|
Cytotoxic activity against human lymphoblast tumor cell line RPMI8402 after 4 days of treatment
|
Homo sapiens
|
570.0
nM
|
|
Journal : J. Med. Chem.
Title : Nitro and amino substitution in the D-ring of 5-(2-dimethylaminoethyl)- 2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-ones: effect on topoisomerase-I targeting activity and cytotoxicity.
Year : 2003
Volume : 46
Issue : 11
First Page : 2254
Last Page : 2257
Authors : Singh SK, Ruchelman AL, Li TK, Liu A, Liu LF, LaVoie EJ.
Abstract : 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one exhibits potent TOP1-targeting activity and pronounced antitumor activity. It was hypothesized that replacement of the two methoxyl groups with a nitro substituent would allow for retention of similar activity. In this study 8-, 9-, and 10-nitro-5H-2,3-methylenedioxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-one and their amino derivatives were synthesized and assessed for their relative TOP1-targeting activity and cytotoxicity. In the case of both the 8- and 9-nitro analogues, their TOP1-targeting activity and cytotoxicity are greater than that of camptothecin and comparable to that of 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one.
|
Growth inhibition of human T24 cells after 4 days by MTT assay
|
Homo sapiens
|
23.8
%
|
|
Journal : Eur. J. Med. Chem.
Title : First synthesis of novel spin-labeled derivatives of camptothecin as potential antineoplastic agents.
Year : 2008
Volume : 43
Issue : 11
First Page : 2610
Last Page : 2614
Authors : Liu YQ, Tian X, Yang L, Zhan ZC.
Abstract : In an effort to improve the stability of labile lactone ring and water solubility of camptothecin, five novel spin-labeled camptothecin derivatives were synthesized in quantitative yield by a simple modification of the carbodiimide method using the combination of scandium triflate (Sc(OTf)(3)) and 4-dimethylaminopyridine (DMAP), and the in vitro pharmacokinetic determination of the lactones of representative compound 13a showed that the biological life span of their lactone forms in human and mouse plasma significantly increased when compared with their mother compound camptothecin. Also, the in vitro cytotoxicity of compounds 13a-13e against human bladder cancer T-24 showed either similar or better activity than that of the parent drug, camptothecin, and clinically available drug, irinotecan.
|
Inhibition of Torpedo californica AChE
|
Torpedo californica
|
26.4
nM
|
|
Journal : J. Med. Chem.
Title : Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors.
Year : 2008
Volume : 51
Issue : 11
First Page : 3154
Last Page : 3170
Authors : Butini S, Campiani G, Borriello M, Gemma S, Panico A, Persico M, Catalanotti B, Ros S, Brindisi M, Agnusdei M, Fiorini I, Nacci V, Novellino E, Belinskaya T, Saxena A, Fattorusso C.
Abstract : Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
|
Inhibition of human AChE
|
Homo sapiens
|
50.5
nM
|
|
Journal : J. Med. Chem.
Title : Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors.
Year : 2008
Volume : 51
Issue : 11
First Page : 3154
Last Page : 3170
Authors : Butini S, Campiani G, Borriello M, Gemma S, Panico A, Persico M, Catalanotti B, Ros S, Brindisi M, Agnusdei M, Fiorini I, Nacci V, Novellino E, Belinskaya T, Saxena A, Fattorusso C.
Abstract : Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
|
Cytotoxicity against human KB3-1 cells by MTT method
|
Homo sapiens
|
680.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 11-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine derivatives as novel topoisomerase I-targeting agents.
Year : 2008
Volume : 16
Issue : 18
First Page : 8598
Last Page : 8606
Authors : Feng W, Satyanarayana M, Tsai YC, Liu AA, Liu LF, LaVoie EJ.
Abstract : Several 11-substituted benzo[i]phenanthridine derivatives were synthesized, and their TOP1-targeting activity and cytotoxicity were assessed. Comparative data indicate that TOP1-targeting was often the primary molecular target associated with their cytotoxicity. Several 11-aminoalkyl derivatives, 11-aminocarboxy derivatives as well as the 11-[(2-dimethylamino)ethyl]carboxamide of 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine were synthesized and did exhibit considerable cytotoxicity with IC(50) values ranging from 20 to 120 nM in the human lymphoblast tumor cell line RPMI8402.
|
Antitumor activity against human SJSA1 cells xenografted in mouse assessed as tumor growth inhibition at 100 mg/kg, ip dosed once weekly for two weeks relative to untreated control
|
Homo sapiens
|
0.0002
%
|
|
Journal : J. Med. Chem.
Title : Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction.
