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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
journal contribution
posted on 2006-05-18, 00:00 authored by Agnieszka Glebocka, Rafal R. Sicinski, Lori A. Plum, Margaret Clagett-Dame, Hector F. DeLucaIn 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.