title: Bioreduction activated prodrugs of camptothecin: molecular design, synthesis, activation mechanism and hypoxia selective cytotoxicity.
abstract: Several water-soluble derivatives (CPT3, CPT3a-d) of camptothecin (CPT) were synthesized, among which CPT3 bearing an N,N'-dimethyl-1-aminoethylcarbamate side-chain was further conjugated with reductively eliminating structural units of indolequinone, 4-nitrobenzyl alcohol and 4-nitrofuryl alcohol to produce novel prodrugs of camptothecin (CPT4-6). All CPT derivatives were of lower cytotoxicity than their parent compound of CPT. In contrast, CPT4 and CPT6 showed higher hypoxia selectivity of cytotoxicity towards tumor cells than CPT. A mechanism by which a representative prodrug CPT4 is activated in the presence of DT-diaphorase to release CPT was also discussed. The bioreduction activated CPT prodrugs including CPT4 and CPT6 are identified to be promising for application to the hypoxia targeting tumor chemotherapy.
authors.affiliation: Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Nishikyo-ku, Kyoto, 615-8510, Japan.
authors.forename: Zhouen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hatta
authors.forename: Sei-Ichi
authors.initials: S
authors.lastname: Nishimoto
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D002166:Camptothecin / Q000138:chemical synthesis* / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D011355:Prodrugs
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D002166:Camptothecin