SAR of Novel 3-Arylisoquinolinones: -Substitution on the Aryl Ring Dramatically Enhances Antiproliferative Activity through Binding to Microtubules.

A set of -substituted 3-arylisoquinolinones have been identified that show substantial cytotoxicity in breast, liver, lung and colon cancer cell lines; these are up to 700-fold more active than the corresponding analogues. These compounds were initially proposed as inhibitors of -ribosyl dihydronicotinamide (NRH): quinone oxidoreductase 2 (NQO2) but were found to be inactive against the enzyme. Instead, COMPARE analysis suggested that 6-fluoro-3-(-fluorophenyl)isoquinolin-1(2)-one () could mimic colchicine and interact with microtubules, a recognized target for cancer therapy. Subsequent docking, molecular dynamics simulations, and free energy analysis further suggested that compound bound well into the colchicine-binding pocket of tubulin. Indeed, suppressed tubulin polymerization, caused / cell cycle arrest, and induced apoptosis. Also, inhibited the formation of endothelial cell capillary-like tubes and further disrupted the structure of preestablished tubes; the effects were not observed with analogue . In accordance with this, the computed free energy of binding of to tubulin was lower in magnitude than that for and appeared to arise in part from the inability of the substituent to occupy a tubulin subpocket, which is possible in the orientation. In conclusion, the antiproliferative potential of the novel 3-arylisoquinolinones is markedly influenced by a subtle change in the structure ( versus ). The -substituted isoquinolinone is a microtubule-destabilizing agent with potential tumor-selectivity and antiangiogenic and vascular disrupting features.