2. Academic Validation
  3. Design, synthesis, and evaluation of N-phenyl-4-(2-phenylsulfonamido)-benzamides as microtubule-targeting agents in drug-resistant cancer cells, displaying HDAC inhibitory response

Design, synthesis, and evaluation of N-phenyl-4-(2-phenylsulfonamido)-benzamides as microtubule-targeting agents in drug-resistant cancer cells, displaying HDAC inhibitory response

  • Eur J Med Chem. 2020 Apr 15;192:112158. doi: 10.1016/j.ejmech.2020.112158.
Wei-Cheng Wu 1,  Yi-Min Liu 2,  Mei-Hsiang Lin 1,  Yu-Hsuan Liao 1,  Mei-Jung Lai 3,  Hsun-Yueh Chuang 1,  To-Yu Hung 1,  Chun-Han Chen 4,  Jing-Ping Liou 5
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
  • 2 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan; Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
  • 3 TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan.
  • 4 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: brianchc@tmu.edu.tw.
  • 5 School of Pharmacy, 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: jpl@tmu.edu.tw.
PMID: 32171161 DOI: 10.1016/j.ejmech.2020.112158
Abstract

Microtubule-targeting agents (MTA) have enjoyed significant clinical success for decades. However, several mechanisms may cause inactivation of such drugs, leading to acquired resistance in patients treated with them. Therefore, drugs containing a stilbene-like skeleton and possessing dual inhibitory activity may provide a new and differentiated treatment for patients to overcome challenging acquired resistance. A new compound (16c) displays promising Anticancer activity with GI50 of 22 ± 2 and 12 ± 0.1 nM in vincristine-resistant nasopharyngeal (KB-Vin) Cancer cells and etoposide-resistant nasopharyngeal (KB-7D) Cancer cells and is better than vincristine, etoposide, ABT-751, and MS-275. A mechanistic study revealed that 16c interferes with the cell cycle distribution and induces cell cycle arrest at the G2/M phase and severe mitotic spindle defects followed by Apoptosis. In addition, it produces much more significant cytotoxicity than vincristine and etoposide in the corresponding resistant cells, indicating that it may be a promising candidate to overcome drug resistance in Cancer cells. Compound 16c also displays inhibitory activity against HDAC 1 and HDAC 2 with IC50 values of 1.07 μM, and 1.47 μM, respectively. These findings may lead to a new type of structural motif for future development of drugs that could overcome acquired resistance to MTAs.

Keywords

Drug-resistant cancer cells; Histone deacetylases (HDAC); Microtubule-targeting agents.

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