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

Farhana Islam; Arpit Doshi; Andrew J. Robles; Tasdique M. Quadery; Xin Zhang; Xilin Zhou; Ernest Hamel; Susan L. Mooberry; Aleem Gangjee

doi:10.3390/molecules27010321

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

Farhana Islam, Arpit Doshi, Andrew J. Robles, Tasdique M. Quadery, Xin Zhang, Xilin Zhou, Ernest Hamel, Susan L. Mooberry, Aleem Gangjee

Resultado de la investigación: Article › revisión exhaustiva

Resumen

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.

Idioma original	English (US)
Número de artículo	321
Publicación	Molecules
Volumen	27
N.º	1
DOI	https://doi.org/10.3390/molecules27010321
Estado	Published - ene 1 2022

ASJC Scopus subject areas

Analytical Chemistry
Chemistry (miscellaneous)
Molecular Medicine
Pharmaceutical Science
Drug Discovery
Physical and Theoretical Chemistry
Organic Chemistry

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title = "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.",

keywords = "Colchicine site, Gewald reaction, Microtubule targeting agents, Microtubules",

author = "Farhana Islam and Arpit Doshi and Robles, {Andrew J.} and Quadery, {Tasdique M.} and Xin Zhang and Xilin Zhou and Ernest Hamel and Mooberry, {Susan L.} and Aleem Gangjee",

note = "Funding Information: Funding: This work was supported, in part, by a grant from the National Institutes of Health, National Cancer Institute (CA142868 (to A.G., S.L.M.)); by the Greehey Distinguished Chair in Targeted Molecular Therapeutics (to S.L.M.), Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (to A.G.); and by an NSF equipment grant for NMR instrumentation (NMR: CHE 0614785). This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Funding Information: This work was supported, in part, by a grant from the National Institutes of Health, National Cancer Institute (CA142868 (to A.G., S.L.M.)); by the Greehey Distinguished Chair in Targeted Molecular Therapeutics (to S.L.M.), Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (to A.G.); and by an NSF equipment grant for NMR instrumentation (NMR: CHE 0614785). This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.We acknowledge the National Cancer Institute Developmental Therapeutics Program for performing the in vitro evaluation in the NCI 60-cell line panel. Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = jan,

day = "1",

doi = "10.3390/molecules27010321",

language = "English (US)",

volume = "27",

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T1 - Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

AU - Islam, Farhana

AU - Doshi, Arpit

AU - Robles, Andrew J.

AU - Quadery, Tasdique M.

AU - Zhang, Xin

AU - Zhou, Xilin

AU - Hamel, Ernest

AU - Mooberry, Susan L.

AU - Gangjee, Aleem

N1 - Funding Information: Funding: This work was supported, in part, by a grant from the National Institutes of Health, National Cancer Institute (CA142868 (to A.G., S.L.M.)); by the Greehey Distinguished Chair in Targeted Molecular Therapeutics (to S.L.M.), Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (to A.G.); and by an NSF equipment grant for NMR instrumentation (NMR: CHE 0614785). This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Funding Information: This work was supported, in part, by a grant from the National Institutes of Health, National Cancer Institute (CA142868 (to A.G., S.L.M.)); by the Greehey Distinguished Chair in Targeted Molecular Therapeutics (to S.L.M.), Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (to A.G.); and by an NSF equipment grant for NMR instrumentation (NMR: CHE 0614785). This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.We acknowledge the National Cancer Institute Developmental Therapeutics Program for performing the in vitro evaluation in the NCI 60-cell line panel. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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N2 - 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.

AB - 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.

KW - Colchicine site

KW - Gewald reaction

KW - Microtubule targeting agents

KW - Microtubules

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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

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