TEI-9647
目录号 : GC61768TEI-9647是一种VitaminD3Lactone类似物，是一种有效的，特异性的维生素D受体(VDR)拮抗剂。TEI-9647抑制VDR/VDRE介导的1α,25(OH)2D3的基因组作用。TEI-9647可以抑制1α,25(OH)2D3诱导的骨吸收和HL-60细胞分化。TEI-9647有潜力用于抑制Paget病中过度的骨吸收和破骨细胞形成。
Cas No.:173388-20-0
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TEI-9647, a Vitamin D3 Lactone analogue, is a potent and specific vitamin D receptor (VDR) antagonist. TEI-9647 inhibits VDR/VDRE-mediated genomic actions of 1α,25(OH)2D3. TEI-9647 inhibits bone resorption and HL-60 cell differentiation induced by of 1α,25(OH)2D3. TEI-9647 has the potential for suppressing the excessive bone resorption and osteoclast formation in Paget’s disease[1][2][3].
TEI-9647 (100 nM; 24 hours) treatment clearly suppresses p21WAF1,CIP1 gene expression induced by 1α,25(OH)2D3[1].TEI-9647 (10-1000 nM; 96 hours) dose-dependently blocks the reciprocal changes of CD11b and CD71 expression associated with HL-60 cell differentiation induced by 1α,25(OH)2D3. TEI-9647 completely blocks the increase in CD11b and the decrease in CD71 expression at 100 nM[1]. TEI-9647 blocks both 1α,25(OH)2D3-mediated HL-60 cell differentiation and also activation of the luciferase reporter in COS-7 cells that has been transfected with the cDNA containing the DRE of the rat 25(OH)D3-24-hydroxylase gene and cDNA of the human vitamin D nuclear receptor[1].TEI-9647 can not induce cell differentiation even after treatment at 1 μM in HL-60 cell. TEI-9647 alone can not induce activation of NBT-reducing activity or α-NB esterase activity. In contrast, TEI-9647 markedly suppresses the up-regulation induced by 1α,25(OH)2D3 (0.1 nM) in HL-60 cells[1]. TEI-9647 (0.001-1 μM; for 10 days) dose-dependently inhibits bone resorption induced by of 1α,25(OH)2D3 (1 nM). TEI-9647 alone never induces bone resorption even at 1 μM[2]. TEI-9647 (10 nM; 12 h) markedly inhibits TAFII-17 and 25-OH-D3-24-hydroxylase gene expression induced by 1α,25(OH)2D3 (0.1 nM) in bone marrow cells[2]. RT-PCR[1] Cell Line: HL-60 cells
[1]. Miura D, et al. Antagonistic action of novel 1α,25-dihydroxyvitamin D3-26, 23-lactone analogs on differentiation of human leukemia cells (HL-60) induced by 1α,25-dihydroxyvitamin D3. J Biol Chem. 1999 Jun 4;274(23):16392-9. [2]. Seiichi Ishizuka, et al. Vitamin D antagonist, TEI-9647, inhibits osteoclast formation induced by 1α,25-dihydroxyvitamin D3 from pagetic bone marrow cells. J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):331-4. [3]. Kazuya Takenouchi, et al. Synthesis and structure-activity relationships of TEI-9647 derivatives as Vitamin D3 antagonists. J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):31-4.
| Cas No. | 173388-20-0 | SDF | |
| Canonical SMILES | O=C1O[C@@H](C[C@H]([C@H]2CC[C@@]3([H])/C(CCC[C@]23C)=C/C=C4C([C@@H](O)C[C@H](O)C\4)=C)C)CC1=C | ||
| 分子式 | C27H38O4 | 分子量 | 426.59 |
| 溶解度 | Soluble in ethanol | 储存条件 | 4°C, protect from light, stored under nitrogen |
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| 1 mM | 2.3442 mL | 11.7209 mL | 23.4417 mL |
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| 10 mM | 0.2344 mL | 1.1721 mL | 2.3442 mL |
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Vitamin D antagonist, TEI-9647, inhibits osteoclast formation induced by 1alpha,25-dihydroxyvitamin D3 from pagetic bone marrow cells
J Steroid Biochem Mol Biol 2004 May;89-90(1-5):331-4.PMID:15225795DOI:10.1016/j.jsbmb.2004.03.025.
