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.
26-Desmethyl-2-methylene-22-ene-19-nor-1 alpha,25-dihydroxyvitamin D-3 compounds selectively active on intestine
CHIELLINI, GRAZIA;
2014-01-01
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
