2. Academic Validation
  3. A Methylene Group on C-2 of 24,24-Difluoro-19-nor-1α,25-dihydroxyvitamin D3 Markedly Increases Bone Calcium Mobilization in Vivo

A Methylene Group on C-2 of 24,24-Difluoro-19-nor-1α,25-dihydroxyvitamin D3 Markedly Increases Bone Calcium Mobilization in Vivo

  • J Med Chem. 2015 Dec 24;58(24):9731-41. doi: 10.1021/acs.jmedchem.5b01564.
Agnieszka Flores 1,  Ilaria Massarelli 2,  James B Thoden 1,  Lori A Plum 1,  Hector F DeLuca 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, College of Agriculture and Life Sciences, 433 Babcock Drive, University of Wisconsin-Madison , Madison, Wisconsin 53706-1544, United States.
  • 2 Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali , Via Giusti 9, 50121 Firenze, Italy.
PMID: 26630444 DOI: 10.1021/acs.jmedchem.5b01564
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.

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