Novel Podophyllotoxin Derivatives as Potential Tubulin Inhibitors: Design, Synthesis, and Antiproliferative Activity Evaluation

• Published in: Chemistry & biodiversity 2018-11, Vol.15 (11), p.e1800289-n/a
• Main Authors: Han, Hong‐Wei, Lin, Hong‐Yan, He, De‐Liu, Ren, Yao, Sun, Wen‐Xue, Liang, Li, Du, Mei‐Hang, Li, Deng‐Chao, Chu, Yi‐Chun, Yang, Min‐Kai, Wang, Xiao‐Ming, Yang, Yong‐Hua
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Antiproliferatives; Antiviral drugs; Apoptosis; Apoptosis - drug effects; Bcl-2, microtubule; biological activity; Biotechnology; Cancer; Cell cycle; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; Colchicine; cytotoxicity; Derivatives; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; heterocycles; Humans; Mitosis; Molecular Conformation; Molecular docking; Molecular Docking Simulation; Podophyllotoxin; Podophyllotoxin - chemical synthesis; Podophyllotoxin - chemistry; Podophyllotoxin - pharmacology; Polymerization; siRNA; Structure-Activity Relationship; Time dependence; Tubulin; Tubulin - metabolism; Tumor cell lines; Tumor Cells, Cultured; Western blotting
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.201800289

A number of podophyllotoxin derivatives (3A–3J) had been designed and synthesized, and their biological activities were evaluated in this study. Moreover, the antiproliferation activities of these compounds against four human cancer cell lines (HepG2, HeLa, A549, and MCF‐7) were also tested. The results indicated that the most promising compound 3D displayed potent inhibitory activity over the four human cancer cell lines and was further demonstrated to have potent tubulin polymerization inhibitory effects without damaging the non‐cancer cells. Additionally, 3D was verified to effectively interfere with tubulin and could prevent the mitosis of cancer cells, leading to cell cycle arrest and eventually inducing apoptosis in a dose‐ and time‐dependent manner. Moreover, the Western blotting and siRNA results showed that Bcl‐2 was downregulated in HepG2 cells treated with 3D. Finally, the molecular docking simulation results revealed that 3D could fit well in the colchicine‐binding pocket. Taken together, this study has provided certain novel antitubulin agents for possible cancer chemotherapy.