Year : 2009
Volume : 52
Issue : 24
First Page : 7970
Last Page : 7973
Authors : Yu S, Qin D, Shangary S, Chen J, Wang G, Ding K, Ding K, McEachern D, Qiu S, Nikolovska-Coleska Z, Miller R, Kang S, Yang D, Wang S.
Abstract : We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.
|
Cytotoxicity against human H460 cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human PC3 cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human HT-29 cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human SK-MEL-2 cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human A375 cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human MALME-3M cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human DU145 cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human LNCAP cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human IGROV1 cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human H460 cells after 72 hrs by alamar blue assay in presence of 40 mg/ml HSA
|
Homo sapiens
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human MESSA cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human MES-SA/Dx5 cells overexpressing MDR1 after 72 hrs by alamar blue assay
|
Homo sapiens
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human H69 cells after 72 hrs by alamar blue assay
|
Homo sapiens
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human H69AR cells overexpressing MDR1 after 72 hrs by alamar blue assay
|
Homo sapiens
|
250.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against human bone marrow cell by CFU-GM assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
Cytotoxicity against mouse bone marrow cell by CFU-GM assay
|
Mus musculus
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
Year : 2011
Volume : 54
Issue : 6
First Page : 1715
Last Page : 1723
Authors : Duan JX, Cai X, Meng F, Sun JD, Liu Q, Jung D, Jiao H, Matteucci J, Jung B, Bhupathi D, Ahluwalia D, Huang H, Hart CP, Matteucci M.
Abstract : 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
|
DRUGMATRIX: Muscarinic M4 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
217.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
461.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
40.5
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
26.9
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
16.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human MATE1-mediated ASP+ uptake expressed in HEK293 cells at 20 uM after 1.5 mins by fluorescence assay
|
Homo sapiens
|
49.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling.
Year : 2013
Volume : 56
Issue : 3
First Page : 781
Last Page : 795
Authors : Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM.
Abstract : The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug-drug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP(+) uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.
|
Inhibition of human OATP1B3-mediated [3H]CCK-8 at 100 uM after 5 mins relative to control
|
Homo sapiens
|
34.3
%
|
|
Journal : Eur. J. Med. Chem.
Title : Interaction of human organic anion transporter polypeptides 1B1 and 1B3 with antineoplastic compounds.
Year : 2015
Volume : 92
First Page : 723
Last Page : 731
Authors : Marada VV, Flörl S, Kühne A, Burckhardt G, Hagos Y.
Abstract : Antineoplastic compounds are used in the treatment of a variety of cancers. The effectiveness of an antineoplastic compound to exert its activity is largely dependent on transport proteins involved in the entry of the compound into the cells, and those which drive it out of the cell. Organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), belonging to the SLCO family of proteins, are specifically expressed in the sinusoidal membranes of the liver, and are known to interact with a variety of drugs. The present study deals with the interaction of these proteins with antineoplastic compounds routinely used in cancer chemotherapy. The proteins OATP1B1 and OATP1B3 were functionally characterized in stably transfected human embryonic kidney cells using [(3)H] labeled estrone 3-sulfate and [(3)H] labeled cholecystokinin octapeptide (CCK-8) as substrates, respectively. Substrate uptake experiments performed in the presence of antineoplastic compounds showed that vinblastine and paclitaxel strongly interacted with the OATP1B1 with Ki values of 10.2 μM and 0.84 μM, respectively. OATP1B3 showed highly significant interactions with a variety of antineoplastic compounds including chlorambucil, mitoxantrone, vinblastine, vincristine, paclitaxel and etoposide, with Ki values of 40.6 μM, 3.2 μM, 15.9 μM, 30.6 μM, 1.8 μM and 13.5 μM, respectively. We report several novel interactions of the transporter proteins OATP1B1 and OATP1B3 highlighting the need to investigate their role in drug-drug interactions and cancer chemotherapy.
|
Antiproliferative activity against human MCF7 cells assessed as cellular DNA content after 96 hrs by CyQUANT NF fluorescence assay
|
Homo sapiens
|
900.0
nM
|
|
Journal : J. Nat. Prod.
Title : Amorfrutin C Induces Apoptosis and Inhibits Proliferation in Colon Cancer Cells through Targeting Mitochondria.
Year : 2016
Volume : 79
Issue : 1
First Page : 2
Last Page : 12
Authors : Weidner C, Rousseau M, Micikas RJ, Fischer C, Plauth A, Wowro SJ, Siems K, Hetterling G, Kliem M, Schroeder FC, Sauer S.
