
Homo sapiens
|
31.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of new homocamptothecin analogs.
Year : 2012
Volume : 54
First Page : 281
Last Page : 286
Authors : Luo Y, Yu S, Tong L, Huang Q, Lu W, Chen Y.
Abstract : In order to increase the stability of E-ring of homocamptothecins, the electron-withdrawing group -OH or -OAc was induced to α position of ring-E lactone. Ten new homocamptothecin analogs were synthesized. Most compounds showed potent in vitro anticancer activity and potent Topo I inhibition, which was equal or superior to that of CPT, SN-38 and 10-HCPT. The stability studies of this series also displayed significant improvement of the stability.
|
Cytotoxicity against human A549 after 72 hrs by SRB assay
|
Homo sapiens
|
33.6
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of new homocamptothecin analogs.
Year : 2012
Volume : 54
First Page : 281
Last Page : 286
Authors : Luo Y, Yu S, Tong L, Huang Q, Lu W, Chen Y.
Abstract : In order to increase the stability of E-ring of homocamptothecins, the electron-withdrawing group -OH or -OAc was induced to α position of ring-E lactone. Ten new homocamptothecin analogs were synthesized. Most compounds showed potent in vitro anticancer activity and potent Topo I inhibition, which was equal or superior to that of CPT, SN-38 and 10-HCPT. The stability studies of this series also displayed significant improvement of the stability.
|
Cytotoxicity against human PC3 cells expressing alpha5beta3 integrin assessed as cell survival after 72 hrs by SRB assay
|
Homo sapiens
|
78.0
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 A2780 cells overexpressing alpha5beta3 integrin assessed as cell survival after 72 hrs by SRB assay
|
Homo sapiens
|
4.0
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.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
-5.24
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of horse BChE at 2 mg/ml by Ellman's method
|
Equus caballus
|
6.63
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Cytotoxicity against human KB cells by MTT assay
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, cytotoxicity and topoisomerase II inhibitory activity of lomefloxacin derivatives.
Year : 2013
Volume : 23
Issue : 10
First Page : 2974
Last Page : 2978
Authors : Zhou Y, Xu X, Sun Y, Wang H, Sun H, You Q.
Abstract : A novel series of amide derivatives of lomefloxacin were synthesized and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against a panel of five human cancer cell lines. Of the compounds prepared compounds 9d and 9g exhibited strong inhibition against topoisomerase II at 100μM. In addition, docking studies were performed to predict the inhibition mode.
|
Cytotoxicity against human Bel7402 cells by MTT assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, cytotoxicity and topoisomerase II inhibitory activity of lomefloxacin derivatives.
Year : 2013
Volume : 23
Issue : 10
First Page : 2974
Last Page : 2978
Authors : Zhou Y, Xu X, Sun Y, Wang H, Sun H, You Q.
Abstract : A novel series of amide derivatives of lomefloxacin were synthesized and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against a panel of five human cancer cell lines. Of the compounds prepared compounds 9d and 9g exhibited strong inhibition against topoisomerase II at 100μM. In addition, docking studies were performed to predict the inhibition mode.
|
Cytotoxicity against human HCT116 cells by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, cytotoxicity and topoisomerase II inhibitory activity of lomefloxacin derivatives.
Year : 2013
Volume : 23
Issue : 10
First Page : 2974
Last Page : 2978
Authors : Zhou Y, Xu X, Sun Y, Wang H, Sun H, You Q.
Abstract : A novel series of amide derivatives of lomefloxacin were synthesized and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against a panel of five human cancer cell lines. Of the compounds prepared compounds 9d and 9g exhibited strong inhibition against topoisomerase II at 100μM. In addition, docking studies were performed to predict the inhibition mode.
|
Cytotoxicity against human MDA-MB-231 cells by MTT assay
|
Homo sapiens
|
60.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, cytotoxicity and topoisomerase II inhibitory activity of lomefloxacin derivatives.
