title: Synthesis and biological evaluation of bis and monocarbonate prodrugs of 10-hydroxycamptothecins.
abstract: In an effort to improve the stability of labile lactone ring of camptothecins, the bis and mono-alkyl carbonate prodrugs of 10-hydroxycamptothecins were synthesized and their chemical and enzymatical stability as well as antitumor activity were studied. The in vitro evaluation of the stability of these carbonates indicates that the 10,20-biscarbonates are firstly hydrolyzed to afford the stable 20-monocarbonates. And the 10-carbonates are not stable in human plasma, mouse plasma and pH7.4 phosphate buffer, while the 20-carbonates are relatively stable in the three media and can be readily cleaved by porcine liver esterase. The overall toxicity of the tested carbonate against mice bearing S180 sarcoma is much lower when compared with the parent compound, and the antitumor activity is maintained.
authors.affiliation: Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang High-Tech Park, Shanghai 201203, China.
authors.forename: Xungui
authors.initials: X
authors.lastname: He
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Xiqun
authors.initials: X
authors.lastname: Jiang
authors.forename: Junchao
authors.initials: J
authors.lastname: Cai
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D002254:Carbonates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D007783:Lactones / Q000097:blood; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D002254:Carbonates; D007783:Lactones; D011355:Prodrugs; C028098:10-hydroxycamptothecin; D002166:Camptothecin