Abstract : A known (1) and a structurally related new natural product (2), both belonging to the amorfrutin benzoic acid class, were isolated from the roots of Glycyrrhiza foetida. Compound 1 (amorfrutin B) is an efficient agonist of the nuclear peroxisome proliferator activated receptor (PPAR) gamma and of other PPAR subtypes. Compound 2 (amorfrutin C) showed comparably lower PPAR activation potential. Amorfrutin C exhibited striking antiproliferative effects for human colorectal cancer cells (HT-29 and T84), prostate cancer (PC-3), and breast cancer (MCF7) cells (IC50 values ranging from 8 to 16 μM in these cancer cell lines). Notably, amorfrutin C (2) showed less potent antiproliferative effects in primary colon cells. For HT-29 cells, compound 2 induced G0/G1 cell cycle arrest and modulated protein expression of key cell cycle modulators. Amorfrutin C further induced apoptotic events in HT-29 cells, including caspase activation, DNA fragmentation, PARP cleavage, phosphatidylserine externalization, and formation of reactive oxygen species. Mechanistic studies revealed that 2 disrupts the mitochondrial integrity by depolarization of the mitochondrial membrane (IC50 0.6 μM) and permanent opening of the mitochondrial permeability transition pore, leading to increased mitochondrial oxygen consumption and extracellular acidification. Structure-activity-relationship experiments revealed the carboxylic acid and the hydroxy group residues of 2 as fundamental structural requirements for inducing these apoptotic effects. Synergy analyses demonstrated stimulation of the death receptor signaling pathway. Taken together, amorfrutin C (2) represents a promising lead for the development of anticancer drugs.
|
Antiproliferative activity against human PC3 cells assessed as cellular DNA content after 72 hrs by CyQUANT NF fluorescence assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : J. Nat. Prod.
Title : Amorfrutin C Induces Apoptosis and Inhibits Proliferation in Colon Cancer Cells through Targeting Mitochondria.
Year : 2016
Volume : 79
Issue : 1
First Page : 2
Last Page : 12
Authors : Weidner C, Rousseau M, Micikas RJ, Fischer C, Plauth A, Wowro SJ, Siems K, Hetterling G, Kliem M, Schroeder FC, Sauer S.
Abstract : A known (1) and a structurally related new natural product (2), both belonging to the amorfrutin benzoic acid class, were isolated from the roots of Glycyrrhiza foetida. Compound 1 (amorfrutin B) is an efficient agonist of the nuclear peroxisome proliferator activated receptor (PPAR) gamma and of other PPAR subtypes. Compound 2 (amorfrutin C) showed comparably lower PPAR activation potential. Amorfrutin C exhibited striking antiproliferative effects for human colorectal cancer cells (HT-29 and T84), prostate cancer (PC-3), and breast cancer (MCF7) cells (IC50 values ranging from 8 to 16 μM in these cancer cell lines). Notably, amorfrutin C (2) showed less potent antiproliferative effects in primary colon cells. For HT-29 cells, compound 2 induced G0/G1 cell cycle arrest and modulated protein expression of key cell cycle modulators. Amorfrutin C further induced apoptotic events in HT-29 cells, including caspase activation, DNA fragmentation, PARP cleavage, phosphatidylserine externalization, and formation of reactive oxygen species. Mechanistic studies revealed that 2 disrupts the mitochondrial integrity by depolarization of the mitochondrial membrane (IC50 0.6 μM) and permanent opening of the mitochondrial permeability transition pore, leading to increased mitochondrial oxygen consumption and extracellular acidification. Structure-activity-relationship experiments revealed the carboxylic acid and the hydroxy group residues of 2 as fundamental structural requirements for inducing these apoptotic effects. Synergy analyses demonstrated stimulation of the death receptor signaling pathway. Taken together, amorfrutin C (2) represents a promising lead for the development of anticancer drugs.
|
Cytotoxicity against human HepG2 cells assessed as reduction in cell viability after 24 hrs by MTS assay
|
Homo sapiens
|
900.0
nM
|
|
Journal : J. Nat. Prod.
Title : Bioactive Constituents of Glycyrrhiza uralensis (Licorice): Discovery of the Effective Components of a Traditional Herbal Medicine.
Year : 2016
Volume : 79
Issue : 2
First Page : 281
Last Page : 292
Authors : Ji S, Li Z, Song W, Wang Y, Liang W, Li K, Tang S, Wang Q, Qiao X, Zhou D, Yu S, Ye M.
Abstract : Traditional herbal medicines have been reported to possess significant bioactivities. In this investigation, a combined strategy using both phytochemical and biological approaches was conducted to discern the effective components of licorice, a widely used herbal medicine. Altogether, 122 compounds (1-122), including six new structures (1-6), were isolated and identified from the roots and rhizomes of Glycyrrhiza uralensis (licorice). These compounds were then screened using 11 cell- and enzyme-based bioassay methods, including Nrf2 activation, NO inhibition, NF-κB inhibition, H1N1 virus inhibition, cytotoxicity for cancer cells (HepG2, SW480, A549, MCF7), PTP1B inhibition, tyrosinase inhibition, and AChE inhibition. A number of bioactive compounds, particularly isoprenylated phenolics, were found for the first time. Echinatin (7), a potent Nrf2 activator, was selected as an example for further biological work. It attenuated CCl4-induced liver damage in mice (5 or 10 mg/kg, ip) and thus is responsible, at least in part, for the hepatoprotective activity of licorice.
|
Cytotoxicity against human A549 cells assessed as reduction in cell viability after 24 hrs by MTS assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : J. Nat. Prod.
Title : Bioactive Constituents of Glycyrrhiza uralensis (Licorice): Discovery of the Effective Components of a Traditional Herbal Medicine.
Year : 2016
Volume : 79
Issue : 2
First Page : 281
Last Page : 292
Authors : Ji S, Li Z, Song W, Wang Y, Liang W, Li K, Tang S, Wang Q, Qiao X, Zhou D, Yu S, Ye M.
Abstract : Traditional herbal medicines have been reported to possess significant bioactivities. In this investigation, a combined strategy using both phytochemical and biological approaches was conducted to discern the effective components of licorice, a widely used herbal medicine. Altogether, 122 compounds (1-122), including six new structures (1-6), were isolated and identified from the roots and rhizomes of Glycyrrhiza uralensis (licorice). These compounds were then screened using 11 cell- and enzyme-based bioassay methods, including Nrf2 activation, NO inhibition, NF-κB inhibition, H1N1 virus inhibition, cytotoxicity for cancer cells (HepG2, SW480, A549, MCF7), PTP1B inhibition, tyrosinase inhibition, and AChE inhibition. A number of bioactive compounds, particularly isoprenylated phenolics, were found for the first time. Echinatin (7), a potent Nrf2 activator, was selected as an example for further biological work. It attenuated CCl4-induced liver damage in mice (5 or 10 mg/kg, ip) and thus is responsible, at least in part, for the hepatoprotective activity of licorice.
|
Cytotoxicity against human MCF7 cells assessed as reduction in cell viability after 24 hrs by MTS assay
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Nat. Prod.
Title : Bioactive Constituents of Glycyrrhiza uralensis (Licorice): Discovery of the Effective Components of a Traditional Herbal Medicine.
Year : 2016
Volume : 79
Issue : 2
First Page : 281
Last Page : 292
Authors : Ji S, Li Z, Song W, Wang Y, Liang W, Li K, Tang S, Wang Q, Qiao X, Zhou D, Yu S, Ye M.
Abstract : Traditional herbal medicines have been reported to possess significant bioactivities. In this investigation, a combined strategy using both phytochemical and biological approaches was conducted to discern the effective components of licorice, a widely used herbal medicine. Altogether, 122 compounds (1-122), including six new structures (1-6), were isolated and identified from the roots and rhizomes of Glycyrrhiza uralensis (licorice). These compounds were then screened using 11 cell- and enzyme-based bioassay methods, including Nrf2 activation, NO inhibition, NF-κB inhibition, H1N1 virus inhibition, cytotoxicity for cancer cells (HepG2, SW480, A549, MCF7), PTP1B inhibition, tyrosinase inhibition, and AChE inhibition. A number of bioactive compounds, particularly isoprenylated phenolics, were found for the first time. Echinatin (7), a potent Nrf2 activator, was selected as an example for further biological work. It attenuated CCl4-induced liver damage in mice (5 or 10 mg/kg, ip) and thus is responsible, at least in part, for the hepatoprotective activity of licorice.
|
Antiproliferative activity against human HepG2 cells at 10 uM after 24 hrs by MTS assay relative to control
|
Homo sapiens
|
98.9
%
|
|
Journal : J Nat Prod
Title : Glycybridins A-K, Bioactive Phenolic Compounds from Glycyrrhiza glabra.
Year : 2017
Volume : 80
Issue : 2
First Page : 334
Last Page : 346
Authors : Li K, Ji S, Song W, Kuang Y, Lin Y, Tang S, Cui Z, Qiao X, Yu S, Ye M.
