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

Abstract

A potent combretastatin A-4 (CA-4) like tubulin polymerization inhibitor <b>22b</b> was found with strong antitumor activity previously. However, it easily undergoes <i>cis–trans</i> 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 <b>22b</b> were conducted. Accelerated quantitative light stability testing confirmed that the stability of these designed compounds was significantly improved as predicted. Among them, compounds <b>1</b> and <b>3b</b> displayed more potent inhibitory activity on tumor cell growth than <b>22b</b>. In addition, the potent <i>in vivo</i> antitumor activity of compound <b>1</b> 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