【作者】 陈明；

【导师】 刘滔；

【作者基本信息】 浙江大学 ， 药学， 2015， 硕士

【摘要】 恶性肿瘤是威胁人类健康的重大疾病,已取代心脑血管疾病成为全球头号杀手。目前临床上使用的抗肿瘤药物往往存在疗效较差、毒副作用大、易产生耐药性等缺点。因此,研究疗效更好、毒副作用更小的新型抗肿瘤药物是当前新药研究与开发领域的热点。细胞周期依赖性激酶(Cyclin dependent kinases)在调控细胞周期进程中处于核心地位,对肿瘤细胞中过度表达的CDKs进行抑制从而有效地遏制肿瘤细胞增殖,成为一种极具潜力的癌症治疗策略。本文以临床Ⅱ期的CDK抑制剂PHA848125为先导,保留其结构中与铰链区Leu83残基形成关键氢键作用的氨基嘧啶结构。应用开环策略和生物电子等排原理,分别用三氮唑和咪唑代替先导化合物中的吡唑,并在咪唑上引入不同烷基,与蛋白疏水性口袋相互作用,设计并合成了嘧啶-三氮唑类和嘧啶-咪唑类共33个全新结构的目标化合物,经1H NMR和MS分析确证。CDK2/CyclinA活性研究表明,5个化合物(A-5、A-11、B-12、B-15、B-19)表现出较显著的CDK2/CyclinA抑制活性,IC5o为0.22μM～1.42μM。进一步体外肿瘤细胞增殖抑制活性研究表明,化合物A-11显示出一定的抑制活性(HL60 IC50=21.05μM; A549 IC50= 21.53μM)。此外,本文以课题组前期研究中发现的6-氮杂吲哚类衍生物YJY-1为先导,针对其结构稳定性较差的缺点,在母核C-4位引入氰基以提高稳定性。设计并合成了全新结构的4-氰基-6-氮杂吲哚类共8个目标化合物,经1H NMR和MS分析确证。CDK2/CyclinA活性研究表明,该系列化合物在1μg/mL浓度下对CDK2/CyclinA抑制活性不佳；体外肿瘤细胞增殖抑制活性研究表明,化合物C-4和C-7对HCT116的抑制活性IC5o分别为2.7μM和4.0μM。更多还原

【Abstract】 Nowadays, cancer has surpassed the cardiovascular diseases in motality. The traditional anti-cancer agents applied clinically suffer from shortcomings, including poor efficacy, high toxicity and advance of multidrug resistance. Thereby, the exploration of novel anti-cancer drugs that conquer these limitations has emerged to be a focus in the field of drug research and development. CDKs (cyclin dependent kinases) play a vital role in regulating the cell cycle. Inhibition of the overexpressed CDKs of tumor cells to block tumor cell proliferation effectively has become a potential cancer therapy.According to literature survey, clinical candidate PHA848125 was choosed as a lead compound. We retained amino-pyrimidine structure which formed two hydrogen bonds with the hinge region Leu83 amino acid. Based on bioisosterism, triazole ring and imidazole ring were used to replace pyrazole ring of lead compound respectively. The introduction of different substituents on imidazole ring formed interactions with the hydrophobic pocket. Two series bearing 33 compounds were designed, synthesized and confirmed by 1H NMR and MS. After testing them for CDK2/Cyclin A inhibitory activities,5 compounds (A-5* A-11、B-12、B-15、B-19) displayed potent inhibitory activities with IC50 range from 0.22 uM to 1.42μM. Furthermore, the 5 compounds were tested for their in vitro cytotoxic activities. Compound A-11 displayed moderate activities against HL60 and A549 with IC50 of 21.05μM and 21.53 μM respectively.In addition, our previous efforts to discover novel CDK inhibitors led to the identification of a series of 6-azaindole deviratives with poor structural sbabilities. To address this issue,8 compounds containing 4-cyano-6-azaindole skeletion were designed, synthesized and comfirmed by 1H NMR and MS. CDK2/Cyclin A inhibitory assay revealed that these compounds demonstrated weak activities at lμg/mL. Further in vitro cytotoxic evaluation against human colcnic carcinoma cell line (HCT116) showed that compound C-4 and C-7 displayed potent activities with IC50 of 2.7μM and 4.0μM respectively.更多还原