Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

Abstract

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.

A decade's overview of 2‐aminothiophenes and their fused analogs as promising anticancer agents

“…[93] Islam et al used the 2-aminotetrahydrobenzo[b]thiophene scaffold for the design of 4-substitiuted thieno[2,3-d]pyrimidines as potential agents targeting microtubules. [94] A series of 11 compounds was synthesized and biologically evaluated. thiophene derivatives as inhibitors of WEE1 kinase and microtubule assembly.…”

“…Islam et al used the 2‐aminotetrahydrobenzo[ b ]thiophene scaffold for the design of 4‐substitiuted thieno[2,3‐ d ]pyrimidines as potential agents targeting microtubules. [ 94 ] A series of 11 compounds was synthesized and biologically evaluated. Compound 27 with (4‐methoxyphenyl) had the best antiproliferative activity with IC 50 9.0 nM against MDA‐435 cells, Tubulin assembly inhibition by IC 50 0.82 µM, and microtubule depolymerization with EC 50 of 19 nM.…”

Pyrimidines as Anticancer and Antiviral: Synthesis & Reactions (A Review)

“…During the same year, F. Islam et al, reacted 63 chlorothienopyrimidine with different aniline derivatives using toluene as a solvent to obtain thienopyrimidines 75 with anticancer activity via targeting microtubules (Scheme 30). These compounds were tested against nine types of cancer on approximate sixty cell lines and recorded significant activity.…”

2-Alkyl-Substituted-4-Amino-Thieno[2,3-d]Pyrimidines: Anti-Proliferative Properties to In Vitro Breast Cancer Models

“…N4-(4methoxyphenyl)-N4-methyl-5,6,7,8-tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidine-2,4-diamine has demonstrated significant anti-tumor effects in an in vivo xenograft model (MDA-MB-435) [25]. Many investigations on thienopyrimidine's anti-cancer properties have been conducted and published [26][27][28][29].…”

“…xenograft model (MDA-MB-435) [25]. Many investigations on thienopyrimidine's anticancer properties have been conducted and published [26][27][28][29].…”