Novel ring A stereoisomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) and 2-methyl-20-epi-1alpha,25-dihydroxyvitamin D(3): transactivation of target genes and modulation of differentiation in human promyelocytic leukemia (HL-60) cells.
Novel ring A stereoisomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) and 2-methyl-20-epi-1alpha,25-dihydroxyvitamin D(3): transactivation of target genes and modulation of differentiation in human promyelocytic leukemia (HL-60) cells.
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2-甲基-1α,25-二羟基维生素 D(3) 和 2-甲基-20-epi-1α,25-二羟基维生素 D(3) 的新型环 A 立体异构体：人早幼粒细胞白血病靶基因的反式激活和分化调节（
DOI：
10.1016/s0006-2952(99)00357-3
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发表时间：
2000
影响因子：
5.8
通讯作者：
T. Okano
中科院分区：
文献类型：
--
作者：
K. Nakagawa;M. Kurobe;K. Ozono;K. Konno;T. Fujishima;H. Takayama;T. Okano
我们评价了2-甲基-1 α，25-二羟基维生素D3的两组A环立体异构体的生物活性（2-甲基-1 α，25（OH）2D 3）和2-甲基-20-表-1 α，25-二羟基维生素D3（2-甲基-20-epi-1α，25（OH）2D 3），具体如下：包括两个维生素D反应元件（VDRES）的大鼠25-羟基维生素D3-24-羟化酶基因启动子的反式激活和包括VDRE的人骨钙素基因启动子;维生素D受体（VDR）介导的应答，使用VDR-GAL 4单杂交荧光素酶报告系统和类维生素A X受体α（RXRα）-在转染的人宫颈上皮样癌（HeLa）细胞中使用表达的VDR/RXRα-GAL 4修饰的双杂交荧光素酶报告系统介导的反应;以及调节人白血病（HL-60）细胞中的细胞表面CD 11b抗原表达。这两种类似物的所有非对映异构体都表现出独特的生物活性，这取决于C-1和C-3羟基、A环中的C-2甲基和侧链中的C-20甲基的构型。在2-甲基类似物的8种可能的非对映异构体中，2α-甲基-1 α，25（OH）2D 3是最有效的，并且表现出与1α，25（OH）2D 3相当或甚至更高的生物学效力。在2-甲基-20-epi类似物的8种可能的非对映异构体中，2α-甲基-20-epi-1 α，25（OH）2D 3是最有效的，其转录活性比1α，25（OH）2D 3高100- 200倍，并且具有极高的细胞调节活性。2β-甲基-20-差向-1 α，25（OH）2D 3与其2-差向异构体2α-甲基-20-差向-1 α，25（OH）2D 3的效力几乎相同，而其20-差向异构体2β-甲基-1 α，25（OH）2D 3几乎完全无生物活性。在这些方面，可以推测，2-甲基取代和20-差向异构化的双重修饰1α，25（OH）2D 3诱导VDR/RXRα/VDRE介导的信号转导反应的显着变化，并大大增强生物活性。另一个惊人的发现是2β-甲基-20-表-3-表-1 β，25（OH）2D 3在转录上比1α，25（OH）2D 3更活跃，尽管缺乏1α-羟基，这被认为是表达VDR介导的基因转录所必需的。由于C-20天然对应物2β-甲基-3-差向-1 β，25（OH）2D 3几乎完全没有生物活性，因此20-差向异构化可能是基因表达激活的原因。虽然早期对维生素D类似物的广泛结构-活性研究表明1α，25（OH）2D 3的C-1、C-3和C-20的立体化学是维生素D作用的关键结构基序，我们的结果清楚地表明，C-2位的立体化学也是维生素D作用的重要结构基序，并暗示2-甲基取代可能诱导环A中的构象变化，这取决于C-1和C-3羟基的构型与C-20立体化学的组合。因此，这些类似物中的一些在分子和细胞水平上表现出异常高或出乎意料的生物活性。这些结果表明，1α，25（OH）2D 3的2-甲基取代以及A环和侧链上的立体化学改变将为结构-活性研究和开发具有独特生物活性特征的治疗药物提供有用的类似物。
We evaluated the biological activity of two sets of ring A stereoisomers of 2-methyl-1α,25-dihydroxyvitamin D3(2-methyl-1α,25(OH)2D3) and 2-methyl-20-epi-1α,25-dihydroxyvitamin D3(2-methyl-20-epi-1α,25(OH)2D3) in terms of the following: transactivation of a rat 25-hydroxyvitamin D3-24-hydroxylase gene promoter including two vitamin D response elements (VDREs) and a human osteocalcin gene promoter including a VDRE in transfected human osteosarcoma (MG-63) cells; a vitamin D receptor (VDR)-mediated response using a VDR–GAL4 one-hybrid luciferase reporter system and a retinoid X receptor α (RXRα)-mediated response using an expressed VDR/RXRα–GAL4 modified two-hybrid luciferase reporter system in transfected human epitheloid carcinoma, cervix (HeLa) cells; and modulation of cell surface CD11b antigen expression in human leukemia (HL-60) cells. All the diastereomers of both analogues exhibited unique biological activity profiles depending upon the configurations of the C-1 and C-3 hydroxyl groups, the C-2 methyl