Selective synthesis of A-ring E-arylidene derivatives from -sitosterol and their activity

A series of 24-ethylcholest-4-ene-3,6-dione 2E-arylidene-derivatives has been synthesized by a Claisen-Schmidt reaction from a natural phytosterol beta-sitosterol with yields of 80-85%. The structure of the obtained compounds was confirmed by NMR spectroscopy, including two-dimensional correlation experiments. The synthesized compounds were evaluated for their in vitro cytotoxicity and alpha-glucosidase inhibitory activity. It was established that compound 3 with pyridin-3-ylmethylene moiety exhibited a selective cytotoxic effect against the U251 cancer cell line with 99.31% inhibition of cancer cell growth. Compounds with pyridin-4ylmethylene 4 -and furan-2-ylmethylene-5 fragments were the most active inhibitors of alpha-glucosidase with IC50 64.00 and 38.95 mu M, being 3- and 5-times more active than acarbose. Binding mode to alpha-glucosidase and ADMET characteristics for the lead molecule 5 were proposed computationally. To sum up, an efficient approach to the derivatives with promising antidiabetic activity based on available natural product beta-sitosterol is suggested. [GRAPHICS] .