Discovery and mechanistic insights into thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines inhibitors targeting tubulin for cancer therapy,European Journal of Medicinal Chemistry

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Discovery and mechanistic insights into thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines inhibitors targeting tubulin for cancer therapy
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-07-04 , DOI: 10.1016/j.ejmech.2024.116649
Chengyong Wu ₁ , Lele Zhang ₁ , Zhilan Zhou ₁ , Lun Tan ₁ , Zhijia Wang ₁ , Cuiyu Guo ₁ , Yuxi Wang ₂

Affiliation

Guided by the X-ray cocrystal structure of the lead compound 4a, we developed a series of thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines demonstrating potent antiproliferative activity against four tumor cell lines. Two analogs, 13 and 25d, exhibited IC50 values around 1 nM and overcame P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). At low concentrations, 13 and 25d inhibited both the colony formation of SKOV3 cells in vitro and tubulin polymerization. Furthermore, mechanistic studies showed that 13 and 25d induced G2/M phase arrest and apoptosis in SKOV3 cells, as well as dose-dependent inhibition of tumor cell migration and invasion at low concentrations. Most notably, the X-ray cocrystal structures of compounds 4a, 25a, and the optimal molecule 13 in complex with tubulin were elucidated. This study identifies thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines as representatives of colchicine-binding site inhibitors (CBSIs) with potent antiproliferative activity.

中文翻译：

噻吩并[3,2-d]嘧啶和杂环稠合嘧啶抑制剂靶向微管蛋白治疗癌症的发现和机制见解

在先导化合物 4a 的 X 射线共晶结构的引导下，我们开发了一系列噻吩并[3,2-d] 嘧啶和杂环熔融嘧啶，显示出对四种肿瘤细胞系的强效抗增殖活性。两个类似物 13 和 25d 的 IC50 值约为 1 nM，并克服了 P-糖蛋白（P-gp）介导的多药耐药性（MDR）。在低浓度下，13 和 25d 抑制 SKOV3 细胞在体外的集落形成和微管蛋白聚合。此外，机制研究表明，13 和 25d 诱导 SKOV3 细胞 G2/M 期阻滞和凋亡，以及在低浓度下对肿瘤细胞迁移和侵袭的剂量依赖性抑制。最值得注意的是，阐明了化合物 4a 、 25a 和与微管蛋白复合物中最佳分子 13 的 X 射线共晶结构。本研究确定噻吩并[3,2-d]嘧啶和杂环稠合嘧啶是具有强大抗增殖活性的秋水仙碱结合位点抑制剂（CBSI）的代表。

更新日期：2024-07-04

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