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

A set of meta-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 moreactive than the correspondingparaanalogues. These compoundswere initially proposed as inhibitors ofN-ribosyl dihydronicotina-mide (NRH): quinone oxidoreductase 2 (NQO2) but were foundto be inactive against the enzyme. Instead, COMPARE analysissuggested that 6-fluoro-3-(meta-fluorophenyl)isoquinolin-1(2H)-one (4) could mimic colchicine and interact with microtubules, arecognized target for cancer therapy. Subsequent docking,molecular dynamics simulations, and free energy analysis furthersuggested that compound4bound well into the colchicine-binding pocket of tubulin. Indeed,4suppressed tubulin polymerization,causedG2/Mcell cycle arrest, and induced apoptosis. Also,4inhibited the formation of endothelial cell capillary-like tubes andfurther disrupted the structure of preestablished tubes; the effects were not observed withparaanalogue5. In accordance with this,the computed free energy of binding of5to tubulin was lower in magnitude than that for4and appeared to arise in part from theinability of theparasubstituent to occupy a tubulin subpocket, which is possible in themetaorientation. In conclusion, theantiproliferative potential of the novel 3-arylisoquinolinones is markedly influenced by a subtle change in the structure (metaversuspara). Themeta-substituted isoquinolinone4is a microtubule-destabilizing agent with potential tumor-selectivity and antiangiogenic and vascular disrupting features

Automated summary

A set of meta-substituted 3-arylisoquinolinones with substantial cytotoxicity in various cancer cell lines has been discovered. These compounds have the potential to mimic colchicine and interact with microtubules, leading to antiproliferative effects and inhibition of endothelial cell formation.