title: Highly active analogs of 1alpha,25-dihydroxyvitamin D(3) that resist metabolism through C-24 oxidation and C-3 epimerization pathways.
abstract: The secosteroid hormone 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] is metabolized in its target tissues through modifications of both the side chain and the A-ring. The C-24 oxidation pathway, the main side chain modification pathway is initiated by hydroxylation at C-24 of the side chain and leads to the formation of the end product, calcitroic acid. The C-23 and C-26 oxidation pathways, the minor side chain modification pathways are initiated by hydroxylations at C-23 and C-26 of the side chain and lead to the formation of the end product, calcitriol lactone. The C-3 epimerization pathway, the newly discovered A-ring modification pathway is initiated by epimerization of the hydroxyl group at C-3 of the A-ring to form 1alpha,25(OH)(2)-3-epi-D(3). A rational design for the synthesis of potent analogs of 1alpha,25(OH)(2)D(3) is developed based on the knowledge of the various metabolic pathways of 1alpha,25(OH)(2)D(3). Structural modifications around the C-20 position, such as C-20 epimerization or introduction of the 16-double bond affect the configuration of the side chain. This results in the arrest of the C-24 hydroxylation initiated cascade of side chain modifications at the C-24 oxo stage, thus producing the stable C-24 oxo metabolites which are as active as their parent analogs. To prevent C-23 and C-24 hydroxylations, cis or trans double bonds, or a triple bond are incorporated in between C-23 and C-24. To prevent C-26 hydroxylation, the hydrogens on these carbons are replaced with fluorines. Furthermore, testing the metabolic fate of the various analogs with modifications of the A-ring, it was found that the rate of C-3 epimerization of 5,6-trans or 19-nor analogs is decreased to a significant extent. Assembly of all these protective structural modifications in single molecules has then produced the most active vitamin D(3) analogs 1alpha,25(OH)(2)-16,23-E-diene-26,27-hexafluoro-19-nor-D(3) (Ro 25-9022), 1alpha,25(OH)(2)-16,23-Z-diene-26,27-hexafluoro-19-nor-D(3) (Ro 26-2198), and 1alpha,25(OH)(2)-16-ene-23-yne-26,27-hexafluoro-19-nor-D(3) (Ro 25-6760), as indicated by their antiproliferative activities.
authors.affiliation: Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Uskokovic
authors.forename: A W
authors.initials: AW
authors.lastname: Norman
authors.forename: P S
authors.initials: PS
authors.lastname: Manchand
authors.forename: G P
authors.initials: GP
authors.lastname: Studzinski
authors.forename: M J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
authors.forename: A
authors.initials: A
authors.lastname: Takeuchi
authors.forename: M L
authors.initials: ML
authors.lastname: Siu-Caldera
authors.forename: D S
authors.initials: DS
authors.lastname: Rao
authors.forename: G S
authors.initials: GS
authors.lastname: Reddy
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: C090785:1,25-dihydroxy-24-oxo-16-ene-vitamin D3; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D002117:Calcitriol