title: A Methylene Group on C-2 of 24,24-Difluoro-19-nor-1α,25-dihydroxyvitamin D3 Markedly Increases Bone Calcium Mobilization in Vivo.
abstract: Four side chain fluorinated analogues of 1α,25-dihydroxy-19-norvitamin D have been prepared in convergent syntheses using the Wittig-Horner reaction as a key step. Structures and absolute configurations of analogues 3 and 5 were confirmed by X-ray crystallography. All analogues showed high potency in HL-60 cell differentiation and vitamin D-24-hydroxylase (24-OHase) transcription as compared to 1α,25-dihydroxyvitamin D3 (1). Most important is that all of the 20S-configured derivatives (4 and 6) had high bone mobilizing activity in vivo. However, in the 20R series, a 2-methylene group was required for high bone mobilizing activity. A change in positioning of the 20R molecule in the vitamin D receptor when the 2-methylene group is present may provide new insight into the molecular basis of bone calcium mobilization induced by vitamin D.
authors.affiliation: Department of Biochemistry, College of Agriculture and Life Sciences, 433 Babcock Drive, University of Wisconsin-Madison , Madison, Wisconsin 53706-1544, United States.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Flores
authors.affiliation: Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali , Via Giusti 9, 50121 Firenze, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Massarelli
authors.affiliation: Department of Biochemistry, College of Agriculture and Life Sciences, 433 Babcock Drive, University of Wisconsin-Madison , Madison, Wisconsin 53706-1544, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: Thoden
authors.affiliation: Department of Biochemistry, College of Agriculture and Life Sciences, 433 Babcock Drive, University of Wisconsin-Madison , Madison, Wisconsin 53706-1544, United States.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.affiliation: Department of Biochemistry, College of Agriculture and Life Sciences, 433 Babcock Drive, University of Wisconsin-Madison , Madison, Wisconsin 53706-1544, United States.
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 / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; C083610:1,25-dihydroxy-19-norvitamin D3; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002118:Calcium