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

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 GI ₅₀ 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 IC ₅₀ 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020. Published by Elsevier Masson SAS.)