Abstract : In an attempt to discover bioactive agents from the herbal medicine Glycyrrhiza glabra (widely known as licorice), 11 new phenolic compounds, glycybridins A-K (1-11), along with 47 known phenolics (12-58) were isolated. Their structures were elucidated on the basis of extensive NMR and MS analyses as well as experimental and computed ECD data. According to the clinical therapeutic effects of licorice, enzyme or cell-based bioactivity screenings of 1-58 were conducted. A number of compounds significantly activate Nrf2, inhibit tyrosinase or PTP1B, inhibit LPS-induced NO production and NF-κB transcription, and inhibit the proliferation of human cancer cells (HepG2, SW480, A549, MCF7). Glycybridin D (4) showed moderate cytotoxic activities against the four cancer cell lines, with IC50 values ranging from 4.6 to 6.6 μM. Further studies indicated that 4 (10 mg/kg, ip) decreased tumor mass by 39.7% on an A549 human lung carcinoma xenograft mice model, but showed little toxicity.
|
Antiproliferative activity against human A549 cells at 10 uM after 24 hrs by MTS assay relative to control
|
Homo sapiens
|
91.8
%
|
|
Journal : J Nat Prod
Title : Glycybridins A-K, Bioactive Phenolic Compounds from Glycyrrhiza glabra.
Year : 2017
Volume : 80
Issue : 2
First Page : 334
Last Page : 346
Authors : Li K, Ji S, Song W, Kuang Y, Lin Y, Tang S, Cui Z, Qiao X, Yu S, Ye M.
Abstract : In an attempt to discover bioactive agents from the herbal medicine Glycyrrhiza glabra (widely known as licorice), 11 new phenolic compounds, glycybridins A-K (1-11), along with 47 known phenolics (12-58) were isolated. Their structures were elucidated on the basis of extensive NMR and MS analyses as well as experimental and computed ECD data. According to the clinical therapeutic effects of licorice, enzyme or cell-based bioactivity screenings of 1-58 were conducted. A number of compounds significantly activate Nrf2, inhibit tyrosinase or PTP1B, inhibit LPS-induced NO production and NF-κB transcription, and inhibit the proliferation of human cancer cells (HepG2, SW480, A549, MCF7). Glycybridin D (4) showed moderate cytotoxic activities against the four cancer cell lines, with IC50 values ranging from 4.6 to 6.6 μM. Further studies indicated that 4 (10 mg/kg, ip) decreased tumor mass by 39.7% on an A549 human lung carcinoma xenograft mice model, but showed little toxicity.
|
Antiproliferative activity against human MCF7 cells at 10 uM after 24 hrs by MTS assay relative to control
|
Homo sapiens
|
93.6
%
|
|
Journal : J Nat Prod
Title : Glycybridins A-K, Bioactive Phenolic Compounds from Glycyrrhiza glabra.
Year : 2017
Volume : 80
Issue : 2
First Page : 334
Last Page : 346
Authors : Li K, Ji S, Song W, Kuang Y, Lin Y, Tang S, Cui Z, Qiao X, Yu S, Ye M.
Abstract : In an attempt to discover bioactive agents from the herbal medicine Glycyrrhiza glabra (widely known as licorice), 11 new phenolic compounds, glycybridins A-K (1-11), along with 47 known phenolics (12-58) were isolated. Their structures were elucidated on the basis of extensive NMR and MS analyses as well as experimental and computed ECD data. According to the clinical therapeutic effects of licorice, enzyme or cell-based bioactivity screenings of 1-58 were conducted. A number of compounds significantly activate Nrf2, inhibit tyrosinase or PTP1B, inhibit LPS-induced NO production and NF-κB transcription, and inhibit the proliferation of human cancer cells (HepG2, SW480, A549, MCF7). Glycybridin D (4) showed moderate cytotoxic activities against the four cancer cell lines, with IC50 values ranging from 4.6 to 6.6 μM. Further studies indicated that 4 (10 mg/kg, ip) decreased tumor mass by 39.7% on an A549 human lung carcinoma xenograft mice model, but showed little toxicity.
|
Antiproliferative activity against human SW480 cells at 10 uM after 24 hrs by MTS assay relative to control
|
Homo sapiens
|
95.0
%
|
|
Journal : J Nat Prod
Title : Glycybridins A-K, Bioactive Phenolic Compounds from Glycyrrhiza glabra.
Year : 2017
Volume : 80
Issue : 2
First Page : 334
Last Page : 346
Authors : Li K, Ji S, Song W, Kuang Y, Lin Y, Tang S, Cui Z, Qiao X, Yu S, Ye M.
