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

Molecules. 2022 Jan 5;27(1):321. doi: 10.3390/molecules27010321.

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.

Keywords: Gewald reaction; colchicine site; microtubule targeting agents; microtubules.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemistry Techniques, Synthetic*
  • Drug Design*
  • Drug Resistance, Neoplasm
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Protein Multimerization / drug effects
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Tubulin / chemistry
  • Tubulin / metabolism
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / chemistry*
  • Tubulin Modulators / pharmacology*

Substances

  • Pyrimidines
  • Tubulin
  • Tubulin Modulators