Novel Combretastatin-2-aminoimidazole Analogues as Potent Tubulin Assembly Inhibitors: Exploration of Unique Pharmacophoric Impact of Bridging Skeleton and Aryl Moiety

Combretastatin
A-4 (CA-4) in phosphate and serine pro-drug forms is under phase II
clinical trials. With our interest of discovering CA-4 inspired new
chemical entities, a novel series of 4,5-diaryl-2-aminoimidazole analogues
of the compound was designed and synthesized by an efficient and diversity
feasible route involving atom economical arene C–H bond arylation.
Interestingly, four compounds showed potent cell-based antiproliferative
activities in nanomolar concentrations. Among the compounds, compound 12 inhibited the proliferation of several types of cancer
cells much more efficiently than CA-4. It depolymerized microtubules,
induced spindle defects, and stalled mitosis in cells. Compound 12 bound to tubulin and inhibited the polymerization of tubulin
in vitro. In addition, podophyllotoxin and CA-4 inhibited the binding
of compound 12 to tubulin. The distinctive pharmacophoric
features of the bridging motif as well as quinoline nucleus were explored.
We noted also a valuable quality of compound 12 as a
potential probe in characterizing new CA-4 analogues.