Design, synthesis, and biological evaluation of hydantoin bridged analogues of combretastatin A-4 as potential anticancer agents.

Abstract

A series of novel hydantoin-bridged analogues of combretastatin A-4 (CA-4) were designed, synthesized and evaluated for antiproliferative activities in vitro and in vivo. The most potent compound 8d, showed potent cytotoxicity against four human cancer cell lines with IC50 values of 0.186-0.279 μM, and possessed the efficacy of inhibiting tubulin polymerization, disrupting in vitro vascularization, blocking cell cycle in G2/M phase and inducing cell apoptosis. In the nude mice xenograft model, 8d significantly inhibited the tumor growth and showed low toxicity. Further chiral separation proved (R)-(-)-8d to be the preferential enantiomer with IC50 values of 0.081-0.157 M. These results indicated that the hydantoin derivatives merit further investigation as potential anticancer agents that inhibit tubulin polymerization.

• Authors: Mao Zhang, Yu-Ru Liang, Huan Li, Ming-Ming Liu, Yang Wang
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 25 Issue 24 Pg. 6623-6634 (12 15 2017) ISSN: 1464-3391 [Electronic] England
• PMID: 29126741 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Hydantoins
• Stilbenes
• fosbretabulin

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Female
• HeLa Cells
• Humans
• Hydantoins (chemical synthesis, chemistry, pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Structure
• Neoplasms, Experimental (drug therapy, pathology)
• Stilbenes (chemistry, pharmacology)
• Structure-Activity Relationship