Title: New 1α,25-Dihydroxy-19-norvitamin D<sub>3</sub> Compounds of High Biological Activity: Synthesis and Biological Evaluation of 2-Hydroxymethyl, 2-Methyl, and 2-Methylene Analogues
Abstract: New highly active isomers of the natural hormone 1α,25-dihydroxyvitamin D3 possessing an exomethylene group at the 2-position were prepared in a convergent manner, starting with (−)-quinic acid and the corresponding (20R)- and (20S)-25-hydroxy Grundmann ketones. These 2-methylene-19-norvitamins were efficiently converted to the 2-methyl and 2-hydroxymethyl derivatives, some of which exhibited pronounced in vivo biological activity. Configurations of the A-ring substituents were determined by 1H NOE difference spectroscopy as well as by spin decoupling experiments. It was established that the bulky methyl and hydroxymethyl substituents at C-2, due to their large conformational free energies, occupy mainly equatorial positions. Additionally, hydroxylation of the C(10)−C(19) double bond in 1α,25-(OH)2D3 was performed, resulting in 1α,19,25-trihydroxy-10,19-dihydrovitamin D3 derivatives in which the hydroxymethyl substituent at C-10, for steric reasons, is forced to occupy an axial position. In consequence, the vitamin D3 analogues were synthesized in which the 1α-hydroxy group, required for biological activity, is almost exclusively axially or equatorially oriented because of stabilization of the single A-ring chair conformations. The relative ability of the synthesized analogues to bind the porcine intestinal vitamin D receptor was assessed and compared with that of the natural hormone. It was established that vitamins possessing the axial orientation of the 1α-hydroxy substituent exhibit a significantly increased receptor binding affinity. Compounds with a 2-methylene substituent showed selective calcemic activity profiles, being extremely effective on bone calcium mobilization. 2α-Methyl-substituted vitamins proved to be much more active in vivo than the corresponding epimers with 2β-configuration. All of the 2-substituted vitamins exhibited pronounced HL-60 differentiating activity, those 2α-substituted in the 20S-series being especially potent. The present studies imply that the axial orientation of the 1α-hydroxy group is necessary for biological activity of vitamin D compounds.
Publication Year: 1998
Publication Date: 1998-10-22
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 154
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