title: Novel 20(S)-sulfonylamidine derivatives of camptothecin and the use thereof as a potent antitumor agent: a patent evaluation of WO2015048365 (A1).
abstract: 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.
authors.affiliation: a Fondazione IRCCS Istituto Nazionale dei Tumori Milano , Milano , Italy.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Beretta
authors.affiliation: a Fondazione IRCCS Istituto Nazionale dei Tumori Milano , Milano , Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: b Institute for the Organic Synthesis and Photoreactivity , Italian National Research Council , Bologna , Italy.
authors.forename: Greta
authors.initials: G
authors.lastname: Varchi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010330:Patents as Topic
chemical_list: D000970:Antineoplastic Agents; D002166:Camptothecin
keywords: Camptothecins; Copper catalysis; DNA Topoisomerase I; Drug resistance; Lactone ring-opening; Sulfonylamidine