Abstract : In an attempt to discover bioactive agents from the herbal medicine Glycyrrhiza glabra (widely known as licorice), 11 new phenolic compounds, glycybridins A-K (1-11), along with 47 known phenolics (12-58) were isolated. Their structures were elucidated on the basis of extensive NMR and MS analyses as well as experimental and computed ECD data. According to the clinical therapeutic effects of licorice, enzyme or cell-based bioactivity screenings of 1-58 were conducted. A number of compounds significantly activate Nrf2, inhibit tyrosinase or PTP1B, inhibit LPS-induced NO production and NF-κB transcription, and inhibit the proliferation of human cancer cells (HepG2, SW480, A549, MCF7). Glycybridin D (4) showed moderate cytotoxic activities against the four cancer cell lines, with IC50 values ranging from 4.6 to 6.6 μM. Further studies indicated that 4 (10 mg/kg, ip) decreased tumor mass by 39.7% on an A549 human lung carcinoma xenograft mice model, but showed little toxicity.
|
Antiproliferative activity against human Maver2 cells after 72 hrs by MTT assay
|
Homo sapiens
|
740.0
nM
|
|
Journal : Eur J Med Chem
Title : Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors.
Year : 2018
Volume : 143
First Page : 2005
Last Page : 2014
Authors : Cincinelli R, Musso L, Artali R, Guglielmi M, Bianchino E, Cardile F, Colelli F, Pisano C, Dallavalle S.
Abstract : Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.
|
Antitumor activity against human MM473 cells xenografted in CD1 nude mouse assessed as inhibition of tumor volume at 20 mg/kg, iv administered every 4 days per week for 3 weeks measured 10 days post last dose by luciferase reporter assay relative to vehicle-treated control
|
Homo sapiens
|
37.0
%
|
|
Journal : Eur J Med Chem
Title : Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors.
Year : 2018
Volume : 143
First Page : 2005
Last Page : 2014
Authors : Cincinelli R, Musso L, Artali R, Guglielmi M, Bianchino E, Cardile F, Colelli F, Pisano C, Dallavalle S.
Abstract : Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.
|
Cytotoxicity against human MCF7 cells incubated for 24 hrs by MTT assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : J Nat Prod
Title : Antcamphorols A-K, Cytotoxic and ROS Scavenging Triterpenoids from Antrodia camphorata.
Year : 2020
Volume : 83
Issue : 1
First Page : 45
Last Page : 54
Authors : Li B, Kuang Y, He JB, Tang R, Xu LL, Leung CH, Ma DL, Qiao X, Ye M.
Abstract : Antrodia camphorata is a rare and valuable medicinal mushroom. In this work, 11 new triterpenoids, namely, antcamphorols A-K (1-11), together with 10 known triterpenoids, 12-21, were isolated from dish-cultured A. camphorata. Compound 1 is an unprecedented C31 lanostane-type triterpenoid featuring a methyl group at C-15 and a C-21-O-C-24 tetrahydropyran ring at C-17. Compounds 2-11 are ergostane-type triterpenoids, and they include two pairs of norergostanes 2-5. The structures of the new compounds were identified by NMR, 2D NMR, and HRESIMS data analyses. The absolute configurations of 1 and 6 were defined by X-ray diffraction data, and the absolute configuration at C-25 of 4 was determined by the modified Mosher's method. Compounds 7, 9, 10, 16, and 19 showed significant ROS scavenging activities (63.9-70.5% at 20 μM) in high-glucose-induced HUVECs. Compounds 3 and 8 exhibited moderate cytotoxic activities against U251 (IC50, 9.2 μM) and MCF-7 (IC50, 8.1 μM) human cancer cell lines, respectively.
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Antiproliferative activity against human HCT116 cells assessed as reduction in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
498.0
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
|
121.15
%
|
|
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
|
0.01
%
|
|
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
|
0.01
%
|
|
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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Antiproliferative activity against human HeLa cells after 72 hrs by MTT assay
|
Homo sapiens
|
32.0
nM
|
|
Journal : Eur J Med Chem
Title : Quinolone hybrids and their anti-cancer activities: An overview.
Year : 2019
Volume : 165
First Page : 59
Last Page : 79
Authors : Gao F, Zhang X, Wang T, Xiao J.
Abstract : The global pandemic of drug-sensitive cancers and the increasing threat from drug-resistant cancers make an urgent need to develop more effective anti-cancer candidates. Quinolone derivatives possess promising anti-cancer activity, and some of them have already been approved to treat cancers or under clinical trials. Hybridization of quinolone with other anti-cancer pharmacophores may provide more efficient anti-cancer candidates, so quinolone hybrids worth to be investigated. In this review, the recent advances in the development of novel quinolone hybrids as potential anti-cancer agents are highlighted, and the structure-activity relationship is also discussed to provide an insight for further development of more active quinolone hybrids.
|
Antiproliferative activity against human A549 cells after 72 hrs by MTT assay
|
Homo sapiens
|
32.0
nM
|
|
Journal : Eur J Med Chem
Title : Quinolone hybrids and their anti-cancer activities: An overview.
