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Acta Pharmacologica Sinica 2003年第2期24卷 109-119页

作者： Panayotis PANTAZIS John MENDOZA Janet EARLY anthony kozielski Nick HARRIS Beppino GIOVANELLA The Stehlin Foundation for Cancer Research at St. Joseph Hospital 1918 Chenevert Houston Texas 77003 USA The Stehlin Foundation for Cancer Research at St. Joseph Hospital 1918 Chenevert Houston Texas 77003 USA The Stehlin Foundation for Cancer Research at St. Joseph Hospital 1918 Chenevert Houston Texas 77003 USA The Stehlin Foundation for Cancer Research at St. Joseph Hospital 1918 Chenevert Houston Texas 77003 USA The Stehlin Foundation for Cancer Research at St. Joseph Hospital 1918 Chenevert Houston Texas 77003 USA The Stehlin Foundation for Cancer Research at St. Joseph Hospital 1918 Chenevert Houston Texas 77003 USA

AIM: To study the structure-activity relationship of alkyl 9-nitrocamptothecin esters. METHODS: Two alkyl 9-nitrocamptothecin (9NC) esters 5g and 5h were prepared by esterification reactions of 9NC with valeric anhydride and heptanoic anhydride, respectively. Eight 9NC esters 5a-5h were tested for cytotoxicity against human leukemia cell lines HL-60 and U-937. Flow cytometry analysis was used to identify the cell cycle phase targeted by the esters and quantify the extent of ester-induced cell death (apoptosis). RESULTS: Esters 5b and 5c demonstrated great abilities to inhibit growth of the leukemia cells followed by induction of apoptosis; esters 5a, 5e, and 5g induced slight perturbations in the cell cycle at high concentrations; and esters 5d, 5f, and 5h were completely inactive against the cell lines tested. Thus these esters showed the cell anti-proliferative activity in an order of 5b≈5c>5a≈5e≈5g>5d≈5f≈5h. Esters 5b, 5c, and 5e were tested in vivo against various human carcinomas in nude mice grown as xenografts. Only 5b and 5c showed a significant antitumor activity. Particularly, ester 5b demonstrated an antitumor activity against a broad spectrum of human carcinomas including breast, lung, colon, pancreas, stomach, ovarian, and melanoma, etc. CONCLUSION: These esters act like prodrugs of their parental 9-nitrocamptothecin. High drug doses need to be administered to animals in order to inhibit growth, and induce regression, of human tumor xenografts in nude mice. These compounds may be developed into potent anticancer drugs due to their low toxicity.

关键词：喜树碱酯类药物前体抗肿瘤药毒性构效关系

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Sulfuric Acid Catalyzed Preparation of Alkyl and Alkenyl Camptothecin Ester Derivatives and Antitumor Activity against Human Xenografts Grown in Nude Mice

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Open Journal of Medicinal Chemistry 2012年第1期2卷 10-14页

作者： Zhisong Cao anthony kozielski Dana Vardeman Beppino Giovanella Christus Stehlin Foundation for Cancer Research Houston USA

Camptothecin-20-propinate (CZ48) and other camptothecin ester derivatives were prepared by the esterification reac-tions of camptothecin or 9-nitrocamptothecin with the corresponding acylating agents such as organic acid anhydride or chloride with concentrate sulfuric acid as the catalyst. The sulfuric acid-catalyzed reactions gave high yields of camptothecin ester *** the 11 compounds prepared by this method, camptothecin-20-O-propionate, camptothecin-20-O-crotonate, and 9-nitrocamptothecin-20-O-propionate showed good anticancer activity against various types of human tumors grown as xenografts in nude mice. The methodology developed for the preparation of camptothecin esters in this article can be applied to a wide scope of other ester derivatives.

关键词： Anti-Cancer Drugs Activity Esterification Camptothecin 9-Nitrocamptothecin

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