Broadening the Steroidal Toolkit by Late-Stage γ-C(sp³)-H (Hetero)arylation of Homologously Dissected Deoxycholic Acid

A regioselective protocol for Pd(II)-catalyzed intermolecular γ-C(sp³)-H (hetero)arylation of homologously dissected deoxycholyl amides has been developed to afford a series of functionally decorated modified deoxycholyl amides in good-to-excellent yields. This strategy has been further expanded to facilitate the conjugation of drug candidates and natural products, such as paracetamol, amino acids, menthol, cholesterol, and cholic acid, to the C-21 primary methyl carbon of the bile acid skeleton. Preliminary antiproliferative activity studies of these 21-(hetero)arylated products indicated moderate-to-good cytotoxic efficacy against the MCF-7 cancer cell line, with the unprotected arylated products being the most effective and exhibiting nontoxicity toward the normal human embryonic kidney cell line (HEK-293).