Year : 2013
Volume : 23
Issue : 10
First Page : 2974
Last Page : 2978
Authors : Zhou Y, Xu X, Sun Y, Wang H, Sun H, You Q.
Abstract : A novel series of amide derivatives of lomefloxacin were synthesized and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against a panel of five human cancer cell lines. Of the compounds prepared compounds 9d and 9g exhibited strong inhibition against topoisomerase II at 100μM. In addition, docking studies were performed to predict the inhibition mode.
|
Cytotoxicity against human A549 cells by MTT assay
|
Homo sapiens
|
70.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, cytotoxicity and topoisomerase II inhibitory activity of lomefloxacin derivatives.
Year : 2013
Volume : 23
Issue : 10
First Page : 2974
Last Page : 2978
Authors : Zhou Y, Xu X, Sun Y, Wang H, Sun H, You Q.
Abstract : A novel series of amide derivatives of lomefloxacin were synthesized and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against a panel of five human cancer cell lines. Of the compounds prepared compounds 9d and 9g exhibited strong inhibition against topoisomerase II at 100μM. In addition, docking studies were performed to predict the inhibition mode.
|
Cytotoxicity against human A375 cells after 72 hrs by sulforhodamine B assay
|
Homo sapiens
|
150.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antitumor activities of naturally occurring oleanolic acid triterpenoid saponins and their derivatives.
Year : 2013
Volume : 64
First Page : 1
Last Page : 15
Authors : Liu Q, Liu H, Zhang L, Guo T, Wang P, Geng M, Li Y.
Abstract : Twenty-six naturally occurring oleanolic acid saponins and their derivatives, 16 of which were synthesized in this study, were preliminarily evaluated against human cancer cells. From SAR studies, the presence of α-l-rhamnosyl residue at the terminal of both C-3 and C-28 position for oleanolic acid bidesmosides was important to enhance cytotoxicity, and introducing more sugar residues at C3-OH of compound 12 with C-28 carboxylic acid is a favorable modification to ameliorate the anticancer activity. Furthermore, α-l-rhamnosyl moiety linked to C2-OH of the first monosaccharide (α-l-alabinose, β-d-xylose, β-d-galactose or β-d-glucose) in C3-OH of oleanolic acid was helpful to improve the cytotoxicity. According to the predicted log P values, lipophilicity of the synthesized saponins was not an important factor for cytotoxicity.
|
Cytotoxicity against human A549 cells after 72 hrs by sulforhodamine B assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antitumor activities of naturally occurring oleanolic acid triterpenoid saponins and their derivatives.
Year : 2013
Volume : 64
First Page : 1
Last Page : 15
Authors : Liu Q, Liu H, Zhang L, Guo T, Wang P, Geng M, Li Y.
Abstract : Twenty-six naturally occurring oleanolic acid saponins and their derivatives, 16 of which were synthesized in this study, were preliminarily evaluated against human cancer cells. From SAR studies, the presence of α-l-rhamnosyl residue at the terminal of both C-3 and C-28 position for oleanolic acid bidesmosides was important to enhance cytotoxicity, and introducing more sugar residues at C3-OH of compound 12 with C-28 carboxylic acid is a favorable modification to ameliorate the anticancer activity. Furthermore, α-l-rhamnosyl moiety linked to C2-OH of the first monosaccharide (α-l-alabinose, β-d-xylose, β-d-galactose or β-d-glucose) in C3-OH of oleanolic acid was helpful to improve the cytotoxicity. According to the predicted log P values, lipophilicity of the synthesized saponins was not an important factor for cytotoxicity.
|
Cytotoxicity against human HL60 cells after 72 hrs by MTT assay
|
Homo sapiens
|
250.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antitumor activities of naturally occurring oleanolic acid triterpenoid saponins and their derivatives.
Year : 2013
Volume : 64
First Page : 1
Last Page : 15
Authors : Liu Q, Liu H, Zhang L, Guo T, Wang P, Geng M, Li Y.