Year : 2019
Volume : 165
First Page : 59
Last Page : 79
Authors : Gao F, Zhang X, Wang T, Xiao J.
Abstract : The global pandemic of drug-sensitive cancers and the increasing threat from drug-resistant cancers make an urgent need to develop more effective anti-cancer candidates. Quinolone derivatives possess promising anti-cancer activity, and some of them have already been approved to treat cancers or under clinical trials. Hybridization of quinolone with other anti-cancer pharmacophores may provide more efficient anti-cancer candidates, so quinolone hybrids worth to be investigated. In this review, the recent advances in the development of novel quinolone hybrids as potential anti-cancer agents are highlighted, and the structure-activity relationship is also discussed to provide an insight for further development of more active quinolone hybrids.
|
Antiproliferative activity against human HL60 cells after 72 hrs by MTT assay
|
Homo sapiens
|
32.0
nM
|
|
Journal : Eur J Med Chem
Title : Quinolone hybrids and their anti-cancer activities: An overview.
Year : 2019
Volume : 165
First Page : 59
Last Page : 79
Authors : Gao F, Zhang X, Wang T, Xiao J.
Abstract : The global pandemic of drug-sensitive cancers and the increasing threat from drug-resistant cancers make an urgent need to develop more effective anti-cancer candidates. Quinolone derivatives possess promising anti-cancer activity, and some of them have already been approved to treat cancers or under clinical trials. Hybridization of quinolone with other anti-cancer pharmacophores may provide more efficient anti-cancer candidates, so quinolone hybrids worth to be investigated. In this review, the recent advances in the development of novel quinolone hybrids as potential anti-cancer agents are highlighted, and the structure-activity relationship is also discussed to provide an insight for further development of more active quinolone hybrids.
|
Antitumor activity against human SK-OV-3 cells xenografted in BALB/c nude mouse assessed as reduction in tumor volume at 20 mg/kg, iv once a week for 3 weeks relative to control
|
Homo sapiens
|
53.5
%
|
|
Journal : Eur J Med Chem
Title : Synthesis, mechanisms of action, and toxicity of novel aminophosphonates derivatives conjugated irinotecan in vitro and in vivo as potent antitumor agents.
Year : 2020
Volume : 189
First Page : 112067
Last Page : 112067
Authors : Huang X,Wang M,You Q,Kong J,Zhang H,Yu C,Wang Y,Wang H,Huang R
Abstract : Twenty novel aminophosphonates derivatives (5a-5j and 6a-6j) conjugated irinotecan were synthesized through esterification reaction, and evaluated their anticancer activities using MTT assay. In vitro evaluation revealed that they displayed similar or superior cytotoxicity compared to the positive drug irinotecan against A549, MCF-7, SK-OV-3, MG-63, U2OS and multidrug-resistant (MDR) SK-OV-3/CDDP cancer cell lines. Among them, 9b displayed the most potent activity, with IC values of 0.92-3.23 μM against five human cancer cells, which exhibited a 5.4-19.1-fold increase in activity compared to the reference drug irinotecan, respectively. Moreover, cellular mechanism studies suggested that 9b arrested cell cycle at S stage and induced cell apoptosis along with the decrease of mitochondrial membrane potential (MMP). Interestingly, 9b significantly inhibited tumor growth in SK-OV-3 xenograft models in vivo without apparent toxicity, which was better than the positive drug irinotecan. Taken together, 9b possessed potent antitumor activity and may be a promising candidate for the potential treatment of human ovarian cancer cells.
|
Anticancer activity against human HCT-116 cells assessed as inhibition of cell proliferation measured after 72 hrs by MTT assay
|
Homo sapiens
|
4.4
nM
|
|
Journal : Bioorg Med Chem
Title : Neothalfine, a potent natural anti-tumor agent against metastatic colorectal cancer and its primary mechanism.
