Design,synthesis, and cytotoxic activity of novel 7-substituted camptothecin derivatives incorporating piperazinyl-sulfonylamidine moieties |
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Authors: | Cheng-Jie Yang Zi-Long Song Masuo Goto Ying-Qian Liu Kan-Yen Hsieh Susan L Morris-Natschke Yong-Long Zhao Jun-Xiang Zhang Kuo-Hsiung Lee |
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Institution: | 1. School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China;2. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States;3. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan |
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Abstract: | In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel 7-substituted CPT derivatives incorporating piperazinyl-sulfonylamidine moieties were designed, synthesized and evaluated for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB, and KB-VIN). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Remarkably, most of the compounds exhibited comparable cytotoxicity against the multidrug-resistant (MDR) KB-VIN and parental KB tumor cell lines, while irinotecan lost activity completely against KB-VIN. Especially, compounds 13r and 13p (IC50 0.38 and 0.85 μM, respectively) displayed the greatest cytotoxicity against the MDR KB-VIN cell line and merit further development into preclinical and clinical drug candidates for treating cancer, including MDR phenotype. |
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Keywords: | CKD-602 belotecan CPT camptothecin CPT-11 irinotecan DMF dimethylformamide MDR multi-drug resistant SAR structure-activity relationship TFA trifluoroacetic acid topo topoisomerase TPT topotecan Camptothecin Cytotoxic activity Piperazine Sulfonylamidine Synthesis |
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