Removal of the 26-Methyl Group from 19-nor-1α,25-Dihydroxyvitamin D₃ Markedly Reduces in Vivo Calcemic Activity without Altering in Vitro VDR Binding, HL-60 Cell Differentiation, and Transcription

Abstract

Twelve new analogs of 19-nor-1α,25-dihydroxyvitamin D 3 (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16), were prepared by convergent syntheses, employing the Wittig-Horner reaction. The necessary Grundmann-type ketones (45, 46, 47 and 48), possessing fixed configurations of the hydroxyl group at C-25, were obtained by a multi-step procedure from commercial vitamin D 2 and enantiomers of 1,3-butanediol (23 and 24). We have examined the influence of removal of one of the methyl groups located at C-25 on the biological in vitro and in vivo activity. The in vivo tests showed that the synthesized vitamin D compounds (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16) exhibit reduced calcemic activity both in bone and in the intestine. But in vitro potency of 2-methylene and 2α-methyl compounds (5, 6, 7, 8, 9, 10, 13 and 14) remained similar or enhanced compared to that of 1α,25-(OH) 2 D 3 .

26-Desmethyl-2-methylene-22-ene-19-nor-1α,25-dihydroxyvitamin D3 compounds selectively active on intestine

“…To a stirred suspension of the phosphonium salt 12 or 15a – b (3.0 equiv) [14] in anhydrous THF (5 mL), n -butyllithium (6.0 equiv) was added at −20 °C. The solution was stirred at −20 °C for 1 h and it turned deep orange.…”

“…A very recent addition to our ongoing structure–activity relationship studies has been the development of 2-methylene-19,26-dinor-1α,25-dihydroxyvitamin D 3 analogs [14]. Indeed, the results of our biological studies revealed that removing only one of the two methyl groups at C-25 and maintaining the 25-hydroxy group is an effective method of weakening calcemic activity [14].…”

“…Indeed, the results of our biological studies revealed that removing only one of the two methyl groups at C-25 and maintaining the 25-hydroxy group is an effective method of weakening calcemic activity [14]. In general, (25 R )-hydroxy analogs exhibit more efficacy, measured both in vitro and in vivo , than (25 S ) diastereoisomers, with the (20 S ,25 R )-2-methylene-19,26-dinor-1α,25(OH) 2 D 3 analog 5 (Fig.…”

“…In general, (25 R )-hydroxy analogs exhibit more efficacy, measured both in vitro and in vivo , than (25 S ) diastereoisomers, with the (20 S ,25 R )-2-methylene-19,26-dinor-1α,25(OH) 2 D 3 analog 5 (Fig. 1), being the most potent of the new series [14]. We have now prepared two new 2-methylene-Δ 22 E -19-nor-1α,25(OH) 2 D 3 compounds 6 ( 20 R ) and 7 ( 20 S ) (Fig.…”

Alterations in 1,25-Dihydroxyvitamin D3 Structure that Produce Profound Changes in in Vivo Activity

“…Elimination of the 21-methyl markedly reduces bone calcium mobilization with a minimal effect on calcium absorption [66]. On the other hand, removal of either the 26-or 27-methyls equally affect both intestinal calcium absorption and bone calcium mobilization [67].…”