- 14-Aminocamptothecins: Their synthesis, preclinical activity, and potential use for cancer treatment
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14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell ines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
- Duan, Jian-Xin,Cai, Xiaohong,Meng, Fanying,Sun, Jessica D.,Liu, Qian,Jung, Donald,Jiao, Hailong,Matteucci, Jackson,Jung, Brian,Bhupathi, Deepthi,Ahluwalia, Dharmendra,Huang, Heli,Hart, Charles P.,Matteucci, Mark
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- CAMPTOTHECIN DERIVATIVES
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Various 14-Nitro, 14-amino, and 14-substituted amino camptothecin derivatives are useful in the treatment of cancer and other hyperproliferative diseases. Various 14-nitro camptothecin derivatives are conveniently prepared by reacting a camptothecin deriv
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Page/Page column 92-93
(2010/12/31)
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