School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA.
Molecules. 2019 Mar 3;24(5):891. doi: 10.3390/molecules24050891.
3,4-dihydropyrimidin-2(1)-one compounds (DHPMs) possess extensive biological activities and are mainly prepared via Biginelli reaction and N-alkylation. In the present study, selective alkylation of N¹ was investigated by using tetrabutylammonium hydroxide. In vitro cytotoxicity study on all synthesized compounds demonstrated that introduction of the aryl chain in the R³ as well as the low electron-donating group in the R¹ of DHPMs contributed to the anti-proliferative potency. A larger value of the partition coefficient (Log P) and suitable polar surface area (PSA) values were both found to be important in order to maintain the antitumor activity. The results from in vivo study indicated the great potential of compound d to serve as a lead compound for novel anti-tumor drugs to treat glioma. Pharmacophore study regarding the structure-activity relations of DHPMs were also conducted. Our results here could provide a guide for the design of novel bioactive 3,4-dihydropyrimidin-2(1)-one compounds.
3,4-二氢嘧啶-2(1H)-酮化合物（DHPMs）具有广泛的生物活性，主要通过Biginelli 反应和 N-烷基化反应制备。本研究通过使用四丁基氢氧化铵研究了 N¹的选择性烷基化。对所有合成化合物的体外细胞毒性研究表明，DHPMs 中 R³引入芳基链以及 R¹中低供电子基团有助于提高抗增殖活性。较大的分配系数（Log P）和合适的极性表面积（PSA）值都被发现对于维持抗肿瘤活性很重要。体内研究结果表明，化合物 d 具有作为治疗神经胶质瘤的新型抗肿瘤药物的先导化合物的巨大潜力。还进行了关于 DHPMs 结构-活性关系的药效团研究。我们的研究结果可为设计新型生物活性 3,4-二氢嘧啶-2(1H)-酮化合物提供指导。
