Utilization of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinone as a cap moiety in design of novel histone deacetylase inhibitors.

Autor: Mohamed MFA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt. Electronic address: mamdouh.fawzi@pharm.sohag.edu.eg., Youssif BGM; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 2014, Aljouf, Saudi Arabia., Shaykoon MSA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt., Abdelrahman MH; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt., Elsadek BEM; Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt., Aboraia AS; Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, 71526 Assiut, Egypt., Abuo-Rahma GEA; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt. Electronic address: gamal.aborahama@mu.edu.eg.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2019 Oct; Vol. 91, pp. 103127. Date of Electronic Publication: 2019 Jul 18.
DOI: 10.1016/j.bioorg.2019.103127
Abstrakt: A series of novel 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives bearing a hydroxamic acid, 2-aminoanilide and hydrazide moieties as zinc-binding group (ZBG) were designed, synthesized and evaluated for the HDAC inhibition activity and antiproliferative activity. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds IVa, IVb, IXa and IXb exhibited significant anti-proliferative activity against the three cell lines tested compared to SAHA as a reference. Compound IVb is equipotent inhibitor for HDAC1 and HDAC2 as SAHA. It is evident that the presence of free hydroxamic acid group is essential for Zn binding affinity with maximal activity with a linker of aliphatic 6 carbons. Docking study results revealed that compound IVb could occupy the HDAC2 binding site and had the potential to exhibit antitumor activity through HDAC inhibition, which merits further investigation.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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