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
  • 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: [email protected].
  • 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: [email protected].
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.