Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Molecules. 2022 Jan 5;27(1):321. doi: 10.3390/molecules27010321.
A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-]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 SAr reactions. Compound was 1.6- and ~7-fold more potent than the lead compound in cell proliferation and microtubule depolymerization assays, respectively. Compounds , and showed the most potent antiproliferative effects (IC values < 40 nM), while compounds , , , and had lower antiproliferative potencies (IC values of 53-125 nM). Additionally, compounds -, and - circumvented Pgp and III-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound exhibited an average GI of ~10 nM in the 40 most sensitive cell lines. Compound demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.
设计并合成了一系列 11 种 4-取代的 5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶，并评价了它们的生物活性。合成涉及 Gewald 反应合成 2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-羧酸乙酯环和 SAr 反应。化合物 在细胞增殖和微管解聚测定中比先导化合物 分别显示出 1.6 倍和 ~7 倍的更高活性。化合物, 和 表现出最强的抗增殖作用（IC 值 < 40 nM），而化合物,,, 和 则具有较低的抗增殖作用（IC 值为 53-125 nM）。此外，化合物 -, 和 - 规避了 Pgp 和 III-微管蛋白介导的药物耐药性，这些机制降低了紫杉醇（PTX）的临床疗效。在 NCI-60 细胞系面板中，化合物 在 40 种最敏感的细胞系中的平均 GI 值约为 10 nM。化合物 在 MDA-MB-435 异种移植模型中显示出统计学显著的抗肿瘤作用。
