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ZK 159222

目录号 : GC48271

An antagonist of the vitamin D receptor

ZK 159222 Chemical Structure

Cas No.:156965-15-0

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500 μg
¥8,549.00
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产品描述

ZK 159222 is an antagonist of the vitamin D receptor (VDR).1,2 It stabilizes the VDR in an antagonistic conformation that prevents interaction with coactivator proteins.3 ZK 159222 inhibits VDR-mediated target gene activation when used at concentrations of 300 and 1,000 nM in reporter assays. Preincubation of preadipocytes with ZK 159222 (0.01 and 1 µM) decreases the secretion of IL-1β, IL-6, IL-8, CCL2, and RANTES induced by macrophage-conditioned medium (MacCM).4 It also decreases the secretion of these cytokines in preadipocytes prestimulated with MacCM and decreases MacCM-induced phosphorylation of p44/42 and p38 MAPK in preadipocytes.

1.Herdick, M., Steinmeyer, A., and Carlberg, C.Antagonistic action of a 25-carboxylic ester analogue of 1ɑ,25-dihydroxyvitamin D3 is mediated by a lack of ligand-induced vitamin D receptor interaction with coactivatorsJ. Biol. Chem.275(22)16506-16512(2000) 2.Herdick, M., Steinmeyer, A., and Carlberg, C.Carboxylic ester antagonists of 1ɑ,25-dihydroxyvitamin D3 show cell-specific actionsChem. Biol.7(11)885-894(2000) 3.Bury, Y., Steinmeyer, A., and Carlberg, C.Structure activity relationship of carboxylic ester antagonists of the vitamin D3 receptorMol. Pharmacol.58(5)1067-1074(2000) 4.Zhu, J., and Wilding, J.P.H.The 1α,25(OH)2D3 analogs ZK159222 and ZK191784 show anti-inflammatory properties in macrophage-induced preadipocytes via modulating the NF-κB and MAPK signalingDiabetes Metab. Syndr. Obes.131715-1724(2020)

Chemical Properties

Cas No. 156965-15-0 SDF
Canonical SMILES C=C1/C(C[C@@H](O)C[C@@H]1O)=C\C=C2CCC[C@@]3(C)[C@@]/2([H])CC[C@]3([H])[C@H](C)/C=C/[C@@H](O)C4(CC4)C(OCCCC)=O
分子式 C32H48O5 分子量 512.7
溶解度 Chloroform: slightly soluble,Methanol: slightly soluble 储存条件 4°C, protect from light, stored under nitrogen
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1 mM 1.9505 mL 9.7523 mL 19.5046 mL
5 mM 0.3901 mL 1.9505 mL 3.9009 mL
10 mM 0.195 mL 0.9752 mL 1.9505 mL
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Research Update

Vitamin D analogs modulate the action of gonadal steroids in human vascular cells in vitro

Am J Hypertens 2000 Apr;13(4 Pt 1):396-403.PMID:10821342DOI:10.1016/s0895-7061(99)00203-4.

We have previously reported that estradiol (E2) and dihydrotestosterone (DHT) regulate cell growth in human umbilical arterial smooth muscle cells (SMC) and in an endothelial cell line (E304). In SMC both gonadal steroids stimulated DNA synthesis at low concentrations and suppressed 3[H] thymidine incorporation at high concentrations, whereas in E304 cells E2 and DHT dose dependently enhanced DNA synthesis. In both cell types gonadal steroids also induced the specific activity of creatine kinase BB (CK). Previous evidence suggets that the in vitro and in vivo CK responses to gonadal steroids in bone cells are upregulated by pretreatment with vitamin D analogs due to increased level of cellular estrogen receptors (ER). Here we analyzed the interaction of the vitamin D analogs hexafluorovitamin D (FL), JK-1624 F2-2 (JKF), and CB 1093 (CB) with gonadal steroids in regulating DNA synthesis and CK activity in human vascular cells in vitro. In E304 cells, daily treatment with FL, JKF, or CB (1 nmol/L for 3 days) increased DNA synthesis by 110 +/- 11%, 65 +/- 16%, and 88 +/- 23% respectively. In contrast, the same analogs inhibited 3[H] thymidine incorporation by 52 +/- 21%, 46 +/- 19%, and 50 +/- 10%, respectively, in SMC. In both cell types all three analogs increased CK by 25% to 75% and amplified the CK response to E2 and to DHT by twofold to threefold. In E304 cells the vitamin D analogs also increased DNA response to gonadal steroids from 50% to 60% to 200% to 280%. In SMC these analogs did not modify the DNA synthetic response to a low E2 concentration, but prevented the suppression of DNA synthesis exerted by high concentrations of E2 and DHT. Vitamin D inhibitors known to block cellular calcium mobilization, had no effect on the proliferative activity induced by vitamin D analogs. However, the inhibitor of the nuclear effects of vitamin D, ZK 159222, blocked the stimulatory effects of CB on DNA synthesis in E304 cells. Finally, both 1,25(OH)2 D3, and JKF decreased the expression of ERbeta proteins in SMC and increased the ERalpha isoform in E304 cells by 40% to 75%. The results indicate that vascular cells are targets for both vitamin D and gonadal steroid action and suggest a possible interaction between these hormones in the regulation of cell proliferation via modulation of vascular ER or interaction with proteins associated with ER.

Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns

Eur J Immunol 2006 Feb;36(2):361-70.PMID:16402404DOI:10.1002/eji.200425995.

Toll-like receptors (TLR) represent an ancient front-line defence system that enables the host organism to sense the presence of microbial components within minutes. As inducers of inflammation, TLR act as important triggers of distinct entities such as sepsis or autoimmune disease exacerbation. We report here that vitamin D3 [1alpha,25-dihydroxycholecalciferol, 1,25(OH)(2)D3] suppresses the expression of TLR2 and TLR4 protein and mRNA in human monocytes in a time- and dose-dependent fashion. Despite 1,25(OH)(2)D3-induced up-regulation of CD14, challenge of human monocytes with either LPS or lipoteichoic acid resulted in impaired TNF-alpha and procoagulatory tissue factor (CD142) production, emphasizing the critical role of TLR in the induction of inflammation. Moreover, reduced TLR levels in 1,25(OH)(2)D3-treated phagocytes were accompanied by impaired NF-kappaB/RelA translocation to the nucleus and by reduced p38 and p42/44 (extracellular signal-regulated kinase 1/2) phosphorylation upon TLR-ligand engagement. Both TLR down-regulation and CD14 up-regulation were substantially inhibited by the vitamin D receptor (VDR) antagonist ZK 159222, indicating that the immunomodulatory effect of 1,25(OH)(2)D3 on innate immunity receptors requires VDR transcription factor activation. Our data provide strong evidence that 1,25(OH)(2)D3 primes monocytes to respond less effectively to bacterial cell wall components in a VDR-dependent mechanism, most likely due to decreased levels of TLR2 and TLR4.

Regulation of Vitamin D hydroxylases gene expression by 1,25-dihydroxyvitamin D3 and cyclic AMP in cultured human syncytiotrophoblasts

J Steroid Biochem Mol Biol 2007 Jan;103(1):90-6.PMID:17079137DOI:10.1016/j.jsbmb.2006.07.010.

Human placenta synthesizes and metabolizes 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)/calcitriol] through the activity of 25-hydroxyvitamin D(3)-1alpha-hydroxylase (CYP27B1) and 1,25(OH)(2)D(3)-24-hydroxylase (CYP24A1), the two key enzymes for Vitamin D metabolism. In this study, calcitriol rapidly generated intracellular cAMP accumulation in cultured human syncytiotrophoblast cells, which in turn enhanced hCG secretion, a marker of trophoblast endocrine activity. The effects of 1,25(OH)(2)D(3) upon the expression of CYP27B1 and CYP24A1 were also investigated. 1,25(OH)(2)D(3) and activators of the PKA signaling system decreased the expression of CYP27B1, whereas increased CYP24A1 gene transcription. The use of a selective inhibitor of PKA (H-89) prevented the effects of calcitriol on CYP27B1 gene and hCG secretion, but not on CYP24A1 transcription. Addition of ZK 159222, a Vitamin D receptor (VDR) antagonist, blocked the calcitriol-mediated upregulation of 24-hydroxylase gene expression but did not affect calcitriol-induced downregulation of CYP27B1 gene or hCG stimulation. In addition, our study also demonstrated a role of calcitonin on Vitamin D hydroxylases gene regulation in placenta. The overall data suggest that calcitriol downregulates CYP27B1 expression via a cAMP-dependent signaling pathway, whereas upregulates 24-hydroxylase gene expression through a VDR-dependent mechanism.