Calcitriol Derivatives with Two Different Side Chains at C-20. II. Diastereoselective Syntheses of the Metabolically Produced 24(R)-Hydroxygemini

• Published in: Journal of medicinal chemistry Vol. 47; no. 26; pp. 6476 - 6484
• Main Authors: Maehr, Hubert, Uskokovic, Milan R, Adorini, Luciano, Reddy, G. Satyanarayana
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.12.2004; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Calcitriol - analogs & derivatives; Calcitriol - chemical synthesis; Calcitriol - chemistry; Calcitriol - pharmacology; Calcium - blood; Cell Line, Tumor; Chemistry, Medicinal; Chromatography, High Pressure Liquid; Hydroxylation; Interferon-gamma - antagonists & inhibitors; Life Sciences & Biomedicine; Medical sciences; Mice; Miscellaneous; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Science & Technology; Stereoisomerism; Structure-Activity Relationship; OXIDATION; D-3; IDENTIFICATION; 1,25-DIHYDROXYVITAMIN-D3; Steroid; Hydroxylation; Cholecalciferol(1,25-dihydroxy); Epimer; Rodentia; Calcitriol; Metabolism; Biological activity; Diastereoselectivity; Vertebrata; Mammalia; Side chain; Geminal compound; Mouse; Vitamin D; Animal; Pharmacokinetics; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049340b

Vitamin D derivatives containing two side chains emanating at C-20 are known as gemini. We have recently synthesized two gemini which are related to calcitriol and 19-norcalcitriol containing two identical side chains. The metabolism of these species involves 24(R)-hydroxylation on one of the side chains. To determine the outcome of this diastereospecific transformation, we synthesized both C-20 epimeric pairs containing the 24(R)-hydroxy group in the gemini and 19-norgemini series. On the basis of the availability of these reference compounds, it was shown that the metabolic hydroxylation occurred at the pro-R side chain in both gemini compounds. In comparison to the parent compounds, the 24-hydroxygemini required higher doses to increase blood calcium levels in mice and to suppress INF-γ release in MLR.