Six new analogs of 2-methylene-19-nor-1 alpha,25-dihydroxyvitamin D-3, 6-7 and 8a,b-9a,b, have been synthesized. All compounds are characterized by a trans double bond located in the side chain between C-22 and C-23. While compounds 6 and 7 possess C-26 and C-27 methyls, compounds 8a,b and 9a,b lack one of these groups. A Lythgoe-based synthesis, employing the Wittig-Horner reaction was used for these preparations. Two different types of Delta E-22-25-hydroxy Grundmann's ketone, having either only one stereogenic center located at position C-20 (20 and 21), or two stereogenic centers located at 20- and 25-positions (24a,b-25a,b) were obtained by a multi-step procedure from commercial vitamin D-2. The introduction of a double bond at C-22 appeared to lower biological activity in vitro and in vivo. Further removal of a 26-methyl in these analogs had little effect on receptor binding, HL-60 differentiation and CYP24A expression but markedly diminished or eliminated in vivo activity on bone calcium mobilization while retaining activity on intestinal calcium transport. (C) 2014 Elsevier Inc. All rights reserved.
|Autori:||Chiellini G.; Grzywacz P.; Plum LA.; Clagett-Dame M.; DeLuca HF.|
|Titolo:||26-Desmethyl-2-methylene-22-ene-19-nor-1 alpha,25-dihydroxyvitamin D-3 compounds selectively active on intestine|
|Anno del prodotto:||2014|
|Digital Object Identifier (DOI):||10.1016/j.steroids.2014.01.012|
|Appare nelle tipologie:||1.1 Articolo in rivista|