Synthesis and Biological Activity of 2-(3′-Hydroxypropylidene)-1α-hydroxy-19-norvitamin D Analogues with Shortened Alkyl Side Chains

• DOI: 10.1021/jm200743p
• Publication Date: 2011-09-08T20:47:43Z
• Authors: Agnieszka Glebocka; Rafal R. Sicinski; Lori A. Plum; Hector F. DeLuca
• Keywords: Side chain; Wittig reaction; Phosphine oxide

As a continuation of our efforts directed to vitamin D compounds promising biological properties, 19-norvitamins 9-13, possessing 3'-hydroxypropylidene fragment attached C-2 and shortened 17β-alkyl chains, were synthesized. A new synthetic pathway providing the CD-ring ketones 20-24 is described starting from epimeric aldehydes 25 26. The hydrindanones subjected Wittig-Horner reaction with phosphine oxide 14, 9-13 obtained after hydroxyl deprotection. In comparison 1α,25-(OH)(2)D(3) (1), prepared analogues, except for 20R-compound 12, only ca. 3 times less potent in binding VDR. Compounds 9-11 13 exhibited HL-60 cellular activity 5-20 lower transcriptional 10 decreased related those hormone 1. When tested vivo, all analogues showed no ability mobilize calcium bone, intestinal transport was observed at high doses vitamins 10, 13.