Abstract : Twenty-six naturally occurring oleanolic acid saponins and their derivatives, 16 of which were synthesized in this study, were preliminarily evaluated against human cancer cells. From SAR studies, the presence of α-l-rhamnosyl residue at the terminal of both C-3 and C-28 position for oleanolic acid bidesmosides was important to enhance cytotoxicity, and introducing more sugar residues at C3-OH of compound 12 with C-28 carboxylic acid is a favorable modification to ameliorate the anticancer activity. Furthermore, α-l-rhamnosyl moiety linked to C2-OH of the first monosaccharide (α-l-alabinose, β-d-xylose, β-d-galactose or β-d-glucose) in C3-OH of oleanolic acid was helpful to improve the cytotoxicity. According to the predicted log P values, lipophilicity of the synthesized saponins was not an important factor for cytotoxicity.
|
Antiproliferative activity against human HepG2 cells after 48 hrs by CCK8 assay
|
Homo sapiens
|
499.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor.
Year : 2015
Volume : 23
Issue : 1
First Page : 118
Last Page : 125
Authors : Tan H, Wang G, Li J, Meng G, Liu Z, Dong M, Li Y, Ju D, Zhang Q.
Abstract : A series of 9-(alkylthiomethyl)-10-hydroxycamptothecins and pyrano-fused camptothecin derivatives were synthesized via the reaction of topotecan hydrochloride with various thiols and alkyl vinyl ethers respectively. In the reactions, topotecan hydrochloride was utilized as ortho-quinonemethide (o-QM) precursor. The configuration of 19 was determined by (1)H NMR and NOESY spectra as syn-isomers, suggesting that the cycloaddition of topotecan with alkyl vinyl ethers could undergo a hetero Diels-Alder reaction. All the synthesized compounds were screened on cancer cell lines HepG2, KB, HCT-8 and SGC7901. Some compounds were selected to assess their inhibitory activity against Topo I via Topo I mediated DNA cleavage assays. The results showed that among those tested 9-(alkylthiomethyl)-10-hydroxycamptothecins, the compounds with bulkier hydrophobic side chains at 9-position have better bioactivities. As well as all pyrano-fused camptothecins possess antiproliferative activity against the tested cancer cell lines. Docking studies suggested that there are more interactions between the novel analogues and the binding site of Topo I.
|
Antiproliferative activity against human KB cells after 48 hrs by CCK8 assay
|
Homo sapiens
|
128.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor.
Year : 2015
Volume : 23
Issue : 1
First Page : 118
Last Page : 125
Authors : Tan H, Wang G, Li J, Meng G, Liu Z, Dong M, Li Y, Ju D, Zhang Q.
Abstract : A series of 9-(alkylthiomethyl)-10-hydroxycamptothecins and pyrano-fused camptothecin derivatives were synthesized via the reaction of topotecan hydrochloride with various thiols and alkyl vinyl ethers respectively. In the reactions, topotecan hydrochloride was utilized as ortho-quinonemethide (o-QM) precursor. The configuration of 19 was determined by (1)H NMR and NOESY spectra as syn-isomers, suggesting that the cycloaddition of topotecan with alkyl vinyl ethers could undergo a hetero Diels-Alder reaction. All the synthesized compounds were screened on cancer cell lines HepG2, KB, HCT-8 and SGC7901. Some compounds were selected to assess their inhibitory activity against Topo I via Topo I mediated DNA cleavage assays. The results showed that among those tested 9-(alkylthiomethyl)-10-hydroxycamptothecins, the compounds with bulkier hydrophobic side chains at 9-position have better bioactivities. As well as all pyrano-fused camptothecins possess antiproliferative activity against the tested cancer cell lines. Docking studies suggested that there are more interactions between the novel analogues and the binding site of Topo I.
|
Antiproliferative activity against human HCT8 cells after 48 hrs by CCK8 assay
|
Homo sapiens
|
181.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor.
