TEI-9648
(Synonyms: TEI-9647对映异构系) 目录号 : GC61769TEI-9648是一种VitaminD3Lactone类似物,是有效的,特异性的维生素D受体(VDR)拮抗剂。TEI-9648抑制VDR/VDRE介导的1α,25(OH)2D3的基因组作用。TEI-9648也可以抑制1α,25(OH)2D3诱导的HL-60细胞分化。TEI-9648有潜力用于骨代谢的研究。
Cas No.:173388-21-1
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TEI-9648, a Vitamin D3 Lactone analogue, is a potent and specific vitamin D receptor (VDR) antagonist. TEI-9648 inhibits VDR/VDRE-mediated genomic actions of 1α,25(OH)2D3. TEI-9648 also inhibits HL-60 cell differentiation induced by of 1α,25(OH)2D3. TEI-9648 has the potential for bone metabolism research[1][2].
TEI-9648 (10-1000 nM) dose-dependently blocks the reciprocal changes of CD11b and CD71 expression associated with HL-60 cell differentiation induced by 1α,25(OH)2D3[1]. TEI-9648 has consistently weaker suppressive effect than TEI-9647[1]. TEI-9648 can not induce cell differentiation even after treatment at 1 μM in HL-60 cell[1]. TEI-9648 alone can not induce activation of NBT-reducing activity or α-NB esterase activity. In contrast, TEI-9648 markedly suppresses the up-regulation induced by 1α,25(OH)2D3 (0.1 nM) in HL-60 cells[1].
[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]. 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. | 173388-21-1 | SDF | |
别名 | TEI-9647对映异构系 | ||
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 | 储存条件 | 4°C, protect from light, stored under nitrogen | |
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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.
Antagonistic action of novel 1alpha,25-dihydroxyvitamin D(3)-26, 23-lactone analogs on 25-hydroxyvitamin-D(3)-24-hydroxylase gene expression induced by 1alpha,25-dihydroxy-vitamin D(3) in human promyelocytic leukemia (HL-60) cells
Arch Biochem Biophys 2000 Aug 1;380(1):92-102.PMID:10900137DOI:10.1006/abbi.2000.1902.
We have demonstrated that 1alpha,25-dihydroxyvitamin D(3)-26, 23-lactone analogs, (23S)- and (23R)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647, TEI-9648, respectively), inhibit HL-60 cell differentiation induced by 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], but not differentiation caused by all-trans retinoic acid (D. Miura et al., 1999, J. Biol. Chem. 274, 16392). To assess whether the antagonistic actions of TEI-9647 and TEI-9648 in HL-60 cells are related to 1alpha,25(OH)(2)D(3) breakdown, we investigated their effects on catabolism of 1alpha,25(OH)(2)D(3). In HL-60 cells, the C-24 but not the C-23 side-chain oxidation pathway of 1alpha,25(OH)(2)D(3) has been reported. Here we demonstrate that 1alpha,25(OH)(2)D(3) was metabolized both to 24,25,26,27-tetranor-1alpha,23-(OH)(2)D(3) and 1alpha,25(OH)(2)D(3)-26,23-lactone; thus HL-60 cells constitutively possess both the 24- and the 23-hydroxylases. Metabolism of 1alpha, 25(OH)(2)D(3) was strongly suppressed by 10(-7) M TEI-9647 or 10(-6) M TEI-9648. 1alpha,25(OH)(2)D(3) alone slightly induced 24-hydroxylase gene expression by 8 h with full enhancement by 24-48 h; this induction was inhibited by 10(-6) M TEI-9647 and 10(-6) M TEI-9648 (86.2 and 31.9%, respectively) 24 h after treatment. However, analogs of TEI-9647 and TEI-9648 without the 25-dehydro functionality induced 24-hydroxylase gene expression. These results indicate that TEI-9647 and TEI-9648 clearly mediate their stereoselective antagonistic actions independent of their actions to block the catabolism of 1alpha,25(OH)(2)D(3). Therefore, TEI-9647 and TEI-9648 appear to be the first antagonists specific for the nuclear 1alpha,25(OH)(2)D(3) receptor-mediated genomic actions of 1alpha,25(OH)(2)D(3) in HL-60 cells.
(23S)- and (23R)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone function as antagonists of vitamin D receptor-mediated genomic actions of 1alpha,25-dihydroxyvitamin D(3)
Steroids 2001 Mar-May;66(3-5):227-37.PMID:11179730DOI:10.1016/s0039-128x(00)00146-x.
We synthesized various analogues of 1alpha,25-(OH)(2)D(3)-26,23-lactone and examined the effects of them on HL-60 cell differentiation using the evaluation system of the genomic action of 1alpha,25-(OH)(2)D(3). We found that (23S)- and (23R)-25-dehydro-1alpha-OH-D(3)-26,23-lactone (TEI-9647 and TEI-9648) strongly bound to the VDR, but did not induce HL-60 cell differentiation. Intriguingly, TEI-9647 and TEI-9648 did inhibit that induced by 1alpha,25-(OH)(2)D(3), whereas they did not suppress that caused by retinoic acid or TPA. On the contrary, the similar 25-dehydrated 24-dehydro analogues, TEI-D1807 and TEI-D1808, weakly but significantly induced HL-60 cell differentiation, never showing inhibitory effect on HL-60 cell differentiation induced by 1alpha,25-(OH)(2)D(3). In other experiments, TEI-9647 and TEI-9648 markedly suppressed 25-OH-D(3)-24-hydroxylase gene expression induced by 1alpha,25-(OH)(2)D(3) in HL-60 cells. TEI-9647 also inhibited the heterodimer formation between VDR and RXRalpha, and the VDR interaction with co-activator SRC-1 according to the results obtained from the mammalian two-hybrid system in Saos-2 cells. Taking all these results into consideration, we reached a manifest conclusion that TEI-9647 and TEI-9648 are the specific and first antagonists of 1alpha,25-(OH)(2)D(3) action, specifically VDR-VDRE mediated genomic action.
