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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
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(N)Ar re...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8747035/ https://www.ncbi.nlm.nih.gov/pubmed/35011550 http://dx.doi.org/10.3390/molecules27010321 |
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author | Islam, Farhana Doshi, Arpit Robles, Andrew J. Quadery, Tasdique M. Zhang, Xin Zhou, Xilin Hamel, Ernest Mooberry, Susan L. Gangjee, Aleem |
author_facet | Islam, Farhana Doshi, Arpit Robles, Andrew J. Quadery, Tasdique M. Zhang, Xin Zhou, Xilin Hamel, Ernest Mooberry, Susan L. Gangjee, Aleem |
author_sort | Islam, Farhana |
collection | PubMed |
description | 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(N)Ar 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 (IC(50) values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC(50) 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 GI(50) 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. |
format | Online Article Text |
id | pubmed-8747035 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87470352022-01-11 Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents Islam, Farhana Doshi, Arpit Robles, Andrew J. Quadery, Tasdique M. Zhang, Xin Zhou, Xilin Hamel, Ernest Mooberry, Susan L. Gangjee, Aleem Molecules Article 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(N)Ar 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 (IC(50) values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC(50) 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 GI(50) 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. MDPI 2022-01-05 /pmc/articles/PMC8747035/ /pubmed/35011550 http://dx.doi.org/10.3390/molecules27010321 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Islam, Farhana Doshi, Arpit Robles, Andrew J. Quadery, Tasdique M. Zhang, Xin Zhou, Xilin Hamel, Ernest Mooberry, Susan L. Gangjee, Aleem Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents |
title | Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents |
title_full | Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents |
title_fullStr | Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents |
title_full_unstemmed | Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents |
title_short | Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents |
title_sort | design, synthesis, and biological evaluation of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as microtubule targeting agents |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8747035/ https://www.ncbi.nlm.nih.gov/pubmed/35011550 http://dx.doi.org/10.3390/molecules27010321 |
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