Effect of Hybrid Compounds of Stilbene and Pentadienone on Inhibition of Tubulin Polymerization

• Published in: Anti-cancer agents in medicinal chemistry Vol. 23; no. 10; p. 1156
• Main Authors: Park, Jihyun, Koh, Dongsoo, Lee, Young Han, Lim, Yoongho, Shin, Soon Young
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2023
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation; Colchicine - pharmacology; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Polymerization; Stilbenes - pharmacology; Structure-Activity Relationship; Tubulin - metabolism; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; in silico docking simulation; stilbene; hybrid; tubulin polymerization; styrylpentadienone; G2/M cell cycle arrest
• ISSN: 1875-5992
• DOI: 10.2174/1871520623666230216091116

Tubulin polymerization inhibitors induce cancer cell death; therefore, they can be developed as chemotherapeutic agents. We hypothesized that hybrid compounds, including the trans-stilbene moiety contained in resveratrol and penta-1,4-dien-3-one contained in curcumin, could inhibit tubulin polymerization. Twenty-six hybrid stilbene and pentadienone compounds were designed and synthesized. The cytotoxicity of the hybrid compounds against MDA-MB-231 human breast cancer cells was determined using a clonogenic long-term survival assay. The relationship between cytotoxicity and structural properties was evaluated. Biological activities, including inhibition of tubulin polymerization and cell cycle progression, were investigated to select compounds with excellent anticancer properties. The molecular binding mode between the selected compound and the α, β-tubulin dimers was investigated. Twenty-six hybrid stilbene and pentadienone compounds were designed and synthesized. Among them, compound 13 exhibited the highest inhibitory effect on the clonogenicity of MDA-MB-231 cells. Compound 13 induced the destabilization of tubulins and inhibited cell cycle progression at the G2/M phase. Through in silico molecular docking analysis, compound 13 was predicted to bind to the colchicine binding site of α, β-tubulin. The stilbene and pentadienone hybrid compound 13 has a binding mode similar to that of colchicine. Compound 13 inhibited the clonogenicity of MDA-MB-231 cells through a mechanism that destabilizes tubulin polymerization, leading to cell cycle arrest at the G2/M phase.