2. Academic Validation
  3. 1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase

1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase

  • Eur J Med Chem. 2019 Jan 15:162:612-630. doi: 10.1016/j.ejmech.2018.10.066.
Mei-Jung Lai 1,  Ritu Ojha 2,  Mei-Hsiang Lin 2,  Yi-Min Liu 1,  Hsueh-Yun Lee 2,  Tony Eight Lin 3,  Kai-Cheng Hsu 3,  Chi-Yen Chang 4,  Mei-Chuan Chen 5,  Kunal Nepali 2,  Jang-Yang Chang 6,  Jing-Ping Liou 7
Affiliations

Affiliations

  • 1 TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan.
  • 2 School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
  • 3 The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 4 National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan.
  • 5 Ph.D. Program for Clinical Drug Development of Chinese Herbal Medicine, College of Pharmacy, Taipei Medical University, Taiwan.
  • 6 Division of Hematology/Oncology, Department of Internal Medicine, National Cheng King University Hospital, College of Medicine, National Cheng King University, Tainan, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan. Electronic address: jychang@nhri.org.tw.
  • 7 School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan. Electronic address: jpl@tmu.edu.tw.
PMID: 30476825 DOI: 10.1016/j.ejmech.2018.10.066
Abstract

We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC50 value of 1.1 μM, better than that of combretastain A-4 (3), and substantial antiproliferative activity against a variety of Cancer cells, including MDR-positive cell lines with an IC50 value of 49 nM (KB), 79 nM (A549), 63 nM (MKN45), 64 nM (KB-VIN10), 43 nM (KB-S15), and 46 nM (KB-7D). Dual inhibitory potential of compound 9 was found as it demonstrated significant inhibitory potential against HDAC1, 2 and 6 in comparison to MS-275 (6). Some key interactions of 9 with the amino acid residues of the active site of tubulin and with amino acid residues of HDAC 1 isoform have been figured out by molecular modeling. Compound 9 also demonstrated significant in vivo efficacy in the human non-small cell lung Cancer A549 xenograft model as well as B-cell lymphoma BJAB xenograft tumor model.

Keywords

Benzamide; Cancer; HDAC; Indoline; Tubulin.

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