title: Synthesis and biological evaluation of hypoxia-activated prodrugs of SN-38.
abstract: We designed new hypoxia-activated prodrugs by conjugating (1-methyl-2-nitro-1H-imidazol-5-yl)methanol with 7-ethyl-10-hydroxy camptothecin (SN-38). Initially, we improved the method of multi-gram scale synthesis of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol, which increased the yield to 42% compared to 8% by the original synthesis method. The improved method was used to synthesize evofosfamide (TH-302) and hypoxia-activated prodrugs of SN-38. Two different linkages between (1-methyl-2-nitro-1H-imidazol-5-yl)methanol and SN-38 were evaluated that afforded different hypoxia-selectivity and toxicity. Compound 16 (IOS), containing an ether linkage, was considered to be a promising hypoxia-selective antitumor agent.
authors.affiliation: School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Jin
authors.affiliation: School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
authors.forename: Qiumeng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China. Electronic address: wlu@chem.ecnu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D015195:Drug Design; D004986:Ether; D006801:Humans; D000860:Hypoxia; D000077146:Irinotecan; D008722:Methods; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D004986:Ether; D000077146:Irinotecan; D002166:Camptothecin
keywords: 2-Nitroimidazole; Hypoxia-activated prodrug; SN-38