Quantum Chemistry Calculation-Aided Structural Optimization of Combretastatin A‑4-like Tubulin Polymerization Inhibitors: Improved Stability and Biological Activity

A potent
combretastatin A-4 (CA-4) like tubulin polymerization
inhibitor 22b was found with strong antitumor activity
previously. However, it easily undergoes cis–trans isomerization under natural light, and the resulting decrease in
activity limits its further applications. In this study, we used quantum
chemistry calculations to explore the molecular basis of its instability.
Aided by the calculations, two rounds of structural optimization of 22b were conducted. Accelerated quantitative light stability
testing confirmed that the stability of these designed compounds was
significantly improved as predicted. Among them, compounds 1 and 3b displayed more potent inhibitory activity on
tumor cell growth than 22b. In addition, the potent in vivo antitumor activity of compound 1 was
confirmed. Quantum chemistry calculations were used in the optimization
of stilbene-like molecules, providing new insight into stilbenoid
optimization and important implications for the future development
of novel CA-4-like tubulin polymerization inhibitors.