Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents.
Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents.
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DOI：
10.3390/molecules27010321
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发表时间：
2022-01-05
期刊：
影响因子：
--
通讯作者：
Gangjee A
中科院分区：
文献类型：
--
作者：
Islam F;Doshi A;Robles AJ;Quadery TM;Zhang X;Zhou X;Hamel E;Mooberry SL;Gangjee A
设计合成了11个4-取代5,6,7,8-四氢苯并[4,5]噻吩[2,3-d]嘧啶，并对其生物活性进行了评价。合成包括Gewald反应合成2-氨基-4,5,6,7-四氢苯乙基[b]噻吩-3-羧酸酯环和SNAr反应。化合物4在细胞增殖和微管解聚实验中分别比先导化合物1强1.6倍和7倍。其中化合物4、5、7的抗增殖作用最强（IC50值< 40 nM），化合物6、8、10、12、13的抗增殖作用较弱（IC50值为53 ~ 125 nM）。此外，化合物4-8、10和12-13绕过Pgp和β iii -微管蛋白介导的耐药机制，降低紫杉醇（PTX）的临床疗效。在NCI-60细胞系面板中，化合物4在40个最敏感细胞系中的平均GI50为~10 nM。化合物4在小鼠MDA-MB-435异种移植瘤模型中显示出具有统计学意义的抗肿瘤作用。
A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and SNAr reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC50 values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC50 values of 53–125 nM). Additionally, compounds 4–8, 10 and 12–13 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI50 of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.
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影响因子：
2.7
作者：
Devambatla RKV;Li W;Zaware N;Choudhary S;Hamel E;Mooberry SL;Gangjee A
通讯作者：
Gangjee A
影响因子：
3.5
作者：
Golani, Lalit K.;Islam, Farhana;Gangjee, Aleem
通讯作者：
Gangjee, Aleem
影响因子：
2.9
作者：
HAMEL, E;LIN, CM
通讯作者：
LIN, CM
影响因子：
2.7
作者：
Islam F;Quadery TM;Bai R;Luckett-Chastain LR;Hamel E;Ihnat MA;Gangjee A
通讯作者：
Gangjee A
影响因子：
4.6
作者：
Al-Taisan, Khulud M.;Al-Hazimi, Hassan M. A.;Al-Shihry, Shar S.
通讯作者：
Al-Shihry, Shar S.