Substituted 6-amino-4H-[1,2]dithiolo[4,3-b]pyrrol-5-ones: synthesis, structure-activity relationships, and cytotoxic activity on selected human cancer cell lines.
An efficient synthesis and the cytotoxic activity of a series of substituted 6-amino-4H-[1,2]dithiolo[4,3-b]pyrrol-5-ones 1a-q is described. The synthesis was accomplished in an expedient manner (seven-steps) from commercially available starting materials. Several of the derivatives tested demonstrated significant in vitro cytotoxic activity against the human cancer cell lines H460 (7nM) and LCC6 (> or =28nM). Following SAR and pharmacokinetic studies a derivative was further evaluated for its in vivo anti-tumor activity against a highly angiogenic human melanoma xenograft where it demonstrated significant efficacy as a mono-therapy and in combination with Taxol and Cisplatin.
Li
Bin
B
Welichem Biotech Incorporated, Technology Place, 316-4475 Wayburne Drive, Burnaby, BC, Canada V5G 3L1.
Lyle
Michael P A
MP
Chen
Genhui
G
Li
Jason
J
Hu
Kaiji
K
Tang
Liren
L
Alaoui-Jamali
Moulay A
MA
Webster
John
J
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011758:Pyrroles / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D006574:Heterocyclic Compounds, 2-Ring; D011758:Pyrroles