Twelve new analogues of 19-nor-1α,25-dihydroxyvitamin D₃ (5-16) were prepared by convergent syntheses, employing the Wittig-Horner reaction. The necessary Grundmann type ketones (45-48), possessing fixed configurations of the hydroxyl group at C-25, were obtained by a multistep procedure from commercial vitamin D₂ and enantiomers of 1,3-butanediol (23 and 24). We have examined the influence of removal of one of the methyl groups located at C-25 on the biological in vitro and in vivo activity. The in vivo tests showed that the synthesized vitamin D compounds (5-16) exhibit reduced calcemic activity both in bone and in the intestine. However, in vitro potency of 2-methylene and 2α-methyl compounds (5-10, 13, and 14) remained similar or enhanced as compared to that of 1α,25-(OH)₂D₃.

Removal of the 26-methyl group from 19-nor-1a,25-dihydroxyvitamin D3 markedly reduces in vivo calcemic activity without altering in vitro VDR binding, HL-60 cell differentiation, and transcription.

CHIELLINI, GRAZIA;
2010-01-01

Abstract

Twelve new analogues of 19-nor-1α,25-dihydroxyvitamin D₃ (5-16) were prepared by convergent syntheses, employing the Wittig-Horner reaction. The necessary Grundmann type ketones (45-48), possessing fixed configurations of the hydroxyl group at C-25, were obtained by a multistep procedure from commercial vitamin D₂ and enantiomers of 1,3-butanediol (23 and 24). We have examined the influence of removal of one of the methyl groups located at C-25 on the biological in vitro and in vivo activity. The in vivo tests showed that the synthesized vitamin D compounds (5-16) exhibit reduced calcemic activity both in bone and in the intestine. However, in vitro potency of 2-methylene and 2α-methyl compounds (5-10, 13, and 14) remained similar or enhanced as compared to that of 1α,25-(OH)₂D₃.
2010
Grzywacz, P; Chiellini, Grazia; Plum, La; Clagett Dame, M; Deluca, H. F.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/137725
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