Structure-Activity Study of Vitamin D Analogues

为了澄清维生素D模拟的结构-功能关系，我们合成了一种新颖的维生素D模拟，并评估了其生物活性。（1） A系列单脱氢化19-nor-1 α，25-二羟基维生素D-23-D2 A-环模拟已合成。模拟可以清楚地分为两个类别;一组，在A环中携带1-α-羟基或3-β-羟基组，是潜在的差异剂和第二组，携带1-β-羟基或3-α-羟基组，是凋亡的潜在刺激剂。这些发现将提供有用的信息，不仅是用于治疗剂的开发，用于白血病和其他癌症的治疗。（2） Biological activities of a series of 2？-substituted analogues of 1？， 25（OH）イD22？D2）DイD23？D2 were evaluated。VDR对目标基因和VDR介导的基因调节的转染潜力的结合，羟基烷基和羟基烷基2β-替代的模拟几乎可以与那些1α， 25（OH）的α，D22（OH） ... More イD23イエD2， while the alkyl and alkenyl analogues were m\less active than 1， 25（OH）イD22イイD23イD2。Furthermore，我们在这些化合物中找到了一个可供骨质疏松症预防性和治疗性药物的候选人（3）两组环绕A立体声异构体的生物活动：2-甲基-1 α，25-二羟基维生素D-23-D-2和2-甲基-20-epi-1 α，25-二羟基维生素D-23-D-2进行了评估。We found that 2β-methyl-20-epi-3-epi-1 β， 25（OH）イイD22イエD23イエD2 transcriptionally more active than 1α， 25（OH）イイD22イエD23イエD2 despite lacking the 1α-hydroxyl group， which was believed to be essential for expressing VDR-mediated gene transcription。自从C-20自然对照部分， 2β-甲基-3-epi-1 β， 25（OH）-D22-D2 D-D23-D2在生物学上几乎完全不活跃，20-epimerization可能对基因表达的激活负责。（4） We found that binding affinity 1α， 25（OH）イイD22イイD22イイD2 and 1α， 25（OH）イD22イイD24イイD2were almost comparable to the effects of 1α， 25（OH）イD22イD23イD2， while 24-epi-1 α， 25（OH）イD22イイD2 and 1α，25（OH）伊D22伊D2 D伊D27伊D2 were much less active than 1， 25（OH）伊D22伊D23伊D2 in these res\。This is the first finding concerning biological assessment of 1α， 25（OH）イイD22イイD22イイD2， 1α， 25（OH）イD22イイD23イイD2，1 α，25（OH）イD22イイD24イイD2，24-epi-1 α， 25（OH）イD22イイD2DイD2 and 1α，25（OH）イイD22イイD27イイD2 at the molecular level， especially with regards to the structural differences at the 24 R-or 24 S-methyl group and a double bond between carbons 22 and 23 in the side chain of 1α， 25（OH）イD22イエD2D derivatives。（5） The effects of 1-， 25（OH）イイD22イイD23イイD2 and its analogues on transmembrane CaイD12+イイD1 influx were examined in the growth phase of rat osteosarcoma ROS 17/2.8 cells.The results suggest that 1-，25（OH）D22 D23 D2 and its analogues modulate transmembrane Ca D12+ D1 influx in osteoblast-like cells by opening L-type Ca D12 + D1 channels which can recognize 1-羟基模拟作为拮抗剂，1β-羟基模拟作为拮抗剂。（6） We demonstrated that 1α， 25（OH）イイD22イイD23イエD2-mediated suppressive effects on the inducible expression of cytokine genes in human T cells may， in part， be due to diminished activity of the transcription factor NFAT。在human IL-2 promoter中指定的D23受体（VDR） specifically bound to the distal NFAT site。Less（低）

To clarify the structure-function relationship of vitamin D analogues, we synthesized novel vitamin D analogues and evaluated their biological activities.(1) A series of singly dehydroxylated 19-nor-1α, 25-dihydroxyvitamin DィイD23ィエD2 A-ring analogues were synthesized. The analogues could be clearly divided into two categories ; one group, bearing 1α-hydroxy or 3β-hydroxy groups in the A-ring, were potent differentiators and the second group, bearing 1β-hydroxy or 3α-hydroxy groups, were potent stimulators of apoptosis. These findings will provide useful information not only for development of therapeutic agents for treatment of leukemia and other cancers.(2) Biological activities of a series of 2β-substituted analogues of 1α, 25(OH)ィイD22ィエD2)DィイD23ィエD2 were evaluated. Binding affinity for VDR, transactivation potency on the target gene and VDR-mediated gene regulation of the hydroxyalkyl and hydroxyalkoxy 2β-substituted analogues were almost comparable to those of 1α, 25(OH)ィイD22ィエD2Dィ … More イD23ィエD2, while the alkyl and alkenyl analogues were much less active than 1α, 25(OH)ィイD22ィエD2DィイD23ィエD2. Furthermore, we found a promising candidate for preventive and therapeutic medicine of osteoporosis among these compounds.(3) The biological activity of two sets of ring A stereo isomers of 2-methyl-1α, 25-dihydroxyvitamin DィイD23ィエD2 and 2-methyl-20-epi-1α, 25-dihydroxyvitamin DィイD23ィエD2 were evaluated. We found that 2β-methyl-20-epi-3-epi-1β, 25(OH)ィイD22ィエD2DィイD23ィエD2 is transcriptionally more active than 1α, 25(OH)ィイD22ィエD2DィイD23ィエD2 despite 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)ィイD22ィエD2DィイD23ィエD2, was almost completely biologically inactive, 20-epimerization is probably responsible for activation of gene expression.(4) We found that binding affinity 1α, 25(OH)ィイD22ィエD2DィイD22ィエD2 and 1α, 25(OH)ィイD22ィエD2DィイD24ィエD2 were almost comparable to the effects of 1α, 25(OH)ィイD22ィエD2DィイD23ィエD2, while 24-epi-1α, 25(OH)ィイD22ィエD2DィイD22ィエD2 and 1α, 25(OH)ィイD22ィエD2DィイD27ィエD2 were much less active than 1α, 25(OH)ィイD22ィエD2DィイD23ィエD2 in these respects. This is the first finding concerning biological assessment of 1α, 25(OH)ィイD22ィエD2DィイD22ィエD2, 1α, 25(OH)ィイD22ィエD2DィイD23ィエD2, 1α, 25(OH)ィイD22ィエD2DィイD24ィエD2, 24-epi-1α, 25(OH)ィイD22ィエD2DィイD22ィエD2 and 1α, 25(OH)ィイD22ィエD2DィイD27ィエD2 at the molecular level, especially with regards to the structural differences at the 24R- or 24S-methyl group and a double bond between carbons 22 and 23 in the side chain of 1α, 25(OH)ィイD22ィエD2D derivatives.(5) The effects of 1α, 25(OH)ィイD22ィエD2DィイD23ィエD2 and its analogues on transmembrane CaィイD12+ィエD1 influx were examined in the growth phase of rat osteosarcoma ROS17/2.8 cells.The results suggest that 1α, 25(OH)ィイD22ィエD2DィイD23ィエD2 and its analogues modulate transmembrane CaィイD12+ィエD1 influx in osteoblast-like cells by opening L-type CaィイD12+ィエD1 channels which can recognize 1α-hydroxy analogues as agonists and 1β-hydroxy analogues as antagonists.(6) We demonstrated that 1α, 25(OH)ィイD22ィエD2DィイD23ィエD2-mediated suppressive effects on the inducible expression of cytokine genes in human T cells may, in part, be due to diminished activity of the transcription factor NFAT. The vitamin DィイD23ィエD2 receptor (VDR) specifically bound to the distal NFAT site in the human IL-2 promoter. Less