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• 作者：Aleem Gangjee ; Ying Zhao ; Sudhir Raghavan ; Cristina C. Rohena ; Susan L. Mooberry ; Ernest Hamel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6829-6844
• 全文大小：692K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

A series of 21 substituted cyclopenta[d]pyrimidines were synthesized as an extension of our discovery of the parent compound (卤)-1路HCl as an anti-microtubule agent. The structure鈥揳ctivity relationship indicates that the N-methyl and a 4N-methoxy groups appear important for potent activity. In addition, the 6-substituent in the parent analogue is not necessary for activity. The most potent compound 30路HCl was a one to two digit nanomolar inhibitor of most tumor cell proliferations and was up to 7-fold more potent than the parent compound (卤)-1路HCl. In addition, 30路HCl inhibited cancer cell proliferation regardless of Pgp or 尾III-tubulin status, both of which are known to cause clinical resistance to several anti-tubulin agents. In vivo efficacy of 30路HCl was demonstrated against a triple negative breast cancer xenograft mouse model. Compound 30路HCl is water-soluble and easily synthesized and serves as a lead compound for further preclinical evaluation as an antitumor agent.