(2S,4S)-hypoglycin A | 144604-88-6

• 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: (2S,4S)-hypoglycin A
• 英文别名: (2S,4S) α-<(methylenecyclopropyl)methyl>glycine；Hypoglycin A；(+)-Hypoglycin A <(+)-(2S,4S)-2-Amino-4,5-methylenhexen-5-saeure>；(2S)-2-azaniumyl-3-[(1S)-2-methylidenecyclopropyl]propanoate
• CAS: 144604-88-6
• 化学式: C₇H₁₁NO₂
• 分子量: 141.17
• InChiKey: OOJZCXFXPZGUBJ-WDSKDSINSA-N

物化性质

• 沸点：
  269.1±23.0 °C(Predicted)
• 密度：
  1.16±0.1 g/cm3(Predicted)
• 颜色/状态：
  Yellow plates from methanol + water
• 熔点：
  280-284 °C
• 旋光度：
  Specific optical rotation at 32 °C for D (sodium) line = +9.2 deg.
• 分解：
  When heated to decomposition it emits toxic fumes of /nitric oxides/.

计算性质

• 辛醇/水分配系数(LogP)：
  -2.5
• 重原子数：
  10
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  63.3
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

转氨基作用导致亚甲基环丙烷丙酮酸的形成，后者通过脱羧反应转变为亚甲基环丙烷乙酸；磷酸吡哆醛加上镁(2+)离子和硫胺素焦磷酸，镁(2+)离子加上辅酶A是这两个反应步骤中涉及的辅因子。

TRANSAMINATION RESULTS IN FORMATION OF METHYLENECYCLOPROPANEPYRUVIC ACID, WHICH UNDERGOES DECARBOXYLATION TO METHYLENECYCLOPROPANE ACETIC ACID; PYRIDOXAL PHOSPHATE PLUS MG(2+) IONS AND THIAMINE PYROPHOSPHATE, MG(2+) IONS PLUS COENZYME-A ARE THE COFACTORS INVOLVED IN THE TWO REACTION STEPS.

来源:Hazardous Substances Data Bank (HSDB)

代谢

大量异常代谢物在服用低糖酸处理的大鼠尿液中被发现...分析。其中十种之前并未与低糖酸给药相关联：这些包括几种羟基化合物，来自缬氨酸和异亮氨酸途径的化合物，2-氧代己二酸，n-丁酰甘氨酸和异戊酰葡萄糖苷酸。这些结果表明，异亮氨酸和缬氨酸代谢途径在各自的酰基辅酶A脱氢步骤上受到抑制，正如之前显示的脂肪酸、亮氨酸和赖氨酸代谢的情况。

Numerous abnormal metabolites were identified in large amounts in the urine of hypoglycin-treated rats... . analysis. ... Ten of them have not been previously associated with hypoglycin administration: these are several hydroxy compounds, including those from the valine and isoleucine pathways, 2-oxo-adipic acid, n-butyrylglycine and isovaleryl glucuronide. These results indicate that the pathways of isoleucine and valine metabolism are inhibited at their respective acyl-CoA dehydrogenation steps, as is the case for fatty acid, leucine and lysine metabolism, as previously shown.

来源:Hazardous Substances Data Bank (HSDB)

代谢

... 14C- 和 3H-标记的软脂酸与低糖素一起给予大鼠，并在尿中的二羧酸中测量放射性。两种同位素都结合到了己二酸和癸二酸中，表明了前体与产物之间的关系。戊二酸基本上未标记。相对于软脂酸的C-1，C-16的优先结合可以被推断出来。因此，似乎脂肪酸的ω-氧化主要发生在链缩短的中期阶段，此时低糖素对β-氧化的抑制作用变得更加明显。

... 14C- and 3H-labelled palmitic acid was administered with hypoglycin to rats, and radioactivity was measured in urinary dicarboxylic acids... . Both isotopes were incorporated into adipic and sebacic acids, indicating a precursor-product relationship. Glutaric acid was, essentially, unlabelled. Preferential incorporation of C-16, relative to C-1 of palmitate ... could be deduced ... . It thus appears that omega-oxidation of the fatty acid intervenes predominantly at an intermediate stage of chain-shortening, when inhibition of beta-oxidation by hypoglycin becomes more pronounced.

