Next Article in Journal
Different Fruit-Specific Promoters Drive AtMYB12 Expression to Improve Phenylpropanoid Accumulation in Tomato
Next Article in Special Issue
Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of c-myc G-Quadruplex DNA
Previous Article in Journal
Cool Temperature Enhances Growth, Ferulic Acid and Flavonoid Biosynthesis While Inhibiting Polysaccharide Biosynthesis in Angelica sinensis
Previous Article in Special Issue
Cyclodextrin Polymers as Delivery Systems for Targeted Anti-Cancer Chemotherapy
Article

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

1
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA
2
Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
3
Mays Cancer Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
4
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
*
Authors to whom correspondence should be addressed.
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)
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 48, 10 and 1213 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 microtubules; colchicine site; microtubule targeting agents; Gewald reaction
Show Figures

Graphical abstract

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

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop