New 2-Alkylidene 1α,25-Dihydroxy-19-norvitamin D<sub>3</sub> Analogues of High Intestinal Activity: Synthesis and Biological Evaluation of 2-(3‘-Alkoxypropylidene) and 2-(3‘-Hydroxypropylidene) Derivatives
2006-05-18T00:00:00Z (GMT) by
In a search for novel vitamin D compounds of potential therapeutic value, <i>E</i>- and <i>Z</i>-isomers of 1α,25-dihydroxy-2-(3‘-hydroxypropylidene)-19-norvitamin D<sub>3</sub>, 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 <b>11</b>, and a substituted hydroxypropylidene group was attached by Wittig reaction yielding pairs of isomeric compounds <b>12</b>, <b>13</b> and <b>14</b>, <b>15</b>. These olefinic products were then transformed into phosphine oxides <b>32</b>−<b>34</b> which were subjected to Lythgoe type Wittig−Horner coupling with C,D-fragments <b>35a</b> and<b> 35b</b>. An alternative route was also elaborated that comprised Julia coupling of sulfones <b>39a</b> and <b>39b</b> with the cyclohexanone derivative <b>23</b>. 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)<sub>2</sub>D<sub>3</sub>. The in vivo tests have revealed that the calcemic activity of all analogues in the <i>E</i>-series (<b>5a</b>, <b>6a</b>, <b>6b</b>) is considerably higher than that of the native hormone.