disodium L-homocysteinate | 50615-55-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: disodium L-homocysteinate
• CAS: 50615-55-9
• 化学式: C₄H₇NO₂S*2Na
• 分子量: 179.151
• InChiKey: YYSHBZOKAHGUAY-DFWYDOINSA-L

计算性质

• 辛醇/水分配系数(LogP)：
  -5.0
• 重原子数：
  9.0
• 可旋转键数：
  3.0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  66.15
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  disodium L-homocysteinate 、 5'-chloro-5'-deoxy-N⁶-cyclopentyladenosine 在 potassium iodide 作用下， 以 水 为溶剂， 生成 (2S)-2-amino-4-[[(2S,3S,4R,5R)-5-[6-(cyclopentylamino)purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]butanoic acid
  参考文献：
  名称：

  等位基因特异性蛋白质甲基转移酶抑制剂的设计

  摘要：

  蛋白质精氨酸甲基转移酶催化甲基从 S-腺苷甲硫氨酸 (SAM) 转移到靶蛋白中的精氨酸侧链，调节转录、RNA 加工和受体介导的信号传导。为了专门解决该家族各个成员的功能作用，我们采用了“凹凸洞”的方法，并设计了一系列针对酵母蛋白的 N(6)-取代的 S-腺苷高半胱氨酸 (SAH) 类似物甲基转移酶 RMT1。在 Rmt1 中发现了一个点突变 (E117G)，这使得该酶容易受到 SAH 类似物的选择性抑制。基于质谱的酶分析表明，N(6)-苄基-和 N(6)-萘甲基-SAH 两种化合物可以抑制突变酶，选择性大于 20。当 E117G 突变被引入酿酒酵母染色体时，Npl3p（一种已知的体内 Rmt1 底物）的甲基化可以通过 N(6)-萘基甲基-SAH 在所得等位基因中适度降低。此外，发现 N(6)-苄基-SAM 类似物可作为正交 SAM 辅因子。相对于选择性大于 67 的野生型酶，这种类似物优先

  DOI：

  10.1021/ja011423j

文献信息

• Approaches to isozyme-specific inhibitors. 16. A novel methyl-C5' covalent adduct of L-ethionine and .beta.,.gamma.-imido-ATP as a potent multisubstrate inhibitor of rat methionine adenosyltransferases
  作者：Vivekananda M. Vrudhula、Francis Kappler、Carol Afshar、Stephan L. Ginell、Leslie Lessinger、Alexander Hampton

  DOI：10.1021/jm00124a026

  日期：1989.4

  homologous methionine-ATP adducts, the alpha-amino acid group was protected, a beta,gamma-imidotriphosphoryl group was introduced at O5', and blocking groups were removed to give the title adduct as a 2:3 mixture of its two 5' epimers. It was a powerful inhibitor [KM(ATP)/Ki = 520 and 340] of the M-2 (normal tissue) and M-T (hepatoma tissue) forms, respectively, of the title enzyme and displayed predominantly

  通过一锅5'-O-三甲基甲硅烷基化，N6-苯甲酰基化和去甲硅烷基化容易地合成的N6，N6-二苯甲酰基-2'，3'-O-异丙基亚氨腺苷被转化为相应的5'-醛。将其用CH 2 ＝ CHMgBr处理，在脱苯甲酰化后，分别得到5′-C-乙烯基-2′，3′-O-异丙基亚氨腺苷的5′S和5′R差向异构体的1∶3混合物。通过对5'R差向异构体的单晶X射线衍射分析来确定构型。混合的差向异构5'-C-乙烯基核苷的5'-O-四氢吡喃基衍生物的氢硼化反应很容易提供5'（S，R）-C-（2-羟乙基）-2'，3'-O-异丙基亚丙基腺苷。用L-高半胱氨酸二钠处理该5'（S，R）-C-（2-O-甲苯磺酰基）衍生物可方便地引入L-乙硫氨酸系统。用较早的合成蛋氨酸-ATP加合物的方法，保护了α-氨基酸，在O5'处引入了β，γ-亚氨基三磷酰基，并去除了保护基，得到标题加合物它的两个5'差向异构体的2：3混合物。它是标题酶的M
• Approaches to isozyme-specific inhibitors. 17. Attachment of a selectivity-inducing substituent to a multisubstrate adduct. Implications for facilitated design of potent, isozyme-selective inhibitors
  作者：Francis Kappler、Alexander Hampton

  DOI：10.1021/jm00171a032

  日期：1990.9

  The synthesis is described of a methyl-C5' adduct of L-methionine and beta,gamma-ATP bearing a 6-S-n-Bu group in place of the 6-NH2 group of the parent adduct. The latter is a potent multisubstrate inhibitor in a model system consisting of the M-2 and M-T isozymes of rat methionine adenosyltransferase. When attached to ATP, the 6-S-n-Bu group induces selectivity for M-T inhibition by elevating affinity

  描述了L-蛋氨酸的甲基-C5'加合物和带有6-Sn-Bu基团的β-γ-ATP代替母体加合物的6-NH2基团。后者是由大鼠甲硫氨酸腺苷基转移酶的M-2和MT同工酶组成的模型系统中的有效多底物抑制剂。当与ATP连接时，6-Sn-Bu基团通过提高与MT而不是M-2的ATP位点的亲和力来诱导对MT抑制的选择性。在上述加合物中，它发挥了相似的作用，表现为选择性和对MT的抑制作用增强。这提供了该方法产生相对容易地产生具有中等同工酶选择性的有效抑制剂的能力的第二说明。本文概述了适度的（ca. 底物衍生物通常在各种原子上带有一个短的取代基，通常表现出10倍的同工酶选择性。这与同工酶选择性抑制剂设计的另一种可行方法的特点一起，表明了一种方法，该方法具有促进对同工酶选择性和针对给定代谢转化具有选择性的有效抑制剂设计的潜力。它包括（1）评价上述类型的底物衍生物作为化学治疗上重要的同功酶（靶标和非靶标）的抑制剂的
• Isozyme-specific enzyme inhibitors. 14. 5'(R)-C-[(L-homocystein-S-yl)methyl]adenosine 5'-(.beta.,.gamma.-imidotriphosphate), a potent inhibitor of rat methionine adenosyltransferases
  作者：Francis Kappler、Vivekananda M. Vrudhula、Alexander Hampton

  DOI：10.1021/jm00392a013

  日期：1987.9

  established by conversion of this into the known 5'(S)-C-methyl-2',3'-O-isopropylidene adenosine with Raney nickel. The alpha-amino acid residue was protected as an N-Boc methyl ester, after which the 5'-hydroxyl was phosphorylated with benzyl phosphate and dicyclohexylcarbodiimide. The phosphoanhydride bond with inorganic imidodiphosphate was then created by established methods. Finally, blocking groups were

  标题化合物是L-蛋氨酸（Met）和β，γ-亚氨基-ATP的共价加合物。在其合成过程中，通过CF3CO2H和CH3的连续作用，将5'（R）-C-（氨基甲基）-N6-苯甲酰基-5'-O-甲苯磺酰基-2'，3'-O-异丙基亚丙基腺苷的N-Boc衍生物转化。将HNO 2转化为相应的5'（R）-C-羟甲基衍生物。用L-高半胱氨酸二钠处理显然导致硫在C6'处的侵蚀，显然是通过5'，6'-环氧化物进行的，并且在脱苯甲酰化后在C5'处发生了完全立体选择性转化，从而提供了5'（R）-C- （L-高半胱氨酸-S-甲基）-2'，3'-O-异亚丙基adesine。通过将其转化为具有阮内镍的已知5'（S）-C-甲基-2'，3'-O-异亚丙基腺苷来建立5'构型。α-氨基酸残基被保护为N-Boc甲酯，然后用磷酸苄酯和二环己基碳二亚胺将5'-羟基磷酸化。然后通过确定的方法产生与无机亚氨基二磷酸的磷酸酐键。最后，在不产生其
• Toward the synthesis of isozyme-specific enzyme inhibitors. Potent inhibitors of rat methionine adenosyltransferases. Effect of one-atom elongation of the ribose-P.alpha. bridge in two covalent adducts of L-methionine and .beta.,.gamma.-imido-ATP
  作者：Francis Kappler、Vivekananda M. Vrudhula、Alexander Hampton

  DOI：10.1021/jm00397a020

  日期：1988.2

  With 2',3'-O-isopropylideneadenosine or its N6-benzoyl derivative as starting material, synthetic routes to two novel adducts of L-methionine and beta,gamma-imido-ATP have been devised. One adduct, 14 (2:3 mixture of 6' epimers), had a P alpha OCH(R1)CH2 system [R1 = CH2-L-SCH2CH2CH2CH(NH2)CO2H] in place of the P alpha OC(5')H2 system of ATP, while the other, 16 (2:3 mixture of 5' epimers), had a P alpha OCH2CH2CH(R2) system [R2 = L-SCH2CH2CH(NH2)CO2H]. The ribose-P alpha bridge in 14 and 16 contained one more methylene group than in two homologous methionine-ATP adducts studied previously. Adduct 14 was a potent inhibitor of the rat M-2 (normal tissue) and M-T (Novikoff ascitic hepatoma) variants of methionine adenosyltransferase and gave competitive kinetics vs MgATP (Ki = 0.39 and 0.63 microM, respectively) or vs L-methionine (Ki = 2.2 and 2.7 microM). Adduct 16 was likewise a potent inhibitor competitive vs MgATP (Ki = 0.44 and 0.81 microM, respectively) or L-methionine (Ki = 2.1 and 1.5 microM). The kinetic data indicate that 14 and 16 inhibit by binding simultaneously to the MgATP and L-methionine substrate sites and that the extra methylene group facilitates the interaction of their methionine residues with these methionine sites.
• Isozyme-specific enzyme inhibitors. 13. S-[5'(R)-['N-triphosphoamino)methyl]adenosyl]-L-homocysteine, a potent inhibitor of rat methionine adenosyltransferases
  作者：Vivekananda M. Vrudhula、Francis Kappler、Alexander Hampton

  DOI：10.1021/jm00388a024

  日期：1987.5

  A synthesis is described of the title compound and its 5'S epimer, which are two-substrate adducts of adenosine 5'-triphosphate (ATP) and L-methionine (Met) in which the C(5')H2OP system in ATP is replaced by CH(R)CH2NHP [R = L-S(CH2)2CH(NH2)CO2H]. The 5'R epimer was a potent nonselective competitive inhibitor [averaged Ki = 0.32 microM; KM(ATP)/Ki = 440] vs. ATP of the rat M-2 (normal tissue) and M-T (Novikoff ascitic hepatoma) variants of methionine adenosyltransferase. It produced simple noncompetitive inhibition (averaged Ki = 2.7 microM) vs. Met with both variants. The 5'S epimer inhibited M-T competitively vs. ATP, but was 74-fold less effective than the 5'R epimer. Replacement of the homocysteine moiety in the 5'R epimer by hydrogen markedly reduced inhibitory potency, as indicated by Ki values of 14 microM for competitive inhibition vs. ATP and 580 microM for noncompetitive inhibition vs. Met with M-2. The data suggest that the 5'R epimer can interact simultaneously with two enzymic sites. Information on the kinetic mechanism of a human counterpart of M-2 and inhibitor properties of a previously studied Met-ATP adduct are consistent with the view that the two sites might resemble those that interact with the initial products of the reaction, S-adenosylmethionine and triphosphate.