1,23-二羟基-24,25,26,27-四去甲维他命 D3 | 97903-37-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 1,23-二羟基-24,25,26,27-四去甲维他命 D3
• 中文别名: 二(8-甲基-8-氮杂二环[3.2.1]辛-3-基)1,2,3,4-四氢-1-苯基萘-1,4-二羧酸酯；1,23-二羟基-24,25,26,27-四去甲维他命D3
• 英文名称: 24,25,26,27-tetranor-1,23-(OH)2D3
• 英文别名: 24,25,26,27-tetranor-1,23-dihydroxyvitamin D₃；1α,23-dihydroxy-24,25,26,27-tetranor-vitamin D3；1α,23-dihydroxy-24,25,26,27-tetranorvitamin D3；24,25,26,27-tetranor-1,23-dihydroxyvitamin D3；calcitroic acid；1,23-dihydroxy-24,25,26,27-tetranorvitamin D3；(1S)-1,23-dihydroxy-24,25,26,27-tetranorcalciol；(1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R)-4-hydroxybutan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol
• CAS: 97903-37-2
• 化学式: C₂₃H₃₆O₃
• 分子量: 360.537
• InChiKey: QKSLGXKBRJBRQD-NKLFQLIUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  60.7
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1,23-二羟基-24,25,26,27-四去甲维他命 D3 、 氢(+1)阳离子 、 氧气 、 [2Fe-2S]¹⁺ 生成 (1S)-1-hydroxy-23-oxo-24,25,26,27-tetranorcalciol 、 水 、 [2Fe-2S]²⁺
  参考文献：
  名称：

  涉及维生素D活化和失活的酶。

  摘要：

  已显示六种细胞色素P450（CYP）亚型可羟化维生素D。其中四个，CYP27A1，CYP2R1，CYP3A4和CYP2J3，是参与活化第一步的维生素D 25-羟化酶的候选物。高度管制的肾脏酶25-羟基维生素D-1α-羟化酶包含CYP27B1成分，该成分完成了向激素形式1α，25-二羟基维生素D（3）的激活途径。从1alpha，25-（OH）（2）D（3）到钙柠檬酸的五步失活途径归因于单个多功能CYP CYP24A1，它通过1alpha，25在维生素D目标细胞中转录诱导-（OH）（2）D（3）。根据其他CYP的排列和晶体结构，已经生成了维生素D相关CYP的同源性模型。

  DOI：

  10.1016/j.tibs.2004.10.005
• 作为产物：
  描述：

  (S)-2-((3R,3aR,7S,7aR)-octahydro-7-hydroxy-3a-methyl-1H-inden-3-yl)propyl 4-methylbenzenesulfonate 在 2,6-二甲基吡啶 、 sodium chlorite 、 lithium aluminium tetrahydride 、 正丁基锂 、 sodium dihydrogenphosphate dihydrate 、 2-甲基-2-丁烯 、 四丁基氟化铵 、 二异丁基氢化铝 、 pyridinium chlorochromate 、 三氟乙酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 正己烷 、 二氯甲烷 、 水 、 二甲基亚砜 、 甲苯 、 叔丁醇 为溶剂， 反应 23.25h， 生成 1,23-二羟基-24,25,26,27-四去甲维他命 D3
  参考文献：
  名称：

  高效和可扩展的钙钛酸及其13 C标记衍生物的全合成†

  摘要：

  从商业上可购得的Inhoffen-Lythgoe二醇开始，以11个步骤合成了钙柠檬酸，生理活性维生素D 3代谢产物降钙素的失活形式及其13 C标记的衍生物，总产率为21％。合成的关键步骤是与KCN和K 13 CN形成C1均一的腈，以及与环A氧化膦试剂进行的Horner-Wittig反应。

  DOI：

  10.1039/c4ra04322g

文献信息

• The seleno-acetal route to 1α-hydroxy-vitamin D analogues: synthesis of 24-oxa-1α-hydroxy-vitamin D3, a useful vitamin D metabolism probe
  作者：Martin J. Calverleya、Stephen Strugnell、Glenville Jones

  DOI：10.1016/s0040-4020(01)86276-1

  日期：1993.1

  lithio-demethylseleno-derivative of seleno-acetal 11 with chloromethyl isopropyl ether [shown by NMR to give the (22S)-methylseleno-compound 13a as the major diastereoisomer] is the key reaction in the synthesis of the 24-oxa analogue (MC 1090, 8) of 1α-hydroxyvitamin D3 (4). The metabolism of 8 to calcitroic acid (7) is demonstrated in vitro in a hepatocyte cell (Hep 3B) model. This supports the hypothesis

