title: Enantiomeric deoxycholic acid: total synthesis, characterization, and preliminary toxicity toward colon cancer cell lines.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Pharmacology, Division of Gastroenterology, Washington University in St Louis School of Medicine, St Louis, MO 63110, USA.
authors.forename: Bryson W
authors.initials: BW
authors.lastname: Katona
authors.forename: Nigam P
authors.initials: NP
authors.lastname: Rath
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.forename: William F
authors.initials: WF
authors.lastname: Stenson
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D001647:Bile Acids and Salts / Q000032:analysis / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000648:ultrastructure; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003517:Cyclopentanes / Q000737:chemistry; D003840:Deoxycholic Acid / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; D003517:Cyclopentanes; D003840:Deoxycholic Acid; C471838:3-methyl-1,2-cyclopentanedione