group in ring A, and the C-20 methyl group in the side chain. Of the eight possible diastereomers of the 2-methyl analogues, 2α-methyl-1α,25(OH)2D3was the most potent and exhibited comparable or even greater biological potency than 1α,25(OH)2D3. Of the eight possible diastereomers of the 2-methyl-20-epi analogues, 2α-methyl-20-epi-1α,25(OH)2D3was the most potent and exhibited 100- to 200-fold higher transcriptional potencies than 1α,25(OH)2D3and exceptionally high cell regulatory activities. 2β-Methyl-20-epi-1α,25(OH)2D3was nearly as potent as its 2-epimer, 2α-methyl-20-epi-1α,25(OH)2D3, whereas its 20-epimer, 2β-methyl-1α,25(OH)2D3, was almost completely biologically inactive. In these respects, it can be postulated that the double modification of 2-methyl substitution and 20-epimerization to 1α,25(OH)2D3induces remarkable changes in a VDR/RXRα/VDRE-mediated signaling response and greatly enhances biological activity. The other striking finding was that 2β-methyl-20-epi-3-epi-1β,25(OH)2D3is transcriptionally more active than 1α,25(OH)2D3despite lacking the 1α-hydroxyl group, which was believed to be essential for expressing VDR-mediated gene transcription. Since the C-20 natural counterpart, 2β-methyl-3-epi-1β,25(OH)2D3, was almost completely biologically inactive, 20-epimerization is probably responsible for activation of gene expression. Although earlier extensive structure–activity studies of vitamin D analogues showed stereochemistry at the C-1, C-3, and C-20 of 1α,25(OH)2D3to be the key structural motif for vitamin D action, our results clearly demonstrated that stereochemistry at the C-2 is also an important structural motif for vitamin D action and imply that 2-methyl substitution possibly induces conformational changes in ring A depending upon the combinations of configurations of the C-1 and C-3 hydroxyl groups with C-20 stereochemistry. Consequently, several of these analogues exhibit exceptionally high or unexpected biological activities at the molecular and cellular levels. These results suggest that 2-methyl substitution together with alterations of stereochemistry in both ring A and the side chain of 1α,25(OH)2D3will provide useful analogues for structure–activity studies and development of therapeutic agents with unique biological activity profiles.
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影响因子：
20.3
作者：
R. Bouillon;W. Okamura;A. Norman
通讯作者：
R. Bouillon;W. Okamura;A. Norman
人类骨钙素基因中的维生素 D 反应元件。
DOI：
--
发表时间：
1990
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Ozono,K;Liao,J;Kerner,SA;Scott,RA;Pike,JW
通讯作者：
Pike,JW
骨髓单核细胞的终末分化表面抗原在用化学诱导剂处理的人早幼粒细胞白血病细胞（HL60）中表达。
影响因子：
20.3
作者：
Perussia,B;Lebman,D;Ip,SH;Rovera,G;Trinchieri,G
通讯作者：
Trinchieri,G
使用酵母双杂交系统分析维生素 D 类似物诱导的维生素 D 受体与类视黄醇 X 受体的异二聚化。
DOI：
10.1210/mend.11.3.9895
发表时间：
1997
期刊：
Molecular endocrinology (Baltimore, Md.)
影响因子：
--
作者：
Zhao,XY;Eccleshall,TR;Krishnan,AV;Gross,C;Feldman,D
通讯作者：
Feldman,D
1 α,25-二羟基-20-表维生素 D3：一种非常有效的体外白血病细胞生长抑制剂。
影响因子：
20.3
作者：
Elstner,E;Lee,YY;Hashiya,M;Pakkala,S;Binderup,L;Norman,AW;Okamura,WH;Koeffler,HP
通讯作者：
Koeffler,HP