Design, Synthesis, and Biological Evaluation of Novel Pyridine-Bridged Analogues of Combretastatin-A4 as Anticancer Agents.

Funding Source

National Institutes of Health

Grant Number

8G12MD007595 , 8P20GM103424


Department of Chemistry

Document Type


Publication Date



A series of novel pyridine-bridged analogues of combretastatin-A4 (CA-4) were designed and synthesized. As expected, the 4-atom linker configuration retained little cytotoxicities in the compounds 2e, 3e, 3g, and 4i. Activities of the analogues with 3-atom linker varied widely depending on the phenyl ring substitutions, and the 3-atom linker containing nitrogen represents the more favorable linker structure. Among them, three analogues (4h, 4s, and 4t) potently inhibited cell survival and growth, arrested cell cycle, and blocked angiogenesis and vasculature formation in vivo in ways comparable to CA-4. The superposition of 4h and 4s in the colchicine-binding pocket of tubulin shows the binding posture of CA-4, 4h, and 4s are similar, as confirmed by the competitive binding assay where the ability of the ligands to replace tubulin-bound colchicine was measured. The binding data are consistent with the observed biological activities in antiproliferation and suppression of angiogenesis but are not predictive of their antitubulin polymerization activities.


DOI: 10.1021/jm500002k

PubMed ID: 24669888


This work was supported by NIH-NIMHD through grant 8G12MD007595 and NIH-NIGMS grant 8P20GM103424, and in part by Louisiana Cancer Research Consortium. We thank Thomas Vu, Bria Carmichael, Breanna Jarrett, Eric Stewart, and Sydnie Turner for technical assistance in the CAM assays.