title: Synthesis and biological evaluation of novel 6-substituted analogs of 1α,25-dihydroxy-19-norvitamin D3.
abstract: We have recently described the synthesis and biological evaluation of 1α,25-dihydroxy-6-methylvitamin D3 which binds the vitamin D receptor (VDR) very effectively. Unfortunately, this compound has a strong tendency to rearrange to its previtamin form. Taking this into consideration, we decided to synthesize a series of 6-substituted analogs of 1α,25-dihydroxy-19-norvitamin D3 which lack the exomethylene moiety at C-10 and thus are unable to undergo a conversion to their respective previtamin forms. The synthesis of analogs bearing different substituents at C-6 was accomplished by Suzuki-Miyaura cross-coupling reaction of a bicyclic organoboron derivative (CD-ring fragment) with the respective alkenyl halides (A-ring synthons). The biological in vitro studies of the affinity of synthesized analogs to the full-length recombinant rat VDR indicate that presence of a bulky, polar substituent at C-6 results in decrease in binding ability. Moreover, introduction of a 6-methyl substituent into the 1α,25-dihydroxy-19-norvitamin D3 molecule results in the 9 times lower affinity of the homolog to the VDR while the same modification of calcitriol has not influenced binding activity. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sokolowska
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
authors.forename: Antonio
authors.initials: A
authors.lastname: Mouriño
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical; D018922:HL-60 Cells; D006801:Humans; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018167:Receptors, Calcitriol; D002117:Calcitriol