Organic Chemistry of Vitamin D Analogues (Deltanoids)

Posner, Gary H.; Kahraman, Mehmet

doi:10.1002/ejoc.200300264

Cited by 91 publications

(32 citation statements)

References 25 publications

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“…However, the application of these compounds has been limited by the danger of hypercalcemia. Structural modifications of the vitamin D molecule have led to a search for new analogs that exhibit reduced calcemic potency and selective actions 11. In 2007, we reported the biological properties of two 2-methylene-19-nor analogs ( 2 and 3 ) in which the side chains were modified at C-25 12-13.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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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 .

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Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…We describe here an efficient and alternative convergent synthesis of 1 from ( S )-carvone (9 steps, 13%) that features a palladium catalyzed tandem process that produces the vitamin D triene unit stereoselectively in one pot by coupling enol triflate 3 (A-ring fragment) with an alkenyl metal intermediate 2 (CD-side chain fragment) [34] . For reproducibility reasons we employed Indium intermediates (M = InR 2 ) instead of Zinc intermediates [35] – [37] .…”

Section: Resultsmentioning

confidence: 99%

1α,25(OH)2-3-Epi-Vitamin D3, a Natural Physiological Metabolite of Vitamin D3: Its Synthesis, Biological Activity and Crystal Structure with Its Receptor

et al. 2011

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BackgroundThe 1α,25-dihydroxy-3-epi-vitamin-D3 (1α,25(OH)2-3-epi-D3), a natural metabolite of the seco-steroid vitamin D3, exerts its biological activity through binding to its cognate vitamin D nuclear receptor (VDR), a ligand dependent transcription regulator. In vivo action of 1α,25(OH)2-3-epi-D3 is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1α,25(OH)2D3. To further unveil the structural mechanism and structure-activity relationships of 1α,25(OH)2-3-epi-D3 and its receptor complex, we characterized some of its in vitro biological properties and solved its crystal structure complexed with human VDR ligand-binding domain (LBD).Methodology/Principal FindingsIn the present study, we report the more effective synthesis with fewer steps that provides higher yield of the 3-epimer of the 1α,25(OH)2D3. We solved the crystal structure of its complex with the human VDR-LBD and found that this natural metabolite displays specific adaptation of the ligand-binding pocket, as the 3-epimer maintains the number of hydrogen bonds by an alternative water-mediated interaction to compensate the abolished interaction with Ser278. In addition, the biological activity of the 1α,25(OH)2-3-epi-D3 in primary human keratinocytes and biochemical properties are comparable to 1α,25(OH)2D3.Conclusions/SignificanceThe physiological role of this pathway as the specific biological action of the 3-epimer remains unclear. However, its high metabolic stability together with its significant biologic activity makes this natural metabolite an interesting ligand for clinical applications. Our new findings contribute to a better understanding at molecular level how natural metabolites of 1α,25(OH)2D3 lead to significant activity in biological systems and we conclude that the C3-epimerization pathway produces an active metabolite with similar biochemical and biological properties to those of the 1α,25(OH)2D3.

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“…Potential therapeutic applications of 1,25-(OH) 2 D 3 , which are associated with the inhibition of cell growth and with the stimulation of cell differentiation, are however hampered by the danger of hypercalcemia. This has resulted in attempts at modification of its structure to separate calcemic activities from other biological responses [11,12]. We have focused on side chain modifications [13,14].…”

Section: Introductionmentioning

confidence: 99%

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

Grzywacz

Plum

Clagett‐Dame

et al. 2013

Bioorganic Chemistry

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Twelve new analogues of 19-nor-1α,25-dihydroxyvitamin D3 6–17, were prepared by a multi-step procedure from known alcohols 18 and 19. We have examined the influence of removing two methyl groups located at C-25, as well as the 25-hydroxy group, on the biological in vitro and in vivo biological activity. Surprisingly, removal of the 26- and 27-methyl groups from either the 2α-methyl or 2-methylene-19-nor-1α,25-dihydroxyvitamin D3 reduced vitamin D receptor binding, HL-60 differentiation, and 25-hydroxylase transcription in vitro only slightly to moderately (compounds 6–13). However, these compounds were devoid of in vivo bone mobilization activity and had markedly reduced activity on intestinal calcium transport. The analogues 14–17 with a 2β-methyl substitution had little or no activiy in vitro and in vivo as expected from previous work.

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Organic Chemistry of Vitamin D Analogues (Deltanoids)

Cited by 91 publications

References 25 publications

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

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

1α,25(OH)2-3-Epi-Vitamin D3, a Natural Physiological Metabolite of Vitamin D3: Its Synthesis, Biological Activity and Crystal Structure with Its Receptor

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

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Organic Chemistry of Vitamin D Analogues (Deltanoids)

Cited by 91 publications

References 25 publications

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

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

1α,25(OH)2-3-Epi-Vitamin D3, a Natural Physiological Metabolite of Vitamin D3: Its Synthesis, Biological Activity and Crystal Structure with Its Receptor

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

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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

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