  乙缩醛11的硫代-脱甲基硒代衍生物与氯甲基异丙基醚的烷基化[由NMR显示，以得到（22 S）-甲基硒代化合物13a为主要的非对映异构体]是合成24-氧杂酸酯的关键反应类似物（MC 1090，8 1α羟基d的）3（4）。的代谢8至calcitroic酸（7）证明在体外在肝细胞病毒（Hep 3B）模型。这支持以下假设：8可经历酶促25羟基化类似于活化4，或类似的侧链羟基化反应，但随后以1α，25-二羟基维生素D 3到7缩短了靶细胞侧链的裂解途径。
• Structure-Function Analysis of Vitamin D 24-Hydroxylase (CYP24A1) by Site-Directed Mutagenesis: Amino Acid Residues Responsible for Species-Based Difference of CYP24A1 between Humans and Rats
  作者：Hiromi Hamamoto、Tatsuya Kusudo、Naoko Urushino、Hiroyuki Masuno、Keiko Yamamoto、Sachiko Yamada、Masaki Kamakura、Miho Ohta、Kuniyo Inouye、Toshiyuki Sakaki

  DOI：10.1124/mol.106.023275

  日期：2006.7

  Our previous studies revealed the species-based difference of CYP24A1-dependent vitamin D metabolism. Although human CYP24A1 catalyzes both C-23 and C-24 oxidation pathways, rat CYP24A1 shows almost no C-23 oxidation pathway. We tried to identify amino acid residues that cause the species-based difference by site-directed mutagenesis. In the putative substrate-binding regions, amino acid residue of rat CYP24A1 was converted to the corresponding residue of human CYP24A1. Among eight mutants examined, T416M and I500T showed C-23 oxidation pathway. In addition, the mutant I500F showed quite a different metabolism of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] from both human and rat CYP24A1. These results strongly suggest that the amino acid residues at positions 416 and 500 play a crucial role in substrate binding and greatly affect substrate orientation. A three-dimensional model of CYP24A1 indicated that the A-ring and triene part of 1α,25(OH)2D3 could be located close to amino acid residues at positions 416 and 500, respectively. Our findings provide useful information for the development of new vitamin D analogs for clinical use.

  我们之前的研究揭示了CYP24A1依赖性维生素D代谢的物种差异。虽然人类CYP24A1催化C-23和C-24氧化途径，但大鼠CYP24A1几乎没有C-23氧化途径。我们试图通过定点突变来确定导致物种差异的氨基酸残基。在推测的底物结合区域，大鼠CYP24A1的氨基酸残基被转化为人类CYP24A1的相应残基。在所研究的八个突变体中，T416M和I500T表现出C-23氧化途径。此外，突变体I500F表现出与人类和大鼠CYP24A1截然不同的1α,25-二羟基维生素D3（1α,25(OH)2D3）代谢。这些结果有力地表明，第416和500位的氨基酸残基在底物结合中起着至关重要的作用，并极大地影响底物取向。CYP24A1的三维模型表明，1α,25(OH)2D3的A环和三烯部分可能分别位于靠近第416和500位的氨基酸残基的位置。我们的发现为开发新的维生素D类似物用于临床提供了有用的信息。
• A new insight into the role of rat cytochrome P450 24A1 in metabolism of selective analogs of 1α,25-dihydroxyvitamin D3
  作者：Steve Y. Rhieu、Andrew J. Annalora、Rose M. Gathungu、Paul Vouros、Milan R. Uskokovic、Inge Schuster、G. Tayhas R. Palmore、G. Satyanarayana Reddy

  DOI：10.1016/j.abb.2011.02.004

  日期：2011.5

  We examined the metabolism of two synthetic analogs of 1 alpha,25-dihydroxyvitamin D-3 (1), namely 1 alpha,25-dihydroxy-16-ene-23-yne-vitamin D-3 (2) and 1 alpha,25-dihydroxy-16-ene-23-yne-26,27-dimethyl-vitamin D-3 (4) using rat cytochrome P450 24A1 (CYP24A1) in a reconstituted system. We noted that 2 is metabolized into a single metabolite identified as C26-hydroxy-2 while 4 is metabolized into two metabolites, identified as C26-hydroxy-4 and C26a-hydroxy-4. The structural modification of adding methyl groups to the side chain of 1 as in 4 is also featured in another analog, 1 alpha,25-dihydroxy-22,24-diene-24,26,27-tri-homo-vitamin D-3 (6). In a previous study, 6 was shown to be metabolized exactly like 4, however, the enzyme responsible for its metabolism was found to be not CYP24A1. To gain a better insight into the structural determinants for substrate recognition of different analogs, we performed an in silico docking analysis using the crystal structure of rat CYP24A1 that had been solved for the substrate-free open form. Whereas analogs 2 and 4 docked similar to 1,6 showed altered interactions for both the A-ring and side chain, despite prototypical recognition of the CD-ring. These findings hint that CYP24A1 metabolizes selectively different analogs of 1, based on their ability to generate discrete recognition cues required to close the enzyme and trigger the catalytic mechanism. 2011 Elsevier Inc. All rights reserved.
• Kinetic analysis of human CYP24A1 metabolism of vitamin D via the C24-oxidation pathway
  作者：Elaine W. Tieu、Edith K. Y. Tang、Robert C. Tuckey

  DOI：10.1111/febs.12862

  日期：2014.7

  CYP24A1 is the multicatalytic cytochrome P450 responsible for the catabolism of vitamin D via the C23‐ and C24‐oxidation pathways. We successfully expressed the labile human enzyme in Escherichia coli and partially purified it in an active state that permitted detailed characterization of its metabolism of 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3] and the intermediates of the C24‐oxidation pathway in a phospholipid‐vesicle reconstituted system. The C24‐oxidation pathway intermediates, 1,24,25‐trihydroxyvitamin D3, 24‐oxo‐1,25‐dihydroxyvitamin D3, 24‐oxo‐1,23,25‐trihydroxyvitamin D3 and tetranor‐1,23‐dihydroxyvitamin D3, were enzymatically produced from 1,25(OH)2D3 using rat CYP24A1. Both 1,25(OH)2D3 and 1,23‐dihydroxy‐24,25,26,27‐tetranorvitamin D3 were found to partition strongly into the phospholipid bilayer when in aqueous medium. Changes to the phospholipid concentration did not affect the kinetic parameters for the metabolism of 1,25(OH)2D3 by CYP24A1, indicating that it is the concentration of substrates in the membrane phase (mol substrate·mol phospholipid−1) that determines their rate of metabolism. CYP24A1 exhibited Km values for the different C24‐intermediates ranging from 0.34 to 15 mmol·mol phospholipid−1, with 24‐oxo‐1,23,25‐trihydroxyvitamin D3 [24‐oxo‐1,23,25(OH)3D3] displaying the lowest and 1,24,25‐trihydroxyvitamin D3 [1,24,25(OH)3D3] displaying the highest. The kcat values varied by up to 3.8‐fold, with 1,24,25(OH)3D3 displaying the highest kcat (34 min−1) and 24‐oxo‐1,23,25(OH)3D3 the lowest. The data show that the cleavage of the side chain of 24‐oxo‐1,23,25(OH)3D3 occurs with the highest catalytic efficiency (kcat/Km) and produces 1‐hydroxy‐23‐oxo‐24,25,26,27‐tetranorvitamin D3 and not 1,23‐dihydroxy‐24,25,26,27‐tetranorvitamin D3, as the primary product. These kinetic analyses also show that intermediates of the C24‐oxidation pathway effectively compete with precursor substrates for binding to the active site of the enzyme, which manifests as an accumulation of intermediates, indicating that they dissociate after each catalytic step.
• Metabolism of A-ring diastereomers of 1α,25-dihydroxyvitamin D3 by CYP24A1
  作者：Tatsuya Kusudo、Toshiyuki Sakaki、Daisuke Abe、Toshie Fujishima、Atsushi Kittaka、Hiroaki Takayama、Susumi Hatakeyama、Miho Ohta、Kuniyo Inouye

  DOI：10.1016/j.bbrc.2004.07.040

  日期：2004.9

  The metabolism of 1alpha,25(OH)(2)D-3 (1alpha,3beta) and its A-ring diastereomers, 1beta,25(OH)(2)D-3 (1beta,3beta), 1alpha,25(OH)(2)-3-epi-D-3 (1alpha,3alpha), and 1beta,25(OH)(2)-3-epi-D-3 (1beta,3alpha), was examined to compare the substrate specificity and reaction specificity of CYP24A1 between humans and rats. The ratio between C-23 and C-24 oxidation pathways in human CYP24A1 -dependent metabolism of (1alpha,30() and (1beta,3) was 1:1, although the ratio for (1alpha,3beta) and (1beta,3beta) was 1:4. These results indicate that the orientation of the hydroxyl group at the C-3 position determines the ratio between C-23 and C-24 oxidation pathways. A remarkable increase of metabolites in the C-23 oxidation pathway was also observed in rat CYP24A1 -dependent metabolism. The binding affinity of human CYP24A1 for A-ring diastereomers was (1alpha,3beta) > (1alpha,3alpha) > (1beta,3beta) > (1beta,3alpha), indicating that both hydroxyl groups at C-1 and C-3 positions significantly affect substrate-binding. The information obtained in this study is quite useful for understanding substrate recognition of CYP24A1 and designing new vitamin D analogs. (C) 2004 Elsevier Inc. All rights reserved.