(23S)-25-Dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647) functions an antagonist of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells [J. Biol. Chem. 274 (1999) 16392]. We examined the effect of vitamin D antagonist, TEI-9647, on osteoclast formation induced by 1alpha,25-(OH)(2)D(3) from bone marrow cells of patients with Paget's disease. TEI-9647 itself never induced osteoclast formation even at 10(-6)M, but dose-dependently (10(-10) to 10(-6)M) inhibited osteoclast formation induced by physiologic concentrations of 1alpha,25-(OH)(2)D(3) (41 pg/ml, 10(-10)M) from bone marrow cells of patients with Paget's disease. At the same time, 10(-8)M of TEI-9647 alone did not cause 1alpha,25-(OH)(2)D(3) dependent gene expression, but almost completely suppressed TAF(II)-17, a potential coactivator of VDR and 25-hydroxyvitamin D(3)-24-hydroxylase (25-OH-D(3)-24-hydroxylase) gene expression induced by 10(-10)M 1alpha,25-(OH)(2)D(3) in bone marrow cells of patients with Paget's disease. Moreover, TEI-9647 dose-dependently inhibited bone resorption induced by 10(-9)M 1alpha,25-(OH)(2)D(3) by osteoclasts produced by RANKL and M-CSF treatment of measles virus nucleocapsid gene transduced bone marrow cells. These results suggest that TEI-9647 acts directly on osteoclast precursors and osteoclasts, and that TEI-9647 may be a novel agent to suppress the excessive bone resorption and osteoclast formation in patients with Paget's disease.
Synthesis and structure-activity relationships of TEI-9647 derivatives as Vitamin D3 antagonists
J Steroid Biochem Mol Biol 2004 May;89-90(1-5):31-4.PMID:15225742DOI:10.1016/j.jsbmb.2004.03.046.
The Vitamin D(3) lactone analogues, (23S)- and (23R)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647 and TEI-9648) are antagonists of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells. In order to clarify the structure-Vitamin D antagonistic activity relationship, we paid attention to the unique lactone moiety of TEI-9647 and TEI-9648: alpha-exo-methylene-gamma-lactone structure. We synthesized the exo-methylene-modified analogues (methylene saturated, endo-methylene, methylene-deleted, methyl-substituted, dimethyl-substituted, methylene-replaced with dimethyl and cyclopropane) and oxygen-modified analogues (oxygen atom replaced with nitrogen and carbon atom) by convergent method using palladium-catalyzed coupling reaction or direct modification of VD(3) skeleton. The antagonistic activity in HL-60 cell differentiation evaluating system of these analogues revealed that any exo-methylene-modified analogues and nitrogen analogue did not have the antagonistic activity, on the other hand carbon analogue did show. The results suggest that "alpha-exo-methylene carbonyl" structure of VD(3) side-chain is crucial for antagonistic activity. The structure is integral building block of many natural products which have interesting biological and it is thought that Michael-type addition of alpha-exo-methylene carbonyl structure with protein nucleophiles such as cysteine would play an important role for the activities. According to this theory, Michael-type reaction of TEI-9647 and TEI-9648 with cysteine residue in protein related to VDR/VDRE-mediated genomic actions such as VDR would be essential step of the antagonistic action.
Culture serum-induced conversion from agonist to antagonist of a Vitamin D analog, TEI-9647
J Steroid Biochem Mol Biol 2006 Aug;100(4-5):177-83.PMID:16835013DOI:10.1016/j.jsbmb.2006.04.008.
The nuclear receptor for Vitamin D (VDR) mediates many of the effects of Vitamin D in target tissues by regulating gene expression. The transactivation function of ligand-bound VDR in target tissues is thought to depend on the tissue-type and the cellular-environment, but the molecular basis for these differences has not been fully understood. In this study, during characterization of TEI-9647 as a synthetic ligand for the VDR, we found that depletion of serum from the culture medium converted TEI-9647 from an antagonist to an agonist of VDR-mediated transactivation, whereas it retained antagonistic activity in the presence of serum. Consistent with these results, using a mammalian two-hybrid system, we found that TEI-9647 recruited different coactivators to the VDR in the presence and absence of serum. These findings suggest that an unknown serum factor modulates the transactivation function of the VDR.
Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1alpha-hydroxyvitamin D3-26,23-lactone
Acta Crystallogr D Biol Crystallogr 2010 Aug;66(Pt 8):918-26.PMID:20693691DOI:10.1107/S0907444910020810.
TEI-9647 antagonizes vitamin D receptor (VDR) mediated genomic actions of 1alpha,25(OH)2D3 in human cells but is agonistic in rodent cells. The presence of Cys403, Cys410 or of both residues in the C-terminal region of human VDR (hVDR) results in antagonistic action of this compound. In the complexes of TEI-9647 with wild-type hVDR (hVDRwt) and H397F hVDR, TEI-9647 functions as an antagonist and forms a covalent adduct with hVDR according to MALDI-TOF MS. The crystal structures of complexes of TEI-9647 with rat VDR (rVDR), H305F hVDR and H305F/H397F hVDR showed that the agonistic activity of TEI-9647 is caused by a hydrogen-bond interaction with His397 or Phe397 located in helix 11. Both biological activity assays and the crystal structure of H305F hVDR complexed with TEI-9647 showed that the interaction between His305 and TEI-9647 is crucial for antagonist activity. This study indicates the following stepwise mechanism for TEI-9647 antagonism. Firstly, TEI-9647 forms hydrogen bonds to His305, which promote conformational changes in hVDR and draw Cys403 or Cys410 towards the ligand. This is followed by the formation of a 1,4-Michael addition adduct between the thiol (-SH) group of Cys403 or Cys410 and the exo-methylene group of TEI-9647.
Antagonistic Actions in Vivo of (23S)-25-Dehydro-1alpha-Hydroxyvitamin D(3-)26,23-Lactone on Calcium Metabolism Induced by 1alpha,25-Dihydroxyvitamin D(3)
Endocrinology 2001 Jan;142(1):59-67.PMID:11145567DOI:10.1210/endo.142.1.7925.
The vitamin D analog, (23S)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647), is an antagonist of the 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells. To clarify whether TEI-9647 could function as an antagonist of 1alpha,25(OH)(2)D(3) in vivo, we investigated in vitamin D-deficient (-D) rats the effects of single doses of TEI-9647 on several parameters of calcium metabolism modulated by 1alpha,25(OH)(2)D(3). TEI-9647 (50 microgram/kg iv) acting alone slightly, but significantly, stimulated intestinal calcium transport (ICA) and bone calcium mobilization (BCM) only at 8 h, but not at 24 h. In contrast, TEI-9647 dose-dependently inhibited ICA and BCM stimulated by an iv dose of 0.25 microgram/kg 1alpha,25(OH)(2)D(3) after 24 h, but not after 8 h. With respect to serum PTH levels, the administration of either TEI-9647, 50 microgram/kg, or 1alpha,25(OH)(2)D(3), 0.25 microgram/kg, began to decrease the circulating levels by 4 h, which reached a nadir 24 h after administration. But, when TEI-9647 and 1alpha,25(OH)(2)D(3) were simultaneously administered to -D rats, the TEI-9647 dose-dependently reversed the inhibition of PTH secretion caused by 1alpha,25(OH)(2)D(3), 0.25 microgram/kg, at 8 and 24 h after the treatment. In separate experiments, the daily iv administration of 20 microgram/kg of TEI-9647 alone to +D rats for 2 weeks resulted in no significant changes in the prevailing serum Ca(2+) concentration. But doses of 1-20 microgram/kg of TEI-9647 in combination with 0.5 microgram/kg of 1alpha,25(OH)(2)D(3), for 2 weeks, dose-dependently and significantly suppressed the serum calcium concentration increase caused by the 1alpha,25(OH)(2)D(3). Collectively, these results show that TEI-9647 acting alone displays in vivo weak agonistic actions, but when administered in combination with 1alpha,25(OH)(2)D(3), is a potent antagonist of three genomic-mediated calcium metabolism parameters. We conclude that TEI-9647 can also function as an antagonist of 1alpha,25(OH)(2)D(3) in vivo in the rat.