Design, Synthesis, and Biological Evaluation of Novel Quinazolin-4(3H)-one-Based Histone Deacetylase 6 (HDAC6) Inhibitors for Anticancer Activity
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Published:2023-07-03
Issue:13
Volume:24
Page:11044
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Khetmalis Yogesh Mahadu1, Fathima Ashna2ORCID, Schweipert Markus3, Debarnot Cécile3, Bandaru Naga Venkata Madhusudhan Rao1, Murugesan Sankaranarayanan4, Jamma Trinath2, Meyer-Almes Franz-Josef3ORCID, Sekhar Kondapalli Venkata Gowri Chandra1
Affiliation:
1. Department of Chemistry, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, Telangana, India 2. Department of Biological Sciences, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, Telangana, India 3. Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany 4. Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science Pilani, Pilani Campus, Pilani 333031, Rajasthan, India
Abstract
A series of novel quinazoline-4-(3H)-one derivatives were designed and synthesized as histone deacetylase 6 (HDAC6) inhibitors based on novel quinazoline-4-(3H)-one as the cap group and benzhydroxamic acid as the linker and metal-binding group. A total of 19 novel quinazoline-4-(3H)-one analogues (5a–5s) were obtained. The structures of the target compounds were characterized using 1H-NMR, 13C-NMR, LC–MS, and elemental analyses. Characterized compounds were screened for inhibition against HDAC8 class I, HDAC4 class IIa, and HDAC6 class IIb. Among the compounds tested, 5b proved to be the most potent and selective inhibitor of HDAC6 with an IC50 value 150 nM. Some of these compounds showed potent antiproliferative activity in several tumor cell lines (HCT116, MCF7, and B16). Amongst all the compounds tested for their anticancer effect against cancer cell lines, 5c emerged to be most active against the MCF-7 line with an IC50 of 13.7 μM; it exhibited cell-cycle arrest in the G2 phase, as well as promoted apoptosis. Additionally, we noted a significant reduction in the colony-forming capability of cancer cells in the presence of 5c. At the intracellular level, selective inhibition of HDAC6 was enumerated by monitoring the acetylation of a-tubulin with a limited effect on acetyl-H3. Importantly, the obtained results suggested a potent effect of 5c at sub-micromolar concentrations as compared to the other molecules as HDAC6 inhibitors in vitro.
Funder
State of Hesse Council of Scientific and Industrial Research Birla Institute of Technology and Science, Pilani
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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