Year : 2015
Volume : 23
Issue : 1
First Page : 118
Last Page : 125
Authors : Tan H, Wang G, Li J, Meng G, Liu Z, Dong M, Li Y, Ju D, Zhang Q.
Abstract : A series of 9-(alkylthiomethyl)-10-hydroxycamptothecins and pyrano-fused camptothecin derivatives were synthesized via the reaction of topotecan hydrochloride with various thiols and alkyl vinyl ethers respectively. In the reactions, topotecan hydrochloride was utilized as ortho-quinonemethide (o-QM) precursor. The configuration of 19 was determined by (1)H NMR and NOESY spectra as syn-isomers, suggesting that the cycloaddition of topotecan with alkyl vinyl ethers could undergo a hetero Diels-Alder reaction. All the synthesized compounds were screened on cancer cell lines HepG2, KB, HCT-8 and SGC7901. Some compounds were selected to assess their inhibitory activity against Topo I via Topo I mediated DNA cleavage assays. The results showed that among those tested 9-(alkylthiomethyl)-10-hydroxycamptothecins, the compounds with bulkier hydrophobic side chains at 9-position have better bioactivities. As well as all pyrano-fused camptothecins possess antiproliferative activity against the tested cancer cell lines. Docking studies suggested that there are more interactions between the novel analogues and the binding site of Topo I.
|
Antiproliferative activity against human SGC7901 cells after 48 hrs by CCK8 assay
|
Homo sapiens
|
835.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor.
Year : 2015
Volume : 23
Issue : 1
First Page : 118
Last Page : 125
Authors : Tan H, Wang G, Li J, Meng G, Liu Z, Dong M, Li Y, Ju D, Zhang Q.
Abstract : A series of 9-(alkylthiomethyl)-10-hydroxycamptothecins and pyrano-fused camptothecin derivatives were synthesized via the reaction of topotecan hydrochloride with various thiols and alkyl vinyl ethers respectively. In the reactions, topotecan hydrochloride was utilized as ortho-quinonemethide (o-QM) precursor. The configuration of 19 was determined by (1)H NMR and NOESY spectra as syn-isomers, suggesting that the cycloaddition of topotecan with alkyl vinyl ethers could undergo a hetero Diels-Alder reaction. All the synthesized compounds were screened on cancer cell lines HepG2, KB, HCT-8 and SGC7901. Some compounds were selected to assess their inhibitory activity against Topo I via Topo I mediated DNA cleavage assays. The results showed that among those tested 9-(alkylthiomethyl)-10-hydroxycamptothecins, the compounds with bulkier hydrophobic side chains at 9-position have better bioactivities. As well as all pyrano-fused camptothecins possess antiproliferative activity against the tested cancer cell lines. Docking studies suggested that there are more interactions between the novel analogues and the binding site of Topo I.
|
Antiproliferative activity against human A549 cells after 48 hrs by MTT assay
|
Homo sapiens
|
82.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological evaluation of 3-substituted indenoisoquinoline derivatives as topoisomerase I inhibitors.
Year : 2016
Volume : 26
Issue : 3
First Page : 1068
Last Page : 1072
Authors : Zhao Q, Xu X, Xie Z, Liu X, You Q, Guo Q, Zhong Y, Li Z.
Abstract : A new series of indenoisoquinoline derivatives was designed and synthesized. The in vitro anti-proliferative activity of these novel compounds was evaluated in HepG2, A549 and HCT-116 cell lines. Compounds 9a, 9b, 10a, 10c, 10e, 18a and 18b manifested potent inhibitory activity against the three tested cancer cell lines. Nineteen compounds were also tested for Top I inhibition at 50 μM. Almost all the tested compounds showed potent Top I inhibition activity at this concentration. The most potent compounds 9a and 10a demonstrated more cytotoxicity than HCPT and TPT and was comparable to CPT in inhibitory activities on Top I in our biological assay.
|
Antiproliferative activity against human A549 cells after 48 hrs by MTT assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, facile synthesis and biological evaluations of novel pyrano[3,2-a]phenazine hybrid molecules as antitumor agents.
Year : 2017
Volume : 127
First Page : 928
Last Page : 943
Authors : Lu Y, Yan Y, Wang L, Wang X, Gao J, Xi T, Wang Z, Jiang F.
Abstract : A series of novel pyrano[3,2-a]phenazine derivatives (1a-1r and 2a-2q), designed as hybrid molecules of phenazine and pyran pharmocophores, were facilely synthesized in two steps with 77-93% overall yields in this study. Cytotoxic evaluation indicates that many compounds exhibited cytotoxicity against HCT116, MCF7, HepG2 and A549 cancer cell lines in vitro, in which compounds 1c, 1i, 2e, and 2l were found to have excellent antiproliferative activity against the HepG2 cancer cell line. Thus, inhibitory effect of subcutaneously implanted xenografted mice in vivo (H22H8D8 cells) of the four compounds as well as topoisomerase I and IIα inhibitory activities in vitro (HepG2 cells) were determined. Significantly, compound 1i showed more potent than positive control drug both in vivo and in vitro. Further mechanism studies against HepG2 cells in vitro revealed that compound 1i up-regulated the expression of both p53 and p21, which inhibited the expression of both cyclin B and CDK1, and arrested HepG2 cells in the G2/M phase. Concomitantly, after treating with compound 1i, Bax/Bcl-2 ratio was significantly increased, the cytochrome C was released from mitochondria to cytosol, and the cleavage of caspase-3 and caspase-9 expression levels were both increased. Together, all these evidences implicated that compound 1i acts as topoisomerase I and IIα dual inhibitor, cell cycle arrester and apoptosis inducer against HepG2 cells.
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Antiproliferative activity against human A549 cells after 48 hrs by MTT assay
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Homo sapiens
|
800.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, combinatorial synthesis and biological evaluations of novel 3-amino-1'-((1-aryl-1H-1,2,3-triazol-5-yl)methyl)-2'-oxospiro[benzo[a] pyrano[2,3-c]phenazine-1,3'-indoline]-2-carbonitrile antitumor hybrid molecules.
Year : 2017
Volume : 135
First Page : 125
Last Page : 141
Authors : Lu Y, Wang L, Wang X, Xi T, Liao J, Wang Z, Jiang F.
Abstract : A combinatorial chemical library of fifty-nine novel 3-amino-1'-((1-aryl-1H-1,2,3-triazol-5-yl)methyl)-2'-oxospiro[benzo[a]pyrano[2,3-c]phenazine-1,3'-indoline]-2-carbonitrile, designed as hybrid molecules of phenazine, pyran, indole and 1,2,3-triazole pharmacophores, were constructed in this study. Cytotoxic evaluation indicated that some compounds exhibited moderate cytotoxicity against HCT116, MCF7, HepG2 and A549 cancer cell lines in vitro, in which compound 36 was found to have best antiproliferative activity against the A549 cancer cell line with IC50 value of 5.4 μM. All compounds had low or no effect against L02 and HUVEC non-cancer cell lines. Compound 36 was further confirmed to mainly locate mitochondria in A549 cancer cells via laser-scanning confocal microscopy. Moreover, compound 36 was proved to increase ROS production and induce cell cycle arrest in S phase. Western blot analysis illustrated Bax/Bcl-2 ratio was increased at dose-dependent manner, and both cleaved caspase-3 and cleaved caspase-9 was enhanced by treated with compound 36. All the above evidences in vitro indicated that compound 36 might induce the apoptosis of A549 cancer cells via a mitochondria-dependent pathway.
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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
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Homo sapiens
|
-9.33
%
|
|
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.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-10.86
%
|
|
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.
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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
|
-0.16
%
|
|
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
|
-0.16
%
|
|
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.
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Cytotoxicity against human A549 assessed as reduction in cell viability measured after 72 hrs by MTT assay
|
Homo sapiens
|
80.0
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
|
21.0
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
|
330.0
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.