Year : 2021
Volume : 29
First Page : 115849
Last Page : 115849
Authors : Zhu YY,Jin Q,Chen SS,Jin DN,Wang ZJ,He YJ,Chen HC,Zhao YL,Zhao LX,Dai Z,Luo XD
Abstract : Neothalfine is a natural bisbenzylisoquinoline alkaloid with the abundant resource in medicinal plants and has not been reported its anti-tumor efficacy. In the present study, the anti-tumor efficacy was investigated and it showed broad-spectrum activity against several cancer cell lines, especially metastatic colorectal cancer (HCT116, SW620, T84) with the IC values of 7.2, 5.9, 8.2 nM, respectively, roughly equal to well-known anti-tumor agent docetaxel (4.0, 4.7, 2.7 nM) and nearly 1000 folds than CPT-11 (4.4, 5.1, 6.9 μM). Furthermore, neothalfine inhibited colorectal cell proliferation by resulting in cell cycle arrest at the G2/M phase and induced apoptosis through the dysfunction of mitochondria to trigger intrinsic apoptotic pathway by untargeted metabolomic method, mitochondrial membrane potential, and caspase-3/7 activity assay. Moreover, neothalfine damaged colorectal cancer clonal spheres expansion significantly at the concentration of 3.5 nM with nearly 1000 folds efficacy than CPT-11 (3.0 µM). The results supported that neothalfine might be an anti-tumor lead for further investigation.
|
Anticancer activity against human SW-620 cells assessed as inhibition of cell proliferation measured after 72 hrs by MTT assay
|
Homo sapiens
|
5.1
nM
|
|
Journal : Bioorg Med Chem
Title : Neothalfine, a potent natural anti-tumor agent against metastatic colorectal cancer and its primary mechanism.
Year : 2021
Volume : 29
First Page : 115849
Last Page : 115849
Authors : Zhu YY,Jin Q,Chen SS,Jin DN,Wang ZJ,He YJ,Chen HC,Zhao YL,Zhao LX,Dai Z,Luo XD
Abstract : Neothalfine is a natural bisbenzylisoquinoline alkaloid with the abundant resource in medicinal plants and has not been reported its anti-tumor efficacy. In the present study, the anti-tumor efficacy was investigated and it showed broad-spectrum activity against several cancer cell lines, especially metastatic colorectal cancer (HCT116, SW620, T84) with the IC values of 7.2, 5.9, 8.2 nM, respectively, roughly equal to well-known anti-tumor agent docetaxel (4.0, 4.7, 2.7 nM) and nearly 1000 folds than CPT-11 (4.4, 5.1, 6.9 μM). Furthermore, neothalfine inhibited colorectal cell proliferation by resulting in cell cycle arrest at the G2/M phase and induced apoptosis through the dysfunction of mitochondria to trigger intrinsic apoptotic pathway by untargeted metabolomic method, mitochondrial membrane potential, and caspase-3/7 activity assay. Moreover, neothalfine damaged colorectal cancer clonal spheres expansion significantly at the concentration of 3.5 nM with nearly 1000 folds efficacy than CPT-11 (3.0 µM). The results supported that neothalfine might be an anti-tumor lead for further investigation.
|
Anticancer activity against human T84 cells assessed as inhibition of cell proliferation measured after 72 hrs by MTT assay
|
Homo sapiens
|
6.9
nM
|
|
Journal : Bioorg Med Chem
Title : Neothalfine, a potent natural anti-tumor agent against metastatic colorectal cancer and its primary mechanism.
Year : 2021
Volume : 29
First Page : 115849
Last Page : 115849
Authors : Zhu YY,Jin Q,Chen SS,Jin DN,Wang ZJ,He YJ,Chen HC,Zhao YL,Zhao LX,Dai Z,Luo XD
Abstract : Neothalfine is a natural bisbenzylisoquinoline alkaloid with the abundant resource in medicinal plants and has not been reported its anti-tumor efficacy. In the present study, the anti-tumor efficacy was investigated and it showed broad-spectrum activity against several cancer cell lines, especially metastatic colorectal cancer (HCT116, SW620, T84) with the IC values of 7.2, 5.9, 8.2 nM, respectively, roughly equal to well-known anti-tumor agent docetaxel (4.0, 4.7, 2.7 nM) and nearly 1000 folds than CPT-11 (4.4, 5.1, 6.9 μM). Furthermore, neothalfine inhibited colorectal cell proliferation by resulting in cell cycle arrest at the G2/M phase and induced apoptosis through the dysfunction of mitochondria to trigger intrinsic apoptotic pathway by untargeted metabolomic method, mitochondrial membrane potential, and caspase-3/7 activity assay. Moreover, neothalfine damaged colorectal cancer clonal spheres expansion significantly at the concentration of 3.5 nM with nearly 1000 folds efficacy than CPT-11 (3.0 µM). The results supported that neothalfine might be an anti-tumor lead for further investigation.
|
Cytotoxicity against human MCF7 cells by MTT assay
|
Homo sapiens
|
800.0
nM
|
|
|
Cytotoxicity against human NCI-H526 cells assessed as reduction in cell viability incubated for 72 hrs by PrestoBlue reagent based assay
|
Homo sapiens
|
490.0
nM
|
|
