Purine/purine isoster based scaffolds as new derivatives of benzamide class of HDAC inhibitors

  • Eur J Med Chem. 2020 Jun 15;196:112291. doi: 10.1016/j.ejmech.2020.112291.
Kunal Nepali  1 ,  Ting-Yu Chang  2 ,  Mei-Jung Lai  3 ,  Kai-Cheng Hsu  4 ,  Yun Yen  5 ,  Tony Eight Lin  5 ,  Sung-Bau Lee  6 ,  Jing-Ping Liou  7
Affiliations
  • 1. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
  • 2. Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taiwan; Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taiwan; Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taiwan.
  • 3. Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taiwan.
  • 4. Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan; Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taiwan.
  • 5. Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taiwan.
  • 6. Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taiwan; Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taiwan. Electronic address: [email protected].
  • 7. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan; Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei, Taiwan. Electronic address: [email protected].
PMID: 32325365 DOI: 10.1016/j.ejmech.2020.112291
Abstract

This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast Cancer cells MDA-MB-231 (IC50 = 1.48 μM), MDA-MB-468 (IC50 = 0.65 μM), and liver Cancer cells HepG2 (IC50 = 2.44 μM), better than MS-275 (5) and Chidamide (6). Compared to the well-known HDAC Inhibitor SAHA, 14 showed a higher toxicity (IC50 = 0.33 μM) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, 14 was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, respectively, indicating the potential of 14 to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 (5) and Chidamide (6) were displayed by 14 towards HDAC1, 2 and 3 isoforms with IC50 values of 0.108, 0.585 and 0.563 μM respectively. Compound 14 also exhibited a potent antitumor efficacy in human MDA-MB-231 breast Cancer xenograft mouse model, providing a potential lead for the development of Anticancer agents.

Keywords
Drug resistance; Histone deacetylase inhibitors; Isosters; Purines.
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