Synthesis and Biological Activity of 2-Methylene Analogues of Calcitriol and Related Compounds

摘要

In an attempt to prepare vitamin D analogues that are superagonists, (20R)- and (20S)-isomers of 1 alpha-hydroxy-2-methylenevitamin D-3 and 1 alpha,25-dihydroxy-2-methylenevitamin D-3 have been synthesized. To prepare the desired A-ring dienyne fragment, two different approaches were used, both starting from the (-)-quinic acid. The obtained derivative was subsequently coupled with the C,D-ring enol triflates derived from the corresponding Grundmann ketones, using the Sonogashira reaction. Moreover, (20R)- and (20S)-1 alpha,25-dihydroxy-2-methylenevitamin D-3 compounds with an (SE)-configuration were prepared by iodine catalyzed isomerization. All four 2-methylene analogues of the native hormone were characterized by high in vitro activity. As expected, the 25-desoxy analogues were much less potent. Among the synthesized compounds, two of them, 1 alpha,25-dihydroxy-2-methylenevitamin D-3 and its C-20 epimer, were found to be almost as active as 2-methylene-19-nor-(20S)-1 alpha,25-dihydroxyvitamin D-3 (2MD) on bone but more active in intestine.