Bioreduction activated prodrugs of camptothecin: molecular design, synthesis, activation mechanism and hypoxia selective cytotoxicity.
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.
Zhang
Zhouen
Z
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Nishikyo-ku, Kyoto, 615-8510, Japan.
Tanabe
Kazuhito
K
Hatta
Hiroshi
H
Nishimoto
Sei-Ichi
S
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
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D002166:Camptothecin