Synthesis of 1α,25-dihydroxyvitamin D3 analogues with α,α-difluorocycloketone at the CD-ring side chains and their biological properties in ovariectomized rats.
J Steroid Biochem Mol Biol
; 186: 66-73, 2019 02.
Article
em En
| MEDLINE
| ID: mdl-30253225
ABSTRACT
Two novel 1α,25-dihydroxyvitamin D3 derivatives containing a α,α-difluorocyclopentanone (3) or α,α-difluorocyclohexanone (4) moiety at the CD-ring side chains were designed, synthesized, and evaluated for their biological properties on restoring bone mass in ovariectomized (OVX) rats with established osteopenia. The synthesis of compounds 3 and 4 utilized the Wittig-Horner coupling to build up the vitamin D conjugated triene system, followed by the introduction of the cycloketone fragments at the side chain, and subsequent α,α-difluorination of the ketone by the treatment of the derived silyl enol ether with Selectfluor, as the key synthetic steps. In comparison with the natural 1α,25-dihydroxyvitamin D3 (calcitriol; 200 ng/kg/day), oral administration of compounds 3 and 4 at the dose of 25 ng/kg/day for 6 weeks led to much improved bone mass and bone density related parameters, while maintaining normal serum calcium and serum phosphorus levels. The immunohistochemistry results showed that both compounds remarkably decreased in osteoclast number and moderately decreased in osteoblast number on trabecular bone surface. Therefore, our findings suggested that compounds 3 and 4 successfully rescue bone loss by suppression on bone turnover in OVX rat models.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vitamina D
/
Vitaminas
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Doenças Ósseas Metabólicas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Steroid Biochem Mol Biol
Assunto da revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
Ano de publicação:
2019
Tipo de documento:
Article