Discovery of novel tubulin CBSI from the indanone scaffold for the treatment of colorectal cancer.

In view of the serious adverse reactions and clinical toxicity of first line therapy 5-fluorouracil and lack of small molecule therapeutics in colorectal cancer chemotherapy, a series of natural scaffold-based 3-arylindanone derivatives (9a-q) were designed, synthesized and evaluated as tubulin polymerization inhibitors targeting the colchicine site. The most potent colchicine binding site inhibitor (CBSI), , exhibited 14-38 times more dominant anti-proliferative activity against three colon cancer cell lines than 5-fluorouracil. Particularly, showed higher selectivity against human normal cells compared with 5-fluorouracil and colchicine, and displayed negligible cardiotoxicity through hERG assessment. Furthermore, the binding of to the colchicine site was strongly supported by EBI competition assay and inhibited more tubulin polymerization than colchicine. Besides, the mechanism of action and binding modes of were verified by molecular dynamics simulations and docking. Therefore, could be regarded as a promising CBSI for colorectal cancer therapy.