Antagonistic action of novel 1alpha,25-dihydroxyvitamin D3-26, 23-lactone analogs on differentiation of human leukemia cells (HL-60) induced by 1alpha,25-dihydroxyvitamin D3
J Biol Chem 1999 Jun 4;274(23):16392-9.PMID:10347199DOI:10.1074/jbc.274.23.16392.
We examined the effects of two novel 1alpha,25-dihydroxyvitamin D3-26,23-lactone (1alpha,25-lactone) analogues on human promyelocytic leukemia cell (HL-60) differentiation using the evaluation system of the vitamin D nuclear receptor (VDR)/vitamin D-responsive element (DRE)-mediated genomic action stimulated by 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and its analogues. We found that the 1alpha,25-lactone analogues (23S)-25-dehydro-1alpha-hydroxyvitamin-D3-26,23-lactone (TEI-9647), and (23R)-25-dehydro-1alpha-hydroxyvitamin-D3-26,23-lactone (TEI-9648) bound much more strongly to the VDR than the natural (23S, 25R)-1alpha,25(OH)2D3-26,23-lactone, but did not induce cell differentiation even at high concentrations (10(-6) M). Intriguingly, the differentiation of HL-60 cells induced by 1alpha,25(OH)2D3 was inhibited by either TEI-9647 or TEI-9648 but not by the natural lactone. In contrast, retinoic acid or 12-O-tetradecanoylphorbol-13-acetate-induced HL-60 cell differentiation was not blocked by TEI-9647 or TEI-9648. In separate studies, TEI-9647 (10(-7) M) was found to be an effective antagonist of both 1alpha,25(OH)2D3 (10(-8) M) mediated induction of p21(WAF1, CIP1) in HL-60 cells and activation of the luciferase reporter assay in COS-7 cells transfected with cDNA containing the DRE of the rat 25(OH)D3-24-hydroxylase gene and cDNA of the human VDR. Collectively the results strongly suggest that our novel 1alpha,25-lactone analogues, TEI-9647 and TEI-9648, are specific antagonists of 1alpha, 25(OH)2D3 action, specifically VDR/DRE-mediated genomic action. As such, they represent the first examples of antagonists, which act on the nuclear VDR.
1alpha,25-dihydroxyvitamin D(3)-26,23-lactone analogs antagonize differentiation of human leukemia cells (HL-60 cells) but not of human acute promyelocytic leukemia cells (NB4 cells)
FEBS Lett 1999 Oct 29;460(2):297-302.PMID:10544253DOI:10.1016/s0014-5793(99)01347-2.
We examined the effects of two novel 1alpha,25-dihydroxyvitamin D(3)-26,23-lactone (1alpha,25-(OH)(2)D(3)-26,23-lactone) analogs on 1alpha,25(OH)(2)D(3)-induced differentiation of human leukemia HL-60 cells thought to be mediated by the genomic action of 1alpha, 25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) and of acute promyelocytic leukemia NB4 cells thought to be mediated by non-genomic actions of 1alpha,25-(OH)(2)D(3). We found that the 1alpha,25-(OH)(2)D(3)-26,23-lactone analogs, (23S)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647) and (23R)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9648), inhibited differentiation of HL-60 cells induced by 1alpha,25-(OH)(2)D(3). However, 1beta-hydroxyl diastereomers of these analogs, i.e. (23S)-25-dehydro-1beta-hydroxyvitamin D(3)-26, 23-lactone (1beta-TEI-9647) and (23R)-25-dehydro-1beta-hydroxyvitamin D(3)-26,23-lactone (1beta-TEI-9648), did not inhibit differentiation of HL-60 cells caused by 1alpha,25-(OH)(2)D(3). A separate study showed that the nuclear vitamin D receptor (VDR) binding affinities of the 1-hydroxyl diastereomers were about 200 and 90 times weaker than that of 1alpha-hydroxyl diastereomers, respectively. Moreover, none of these lactone analogs inhibited NB4 cell differentiation induced by 1alpha,25-(OH)(2)D(3). In contrast, 1beta,25-dihydroxyvitamin D(3) (1beta,25-(OH)(2)D(3)) and 1beta,24R-dihydroxyvitamin D(3) (1beta,24R-(OH)(2)D(3)) inhibited NB4 cell differentiation but not HL-60 cell differentiation. Collectively, the results suggested that 1-hydroxyl lactone analogs, i.e. TEI-9647 and TEI-9648, are antagonists of 1alpha,25-(OH)(2)D(3), specifically for the nuclear VDR-mediated genomic actions, but not for non-genomic actions.