Synthesis and biological properties of 2-methylene-19-nor-25-dehydro-1α-hydroxyvitamin D3-26,23-lactones—weak agonists

Chiellini, Grazia; Grzywacz, Pawel; Plum, Lori A.; Barycki, Rafał; Clagett‐Dame, Margaret; DeLuca, Hector F.

doi:10.1016/j.bmc.2008.08.011

Cited by 21 publications

(28 citation statements)

References 36 publications

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“…A solution of diol 5 [25] (0.50 g, 2.35 mmol) in anhydrous pyridine (5 mL) was cooled to −25 °C. A precooled solution of tosyl chloride (0.55 g, 2.90 mmol) in anhydrous pyridine (1 mL) was added dropwise to the diol solution via cannula.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase

et al. 2012

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Selective inhibitors of CYP24A1 represent an important synthetic target in a search for novel vitamin D compounds of therapeutic value. In the present work, we show the synthesis and biological properties of two novel side chain modified 2-methylene-19-nor-1,25(OH)2D3 analogs, the 22-imidazole-1-yl derivative 2 (VIMI) and the 25-N-cyclopropylamine compound 3 (CPA1), which were efficiently prepared in convergent syntheses utilizing the Lythgoe type Horner–Wittig olefination reaction. When tested in a cell-free assay, both compounds were found to be potent competitive inhibitors of CYP24A1, with the cyclopropylamine analog 3 exhibiting an 80–1 selective inhibition of CYP24A1 over CYP27B1. Addition of 3 to a mouse osteoblast culture sustained the level of 1,25(OH)2D3, further demonstrating its effectiveness in CYP24A1 inhibition. Importantly, the in vitro effects on human promyeloid leukemia (HL-60) cell differentiation by 3 were nearly identical to those of 1,25(OH)2D3 and in vivo the compound showed low calcemic activity. Finally, the results of preliminary theoretical studies provide useful insights to rationalize the ability of analog 3 to selectively inhibit the cytochrome P450 isoform CYP24A1.

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Section: Methodsmentioning

confidence: 99%

Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase

et al. 2012

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“…VDR binding, HL-60 differentiation and 24-hydroxylase transcription assays were performed as previously described [16,17]. …”

Section: Experimental Methodsmentioning

confidence: 99%

“…Bone calcium mobilization and intestinal calcium transport were performed as previously described [16,17]. Briefly, weanling rats were made vitamin D-deficient by housing under lighting conditions that block vitamin D production in the skin.…”

Section: Experimental Methodsmentioning

confidence: 99%

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

et al. 2014

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Six new analogs of 2-methylene-19-nor-1α,25-dihydroxyvitamin D3, 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 Δ22E-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 D2. 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.

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“…Not surprisingly, the first analogs of TEI-9647, HLV and GC-3, behaved as agonists in a rat ROS17/2.8 osteoblast transcription assay and were able to increase calcium transport in vivo in D-deficient rats without antagonizing this action in the presence of 1,25-(OH) 2 D 3 (Figure 9) (70). However, in COS7 monkey kidney cells, both compounds behaved as transcriptional antagonists in the presence of 1,25-(OH) 2 D 3 (71, 72).…”

Section: Vdr Antagonists or Allosteric Inhibition Of The Vdr–coregmentioning

confidence: 99%

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

Teske

2016

Vitamin D Hormone

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The vitamin D receptor (VDR) belongs to the superfamily of nuclear receptors and is activated by the endogenous ligand 1,25-dihydroxyvitamin D3. The genomic effects mediated by VDR consist of the activation and repression of gene transcription, which includes the formation of multi-protein complexes with coregulator proteins. Coregulators bind many nuclear receptors and can be categorized according their role as coactivators (gene activation) or corepressors (gene repression). Herein, different approaches to develop compounds that modulate the interaction between VDR and coregulators are summarized. This include coregulator peptides that were identified by creating phage display libraries. Subsequent modification of these peptides including the introduction of a tether or non-hydrolysable bonds resulted in the first direct VDR–coregulator inhibitors. Later, small molecules that inhibit VDR–coregulator inhibitors were identified using rational drug design and high throughput screening. Early on, allosteric inhibition of VDR–coregulator interactions was achieved with VDR antagonists that change the conformation of VDR and modulate the interactions with coregulators. A detailed discussion of their dual agonist/antagonist effects is given as well as a summary of their biological effects in cell-based assays and in vivo studies.

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Synthesis and biological properties of 2-methylene-19-nor-25-dehydro-1α-hydroxyvitamin D3-26,23-lactones—weak agonists

Cited by 21 publications

References 36 publications

Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase

Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase

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

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

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