Key Laboratory of Original New Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Eur J Med Chem. 2012 Nov;57:162-75. doi: 10.1016/j.ejmech.2012.09.002. Epub 2012 Sep 10.
A series of 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives were synthesized and evaluated for their cytotoxic activities against five cancer cell lines. Most of them exhibited moderate to significant cytotoxic activities and high-selectivity against one or more cell lines, and nearly all of them had higher potency than positive controls against MDA-MB-231 cell line. The most promising compound 15f showed strong cytotoxic activities against H460, HT-29 and MDA-MB-231 cell lines, which were 1.7- to 66.5-folds more active than 2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)-1-piperazinyl)methyl)-4-(4-morpholinyl)thieno[3,2-d]pyrimidine(GDC-0941). To investigate the SARs of thieno[3,2-d]pyrimidine derivatives in more details, CoMFA (q(2) = 0.436, r(2) = 0.937) and CoMSIA (q(2) = 0.706, r(2) = 0.947) models on H460 cell line were established. The generated 3D-QSAR models can be used for further rational design of novel thienopyrimidines as highly potent and selective cytotoxic agents.
一系列 2-肼基-4-吗啉噻吩并[3,2-d]嘧啶衍生物被合成并评估了它们对五种癌细胞系的细胞毒性活性。它们中的大多数表现出中等至显著的细胞毒性活性和对一种或多种细胞系的高选择性，并且几乎所有化合物对 MDA-MB-231 细胞系的活性都比阳性对照物高。最有前途的化合物 15f 对 H460、HT-29 和 MDA-MB-231 细胞系表现出强烈的细胞毒性活性，其活性比 2-(1H-吲唑-4-基)-6-((4-(甲基磺酰基)-1-哌嗪基)甲基)-4-(4-吗啉基)噻吩并[3,2-d]嘧啶(GDC-0941)高 1.7-66.5 倍。为了更详细地研究噻吩并[3,2-d]嘧啶衍生物的 SARs，在 H460 细胞系上建立了 CoMFA(q(2) = 0.436，r(2) = 0.937)和 CoMSIA(q(2) = 0.706，r(2) = 0.947)模型。生成的 3D-QSAR 模型可用于进一步合理设计新型噻吩嘧啶作为高效和选择性细胞毒性剂。
