New 2-Alkylidene 1α,25-Dihydroxy-19-norvitamin D3 Analogues of High Intestinal Activity:  Synthesis and Biological Evaluation of 2-(3‘-Alkoxypropylidene) and 2-(3‘-Hydroxypropylidene) Derivatives

Agnieszka Glebocka,†‡ Rafal R. Sicinski,†‡ Lori A. Plum,† Margaret Clagett-Dame,† and Hector F. DeLuca*†
Department of Biochemistry, University of WisconsinMadison, 433 Babcock Drive, Madison, Wisconsin 53706, and Department of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093 Warsaw, Poland
J. Med. Chem., 2006, 49 (10), pp 2909–2920
DOI: 10.1021/jm051082a
Publication Date (Web): April 25, 2006
Copyright © 2006 American Chemical Society
†

 University of WisconsinMadison.

,
‡

 University of Warsaw.

,
*

 To whom correspondence should be addressed. Telephone:  608-262-1620. Fax:  608-262-7122. E-mail:  deluca@biochem.wisc.edu.

Abstract

Abstract Image

In a search for novel vitamin D compounds of potential therapeutic value, E- and Z-isomers of 1α,25-dihydroxy-2-(3‘-hydroxypropylidene)-19-norvitamin D3, as well as a derivative of the former compound possessing a 3‘-(methoxymethoxy)propylidene substituent at C-2, were efficiently prepared. All vitamins were obtained in convergent syntheses, starting with (−)-quinic acid and the protected 25-hydroxy Grundmann ketones. Quinic acid was converted into keto lactone 11, and a substituted hydroxypropylidene group was attached by Wittig reaction yielding pairs of isomeric compounds 12, 13 and 14, 15. These olefinic products were then transformed into phosphine oxides 32−34 which were subjected to Lythgoe type Wittig−Horner coupling with C,D-fragments 35a and 35b. An alternative route was also elaborated that comprised Julia coupling of sulfones 39a and 39b with the cyclohexanone derivative 23. The binding of all synthesized vitamins to the full-length rat recombinant vitamin D receptor (VDR) is either similar to or within one log of 1α,25(OH)2D3. The in vivo tests have revealed that the calcemic activity of all analogues in the E-series (5a, 6a, 6b) is considerably higher than that of the native hormone.

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  • Published In Issue May 18, 2006
  • Received October 25, 2005

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