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

Molecular Pharmacology Branch, Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA

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Academic Editor: Nicola Micale

Molecules 2022, 27(1), 321; https://doi.org/10.3390/molecules27010321

Received: 7 October 2021 / Revised: 21 December 2021 / Accepted: 22 December 2021 / Published: 5 January 2022

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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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. View Full-Text

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

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MDPI and ACS Style

Islam, F.; Doshi, A.; Robles, A.J.; Quadery, T.M.; Zhang, X.; Zhou, X.; Hamel, E.; Mooberry, S.L.; Gangjee, A. Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents. Molecules 2022, 27, 321. https://doi.org/10.3390/molecules27010321

AMA Style

Islam F, Doshi A, Robles AJ, Quadery TM, Zhang X, Zhou X, Hamel E, Mooberry SL, Gangjee A. Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents. Molecules. 2022; 27(1):321. https://doi.org/10.3390/molecules27010321

Chicago/Turabian Style

Islam, Farhana, Arpit Doshi, Andrew J. Robles, Tasdique M. Quadery, Xin Zhang, Xilin Zhou, Ernest Hamel, Susan L. Mooberry, and Aleem Gangjee. 2022. "Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents" Molecules 27, no. 1: 321. https://doi.org/10.3390/molecules27010321

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Author Biographies

Ernest Hamel

Prediction of Biochemical Mechanism of Action from the In Vitro Antitumor Screen of the National Cancer Institute: Ernest Hamel We are in an age when experimental data can be analyzed with unprecedented ease and speed. This permits entirely new approaches to large accumulations of data. The new National Cancer Institute (NCI) in vitro anticancer screening program generates prodigious quantities of information-laden biological test results, captured in an easily accessible computerized database. We describe an analysis of the NCI in vitro database that answers questions that could not be asked in any previous screening program. Our analysis of these data is performed by a program we call COMPARE. A probe or “seed” compound can be specified by using the compound’s NCI accession number (the NSC number). The COMPARE algorithm then proceeds to rank an entire database in the order of the similarity of the responses of the 60 cell lines to the compounds in the database to the responses of the cell lines to the seed compound. Similarity of pattern to that of the seed is expressed quantitatively as a Pearson correlation coefficient (PCC). The results obtained with the COMPARE algorithm indicate that compounds high in this ranking may possess a mechanism of action similar to that of the seed compound.

Susan L. Mooberry

Susan Mooberry, Ph.D. Professor of Pharmacology, Greehey Distinguished Chair in Targeted Molecular Therapeutics A major focus of my laboratory is the discovery of new drugs for the treatment of cancer, primarily breast cancer and solid pediatric cancers. Our historic focus has been on the identification of novel microtubule-targeting agents from natural products and synthetic chemistry efforts. This work continues and we are also evaluating diverse natural product extracts for activity against specific types of cancer, including the molecularly defined subtypes of triple negative breast cancer and pediatric solid tumors. We conduct the initial discovery in mechanism-based and mechanism blind screens, use bioassay-guided fractionation, in collaboration with our chemistry collaborators to identify the active constituents, and then conduct mechanistic studies on the pure compounds and on synthetic and natural analogs. In addition to our drug discovery efforts, a second major initiative is identifying the molecular mechanisms of action of chemically diverse microtubule targeting agents. While microtubule targeting drugs have been used successfully for decades for breast and pediatric cancers, we still do not fully understand why these drugs are effective and which patients will respond best to the different drugs. We are investigating how these drugs differentially interfere with interphase signaling events important for oncogenesis.

Aleem Gangjee

Dr Gangjee has expertise in synthetic medicinal chemistry, computer-assisted drug design, inhibitors of folate metabolizing enzymes, receptor tyrosine kinase inhibitors, antimitotic agents, antitumor agents, anti-opportunistic infection agents, nucleosides, heterocyclic chemistry and stereochemistry.

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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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