Novel 20(S)-sulfonylamidine derivatives of camptothecin and the use thereof as a potent antitumor agent: a patent evaluation of WO2015048365 (A1).
A series of camptothecin (CPT) derivatives featuring acyl-esterification of the 20(S)-hydroxyl group with a residue containing a sulfonylamidine moiety is synthesized via a Cu catalyzed three-component reaction. The compounds show remarkable cytotoxicity against a panel of tumor cells, including a cell line exhibiting Multi-Drug Resistant (MDR) phenotype. The patent develops 9a, the best derivative of the series, that i) selectively poisons DNA Topoisomerase I (TopoI); ii) induces cell-cycle S-phase arrest with activation of the DNA damage response pathway and apoptosis induction and iii) shows considerable in vivo antitumor potency. We envision that the peculiar modification of the 20(S)-hydroxyl group of CPT with a sulfonylamidine residue will play a continuing role in affording new TopoI poison drug candidates for therapeutic applications.
['Beretta|Giovanni Luca|GL|', 'Zaffaroni|Nadia|N|', 'Varchi|Greta|G|']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D002166:Camptothecin D045744:Cell Line, Tumor D004249:DNA Damage D015195:Drug Design D018432:Drug Resistance, Multiple D019008:Drug Resistance, Neoplasm D006801:Humans D051379:Mice D009369:Neoplasms D010330:Patents as Topic
Camptothecins Sulfonylamidine DNA Topoisomerase I Copper catalysis Drug resistance Lactone ring-opening