Design, synthesis and anticancer evaluation of polymethoxy aurones as potential cell cycle inhibitors

Cancer is the most fatal disease in humans and the aberrant activity of various cell cycle proteins results in uncontrolled tumor cell proliferation, thus, regulating the cell cycle is an attractive target in cancer therapy.

Aurone is a naturally occurring active compound with a wide range of biological activities, of which 3, 4, 5-trimethoxyphenyl (TMP) is an important microtubule targeting pharmacophore. Based on the pharmacophore combination principle, we incorporate the TMP pharmacophore into the aurone structure and design a novel polymethoxy derivative that is expected to inhibit tumor cell proliferation through regulating the cell cycle.

By introducing different substituents on C-4' and C-3', a series of new 4, 5, 6-trimethoxy aurone derivatives have been designed and synthesized. DU145, MCF-7 and H1299 cell lines were selected to evaluate their anticancer activity. The compound with the best cytotoxicity was then selected and the anticancer mechanisms were investigated by network pharmacology, flow cytometry, Western blot, and cell heat transfer assay. ADMET prediction evaluated the draggability of aurone derivatives.

Aurones 1b and 1c have selective anti-proliferative activity against DU145 cells. Among them, the compound 1c have better cytotoxicity against DU145. Compound 1c could bind the active cavity of CyclinB1/CDK1/CKS complex protein and induced G2/M phase arrest of DU145 cells by regulating the expression of CyclinB1 and p21. Compound 1c satisfies the Lipinski rule, is suitable for the absorption and metabolism index, and has a lower risk of cardiac toxicity.

Polymethoxy aurones 1c might function as a CyclinB1/CDK1 inhibitor that deserved to be further developed for the treatment of prostate cancer.