Structure-Activity Relationship and in Vitro and in Vivo Evaluation of the Potent Cytotoxic Anti-microtubule Agent N-(4-Methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminium Chloride and Its Analogues As Antitumor Agents
Structure-Activity Relationship and in Vitro and in Vivo Evaluation of the Potent Cytotoxic Anti-microtubule Agent N-(4-Methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminium Chloride and Its Analogues As Antitumor Agents
复制标题
DOI：
10.1021/jm400639z
复制
发表时间：
2013-09-12
影响因子：
7.3
通讯作者：
Hamel, Ernest
中科院分区：
文献类型：
--
作者：
Gangjee, Aleem;Zhao, Ying;Hamel, Ernest
合成了一系列21个取代的环戊二烯并[d]嘧啶，作为我们发现母体化合物（+/-）-1中心点HCl作为抗微管剂的扩展。构效关系表明，N-甲基和α 4 N-甲氧基对有效活性很重要。此外，母体类似物中的6-取代基对于活性不是必需的。最强的化合物30. HCl是大多数肿瘤细胞增殖的一至两位数纳摩尔抑制剂，并且比母体化合物（+/-）-1中心点HCl的效力高7倍。此外，无论Pgp或β III-微管蛋白状态如何，30中心点HCl都能抑制癌细胞增殖，已知这两种状态都会导致对几种抗微管蛋白药物的临床耐药性。针对三阴性乳腺癌异种移植小鼠模型证明了30中心点HCl的体内功效。化合物30中心点HCl是水溶性的并且容易合成，并且作为先导化合物用于作为药物组合物的进一步临床前评价。
A series of 21 substituted cyclopenta[d]pyrimidines were synthesized as an extension of our discovery of the parent compound (+/-)-1 center dot HCl as an anti-microtubule agent. The structure activity 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. 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 (+/-)-1 center dot HCl. In addition, 30 center dot HCl inhibited cancer cell proliferation regardless of Pgp or beta III-tubulin status, both of which are known to cause clinical resistance to several antitubulin agents. In vivo efficacy of 30 center dot HCl was demonstrated against a triple negative breast cancer xenograft mouse model. Compound 30 center dot HCl is water-soluble and easily synthesized and serves as a lead compound for further preclinical evaluation as an