A 20S Combined with a 22R Configuration Markedly Increases both in Vivo and in Vitro Biological Activity of 1α,25-Dihydroxy-22-methyl-2-methylene-19-norvitamin D₃

Abstract

Six new analogues of 1α,25-dihydroxy-19-norvitamin D3 (3a-4b, 5 and 6) were prepared by a convergent synthesis applying the Wittig-Horner reaction as a key step. The influence of methyl groups at C-22 on their biological activity was examined. It was established that both in vitro and in vivo activity is strongly dependent on the configuration of the stereogenic centers at C-20 and C-22. Introduction of the second methyl group at C-22 (analogues 5 and 6) generates the compounds that are slightly more potent than 1α,25-(OH)2D3 in the in vitro tests but much less potent in vivo. The greatest in vitro and in vivo biological activity was achieved when the C-20 is in the S-configuration and the C-22 is in the R configuration. The building blocks for the synthesis, the respective (20R,22R)-, (20R,22S)-, (20S,22R)- and (20S,22S)-diols were obtained by fractional crystallization of mixtures of the corresponding diastereomers. Structures and absolute configurations of the diols 21a, 21b and 22a as well as analogues 3a, 5 and 6 were confirmed by the X-ray crystallography.

26- and 27-Methyl groups of 2-substituted, 19-nor-1α,25-dihydroxylated vitamin D compounds are essential for calcium mobilization in vivo

“…This has been noted in a previously prepared group of both 19-nor compounds [28]. The 20 S -modification increases potency both in vivo and in vitro as previously noted in other series of vitamin D analogues [29,30]. However, increased potency is not the result of improved binding to the receptor.…”

Recent Developments of 19‐Nor‐1,25‐dihydroxyvitamin D3 Analogues

“…Single 22‐methylation of 4 a did not significantly change the affinity for the nuclear receptor relative to their parent compound 2‐methylene‐19‐nor‐1,25(OH) 2 D 3 46. In contrast, the addition of a 22‐methyl group to analogue 4 b , characterized by an “unnatural” 20 S side chain, caused a much stronger effect.…”

“…The activity profiles in bone calcium mobilization partially paralleled the results observed in the in vitro assays. Compound 22 a was substantially more potent than the native hormone 1 , while the 22,22‐dimethylated analogues of 4 a and 4 b exhibited at least 50‐fold lower activity in bone calcium mobilization than the parent compound 1 46…”

A Methylene Group on C-2 of 24,24-Difluoro-19-nor-1α,25-dihydroxyvitamin D3 Markedly Increases Bone Calcium Mobilization in Vivo

“…As shown in Scheme 1, the vitamin D analogues 3 to 6 were prepared from the 20 R - and 20 S - nitriles 7 and 8 . 17 The reduction of the obtained nitriles with DIBALH afforded the respective aldehydes 9 18 and 10 in 90% and 99% yield. The Reformatsky reagent, prepared from ethyl bromodifluoroacetate, adds onto aldehydes and imines.…”