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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 S_NAr 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.

SUBMITTER: Islam F

PROVIDER: S-EPMC8747035 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Islam Farhana F Doshi Arpit A Robles Andrew J AJ Quadery Tasdique M TM Zhang Xin X Zhou Xilin X Hamel Ernest E Mooberry Susan L SL Gangjee Aleem A

Molecules (Basel, Switzerland) 20220105 1

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< ...[more]

PMID: 35011550

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Project description:BackgroundThe high prevalence of skin hyperpigmentation makes it necessary to search for remedies that could hinder this process. Among such substances, tyrosinase inhibitors can be distinguished, which may be pyrimidine derivatives.ObjectivesThis study aimed to investigate new compounds with anti-tyrosinase activity in 2-substituted tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4(3H)-one by an in vitro analysis and investigating their molecular docking.MethodsA molecular docking was performed using AutoDock 4.0 with the 3-dimensional structure of tyrosinase of the fungus Agaricus bisporus from the Protein Data Bank (PDB; rcsb.org) with identification number 2Y9X. A synthesis of 2-substituted tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4(3H)-one was carried out during the heterocyclization reaction of azomethine derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide in glacial acetic acid with the addition of dimethyl sulfoxide. Tyrosinase activity was determined in vitro by the spectrophotometric method.ResultsMolecular docking data suggest the feasibility of synthesizing 2-substituted tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4(3H)-one as possible tyrosinase inhibitors. Of particular interest are compounds with hydroxy groups in the radical. Next, pharmacological screening showed that the leading compound is 4g. It is likely that metal-ligand interactions are the main interactions in the active site of tyrosinase because kojic acid, hydroquinone, and lactic acid (reference compounds), as well as compounds with only hydroxy groups in phenyl substituents (4b, 4c, and 4g), have the greatest anti-tyrosinase activity.ConclusionsAs a result of molecular docking studies, the feasibility of synthesizing 2-substituted tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4(3H)-one as potential tyrosinase inhibitors was justified. 2-Substituted tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4(3H)-one was obtained using new synthesis conditions. The leading compound is 4g containing a fragment of 2,4-dihydroxybenzene.

Dataset Information

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

Publications

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

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