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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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Research Article

Synthesis and Selective Anticancer Activity Evaluation of 2-phenylacrylonitrile Derivatives as Tubulin Inhibitors

Author(s): Ye-Zhi Jin, Ya-Bing Xin, Yuan Li, Xin-Yuan Chen, De-Ao Man and Yu-Shun Tian*

Volume 31, Issue 15, 2024

Published on: 16 October, 2023

Page: [2090 - 2106] Pages: 17

DOI: 10.2174/0109298673263854231009063053

open access plus

TIMBC 2025
Abstract

Objective: This study aimed at synthesizing 13 series of novel derivatives with 2-phenylacrylonitrile, evaluating antitumor activity both in vivo and in vitro, and obtaining novel tubulin inhibitors.

Methods: The 13 series of 2-phenylacrylonitrile derivatives were synthesized by Knoevenagel condensation and the anti-proliferative activities were determined by MTT assay. The cell cycle and apoptosis were analyzed by flow cytometer. Quantitative cell migration was performed using 24-well Boyden chambers. The proteins were detected by western blotting. in vitro kinetics of microtubule assembly was measured using ELISA kit for Human β-tubulin (TUBB). Molecular docking was done by Discovery Studio (DS) 2017 Client online tool.

Results: Among the derivatives, compound 1g2a possessed strong inhibitory activity against HCT116 (IC50 = 5.9 nM) and BEL-7402 (IC50 = 7.8 nM) cells. Compound 1g2a exhibited better selective antiproliferative activities and specificities than all the positive control drugs, including taxol. Compound 1g2a inhibited proliferation of HCT116 and BEL-7402 cells by arresting them in the G2/M phase of the cell cycle, inhibited the migration of HCT116 and BEL-7402 cells and the formation of cell colonies. Compound 1g2a showed excellent tubulin polymerization inhibitory activity on HCT116 and BEL-7402 cells. The results of molecular docking analyses showed that 1g2a may inhibit tubulin to exert anticancer effects.

Conclusion: Compound 1g2a shows outstanding antitumor activity both in vivo and in vitro and has the potential to be further developed into a highly effective antitumor agent with little toxicity to normal tissues.

Keywords: 2-Phenylacrylonitrile, selective toxic effect, cell cycle arrest, apoptosis, xenograft model, tubulin inhibitor.

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