Enantiomeric Deoxycholic Acid: Total Synthesis, Characterization, and Preliminary Toxicity toward Colon Cancer Cell Lines

Deoxycholic acid (DCA) is an endogenous secondary bile acid implicated in numerous pathological
conditions including colon cancer formation and progression and cholestatic liver disease. DCA
involvement in these disease processes results partly from its ability to modulate signaling cascades
within the cell, presumably through both direct receptor activation and general detergent mediated
membrane changes. To further explore DCA induced changes in cell signaling, we completed a total
synthesis of enantiomeric deoxycholic acid (ent-DCA) from achiral 2-methyl-1,3-cyclopentanedione. Using
a modified method of the synthesis of ent-testosterone that proceeds through the (R)-(−)-Hajos−Parrish
ketone, we have completed the successful synthesis of ent-DCA in 25 steps with a yield of 0.3% with all
stereochemical assignments of the product confirmed by X-ray crystallography. Our studies toward this
synthesis also uncovered the methodology for the development of a novel A,B-cis steroidal skeleton
system containing a C3−C9 single bond as well as conditions to selectively ketalize the typically less
reactive 12-carbonyl in poly-keto A,B-cis androgens. The critical micelle concentration (cmc) of ent-DCA, determined by a dye solubilization method, was identical to the cmc of natural DCA. Toxicity
studies toward HT-29 and HCT-116 human colon cancer cell lines demonstrated that ent-DCA had similar
effects on proliferation, yet showed a markedly decreased ability to induce apoptosis as compared to
natural DCA.