title: Synthesis and biological activity of 25-hydroxy-2-methylene-vitamin D3 compounds.
abstract: We have recently obtained 1-desoxy and 3-desoxy analogs of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (2MD), a compound exerting significantly enhanced calcemic activity and currently being evaluated as a potential drug for osteoporosis. In order to further explore this class of pharmacologically important vitamin D compounds we have decided to synthesize analogs characterized by the presence of two A-ring exocyclic methylene groups attached to C-2 and C-10. The Sonogashira coupling of a triflate enol of the protected (20R)- or (20S)-25-hydroxy Grundmann ketone and the corresponding dienyne A-ring fragment provided the target compounds. A new synthetic path was elaborated, leading to the desired A-ring synthon, that started from commercially available 1,4-cyclohexanedione monoethylene acetal. Biological in vitro and in vivo activities of the synthesized 25-hydroxy-2-methylene-vitamin D3 compounds, belonging to 20R- and 20S-series, were evaluated and discussed. 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: Izabela
authors.initials: I
authors.lastname: Sibilska
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; 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; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium