Citation: Jian Song, Shenghui Wang, Qiuge Liu, Xiao Wang, Shuo Yuan, Hongmin Liu, Saiyang Zhang. N-Benzyl arylamide derivatives as novel and potent tubulin polymerization inhibitors against gastric cancers: Design, structure–activity relationships and biological evaluations[J]. Chinese Chemical Letters, ;2025, 36(2): 109678. doi: 10.1016/j.cclet.2024.109678 shu

N-Benzyl arylamide derivatives as novel and potent tubulin polymerization inhibitors against gastric cancers: Design, structure–activity relationships and biological evaluations

Jian Song ^{a, 1} ,
Shenghui Wang ^{a, 1} ,
Qiuge Liu ^a ,
Xiao Wang ^a ,
Shuo Yuan ^d ,
Hongmin Liu ^{b, *,} ,
Saiyang Zhang ^{a, c, *,}

a.
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
b.
School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou 450001, China
c.
State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou 450001, China
d.
Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou 450018, China

liuhm@zzu.edu.cn

saiyangz@zzu.edu.cn

Received Date: 2 January 2024
Revised Date: 20 February 2024
Accepted Date: 22 February 2024
Available Online: 28 February 2024

Figures(4)

In this work, we employed a ring-opening strategy to develop a series of novel N-benzyl arylamide derivatives as tubulin polymerization inhibitors. Notably, 13n (MY-1388) exhibited remarkable antiproliferative potency on fifteen human cancer cell lines, with half maximal inhibitory concentration (IC₅₀) values ranging from 8 nmol/L to 48 nmol/L. Furthermore, 13n effectively suppressed tubulin polymerization by targeting the colchicine-binding site (IC₅₀ = 0.62 µmol/L). 13n also exhibited significant inhibition of cell colony formation, as well as displayed potent effects on inducing G2/M phase cell cycle arrest and promoting apoptosis. Importantly, 13n exhibited enhanced and adequate liver microsomal stability in human and rat liver microsomes, and also exhibited a moderate half-life (T_1/₂ = 0.938 h) in vivo. Meanwhile, 13n demonstrated effective antitumor effects in vivo in suppressing tumor growth in the MGC-803 xenograft model (tumor growth inhibition (TGI) value was 76.4% at the dosage of 30 mg kg⁻¹ day⁻¹) with a good safety profile. Collectively, these results revealed that 13n represents a promising tubulin polymerization inhibitor that deserves further investigation for its efficacy in treating gastric cancers.
- Tubulin,
- Colchicine binding site,
- CA-4,
- N-Benzyl arylamide,
- Antiproliferative activities
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