Utilization of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinone as a cap moiety in design of novel histone deacetylase inhibitors |
| |
| Affiliation: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt;2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt;3. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 2014, Aljouf, Saudi Arabia;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt;5. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt;6. Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt;7. Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, 71526 Assiut, Egypt;8. Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt;1. School of Biological Science and Technology, University of Jinan, Jinan, Shandong Province 250022, China;2. Institute for Translation Medicine, Qingdao University, Qingdao, Shandong Province 266071, China;1. Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education. College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing, 100029, China;2. Laboratory of Natural Products Chemistry and Biomolecules, University of Blida 1, BP 270, Blida, Algeria;1. Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka, 2014, Saudi Arabia;2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt;4. Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt;5. College of Medicine, Al-Rayyan Colleges, Al Madinah Al Munawarah, 41411, Saudi Arabia;6. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt;7. Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt;8. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Aljouf University, Aljouf, Sakaka, 2014, Saudi Arabia;9. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524, Sohag, Egypt;10. School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen, AB243UE, Ireland;1. Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji''nan, Shandong, 250012, PR China;2. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji''nan, Shandong, 250012, PR China;3. Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, SC, 29425, United States;4. Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, 261061, PR China;1. School of Pharmacy, Taipei Medical University, Taipei, Taiwan;2. Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan;3. School of Pharmacy, National Taiwan University, Taipei, Taiwan;4. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan;5. TaiMed Biologics Inc., Taipei, Taiwan;6. School of Pharmacy, National Defense Medical Center, Taipei, Taiwan;7. Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei, Taiwan;8. Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan |
| |
| Abstract: | 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. |
| |
| Keywords: | Histone deacetylase inhibitors Molecular docking Anti-proliferative Apoptotic assay |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
