1α,25-dihydroxy-19-nor-vitamin D3, a novel vitamin D-related compound with potential therapeutic activity

Perlman, Kato L.; Siciński, Rafał R.; Schnoes, Heinrich K.; DeLuca, Hector F.

doi:10.1016/s0040-4039(00)98795-1

Cited by 160 publications

(73 citation statements)

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“…17 was isolated via FCC (10% EtOAc in hexanes) as a clear oil in 84% yield (51.8 mg, 0.084 mmol). 1R,3R,7E,17b)-1,3-Bis[tert-butyl(dimethyl)silyl-oxy]-9,10-secoestra-5,7-dien-17-yl)heptanoic acid (18). A freshly prepared solution of NaClO 2 (30 mg, 0.33 mmol, 3 equiv) and NaH 2 PO 4 (76 mg, 0.55 mmol, 5 equiv) in H 2 O (2 mL) was added to a stirred solution of aldehyde 17 (69 mg, 0.11 mmol, 1 equiv) and 2-methyl-2-butene (0.5 mL) in tBuOH (2 mL) and the mixture was stirred vigorously at room temperature for 1 h. H 2 O (15 mL) was then added, and the mixture was extracted with Et 2 O (3 Â 20 mL).…”

Section: Discussionmentioning

confidence: 99%

“…17 An oxidation/deprotection sequence furnished ketone 10 which subsequently underwent clean Horner coupling with A-ring diphenylphosphine oxide (11) to furnish common precursor 12 as a single geometrical isomer. 18 Ester 12 could be converted to a series of immediate hybrid precursors (Scheme 2). Simple saponification afforded acid 13 in high yield.…”

Section: Chemistrymentioning

confidence: 99%

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Vitamin D receptor agonist/histone deacetylase inhibitor molecular hybrids

Lamblin

Dabbas

Spingarn

et al. 2010

Bioorganic & Medicinal Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Vitamin D receptor agonist/histone deacetylase inhibitor molecular hybrids

Lamblin

Dabbas

Spingarn

et al. 2010

Bioorganic & Medicinal Chemistry

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“…In Vitro and in Vivo Biological Activity-The in vitro biological potency of 19-nor-vitamin D was comparable with that of 1,25(OH) 2 D 3 , whereas its calcemic effects were 50-fold lower (Table I) (4,9,10 (Table I).…”

Section: Resultsmentioning

confidence: 93%

Previtamin D3 with a trans-Fused Decalin CD-ring Has Pronounced Genomic Activity

Verlinden

Verstuyf

Verboven

et al. 2003

Journal of Biological Chemistry

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1,25(OH) 2 D 3 has a central rigid CD-bicyclic ring portion to which two flexible entities, the side chain and the seco-B,Aring, are connected. The characteristic seco structure of vitamin D 3 originates from the photolytic cleavage of the provitamin 7-dehydrocholesterol. The resulting previtamin triene (previtamin D 3 ) then reversibly thermo-isomerizes to the vitamin form in its less stable 6-s-cis conformation. Rapid rotation about the C6-C7 single bond eventually yields vitamin D 3 in its more stable extended 6-s-trans conformation (2, 3). Vitamin D 3 but also its hydroxylated metabolites are in constant equilibrium with their previtamin D 3 isomers. Previous studies with analogs of 1,25(OH) 2 D 3 that are either structurally blocked in the previtamin form (4, 5) or that only slowly isomerize to the vitamin form (6) indicated that the previtamin form of 1,25(OH) 2 D 3 is a poor activator of the genomic signaling pathway with minimal effects on cell proliferation and differentiation (7). However, the previtamin D 3 form is a potent activator of the non-genomic signal transduction pathway (5-7).The aim of this study is to investigate the biological profile and the genomic signaling pathway of four different locked 19-nor-1,25(OH) 2 -(pre)-vitamin D 3 analogs, with or without a modified CD-ring. Indeed, the sigmatropic shift required for the previtamin-vitamin D conversion cannot occur in these analogs because of the deletion of C19 (4). First, the affinity to VDR was determined as well as the stability of VDR conformation after interaction with the ligand. Second, the potency of the analogs to induce interaction of the VDR-RXR heterodimer with DNA (vitamin D-responsive elements) and TIF2 (as a representative of the p160 family of coactivators; Ref. 8) was investigated. Third, the ability of 19-nor-1,25(OH) 2 -(pre)-vitamin D 3 analogs to induce VDR-dependent transcriptional activation was studied in transient transfection experiments and by determining the induction of vitamin D 24-hydroxylase (CYP 24) gene expression. Finally, docking of the analogs in the ligand binding domain (LBD) of VDR was studied by evaluation

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“…A group of analogs known as 19-nor-vitamin D analogs, in which the ring A methylene group on C-19 is replaced with two hydrogen atoms, have been synthesized by Deluca's group (Perlman, Sicinski, Schnoes, & DeLuca, 1990) and Kittaka's group (Ono et al, 2003). One of those analogs, 19-nor-1α,25(OH) 2 D 2 , also called Zemplar ® or paricalcitol, is a FDAapproved drug for the treatment of secondary hyperparathyroidism.…”

Section: The Biological Activity Of 19-nor-vitamin D Analogsmentioning

confidence: 99%

“…One of those analogs, 19-nor-1α,25(OH) 2 D 2 , also called Zemplar ® or paricalcitol, is a FDAapproved drug for the treatment of secondary hyperparathyroidism. This analog has potency similar to 1α,25(OH) 2 D 3 in inducing CYP24A1 promoter activity, and in suppressing parathyroid hormone secretion in hemodialysis patients with secondary hyperparathyroidism, without inducing hypercalcemia or hyperphosphatemia (Llach et al, 1998;Perlman et al, 1990;Slatopolsky et al, 1995). The antiproliferative activity of 19-nor-1α,25(OH) 2 D 2 and 19-nor-1α,25(OH) 2 D 3 has been studied in LNCaP cells, an androgen-dependent cell line, and in the primary cultures of prostate cancer cells Chen, Schwartz, Burnstein, Lokeshwar, & Holick, 2000).…”

Section: The Biological Activity Of 19-nor-vitamin D Analogsmentioning

confidence: 99%