来源:Hazardous Substances Data Bank (HSDB)

代谢

低血糖素A，现在简称为低血糖素，通过转氨作用和氧化脱羧作用代谢为亚甲基环丙基乙酸（MCPA）。

Hypoglycin A, which is now simply called hypoglycin, is metabolized by means of transamination and oxidative decarboxylation to methylene cyclopropyl acetic acid (MCPA).[

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

通常，β-羟基异戊酸是一种氨基酸，与赖氨酸在化学上有关系。它竞争性地与赖氨酸分解代谢中使用的酶结合，这就是它及其代谢物甲基环丙基乙酸（MCPA）有毒的原因。代谢物MCPA还是酰基辅酶A脱氢酶的强效抑制剂，阻止脂肪酸的代谢。已经证实，赖氨酸的氧化被β-羟基异戊酸A抑制。相比之下，缬氨酸和异亮氨酸的氧化并未被这种化合物显著抑制。然而，β-羟基异戊酸A抑制的赖氨酸代谢途径中的具体步骤尚未被精确识别。低血糖和糖原的消耗是由于注射β-羟基异戊酸A后，长链脂肪酸代谢受损导致糖异生减少。β-羟基异戊酸A或其代谢物甲基环丙基乙酸，以及4-戊酸（4-PE）被发现抑制长链脂肪酸的氧化；而直链短链脂肪酸的氧化，包括丁酸盐、己酸盐和辛酸盐并未被抑制。β-羟基异戊酸A在体外抑制了肝片对异戊酰辅酶A和α-甲基丁酰辅酶A的脱氢作用，并且在实验动物体内诱导了异戊酸血症和α-甲基丁酸血症。（PMID: 4636318; PMID:5276292）

Generally, hypoglycin is an amino acid and chemically related to lysine. It competitively binds to enzymes used in the catabolism of lysine and is the reason why it and its metabolitemethylene cyclopropyl acetic acid (MCPA) are toxic. The metabolite MCPA also is a potent inhibitor of acyl CoA dehydrogenase, preventing the metabolism of fatty acids. It has been shown that oxidation of leucine is inhibited by hypoglycin A. In contrast, oxidation of valine and isoleucine are not significantly inhibited by this compound. However, the specific step in the pathway of leucine metabolism that is inhibited by hypoglycin A has not been precisely identified. Hypoglycemia and depletion of glycogen were due to the decreased gluconeogenesis resulting from impairment of long chain fatty acid metabolism after injection of hypoglycin A. Hypoglycin A or its metabolite, methylenecyclopropylacetic acid, and also 4-pentenoic acid (4-PE) were shown to inhibit long-chain fatty acid oxidation; whereas oxidation of straight short chain fatty acids including butyrate, hexanoate, and octanoate was not inhibited. Hypolglycin A inhibits dehydrogenation of isovaleryl-CoA and alpha-methylbutyryl-CoA by liver slices in vitro, and that it induces isovaleric and alpha-methylbutyric acidemias in experimental animals in vivo. (PMID: 4636318; PMID:5276292)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 副作用

神经毒素 - 其他中枢神经系统神经毒素

Neurotoxin - Other CNS neurotoxin

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 相互作用

对禁食的大鼠进行标准饮食并注射hypoglycin会导致严重的虚弱、体温下降和大量的二羧酸尿。在含有氯贝丁酯的饮食中饲养的大鼠在注射hypoglycin后看起来正常，但二羧酸尿明显，但程度低于标准饮食大鼠。在大鼠标准饮食中注射hypoglycin、丁酰辅酶A和癸酰辅酶A，而不是棕榈酰辅酶A，去氢酶活性受到强烈抑制（80-95%）。氯贝丁酯饲养减少了这些去氢酶的抑制，降至大约40-60%。因此得出结论，尽管氯贝丁酯可以防止hypoglycin的毒性作用，但由二羧酸尿指示的某些酶抑制只是部分预防。

... Injection of hypoglycin into fasted rats maintained on a standard diet caused severe prostration, hypothermia and a massive dicarboxylic aciduria. Rats maintained on a diet containing clofibrate appeared normal after injection of hypoglycin, but had a marked dicarboxylic aciduria which was less than that induced in rats on a normal diet. After administration of hypoglycin, butyryl-CoA and decanoyl-CoA, but not palmitoyl-CoA, dehydrogenase activities were strongly inhibited (80-95%) in the livers of animals on a standard diet. Clofibrate feeding decreased the inhibition of these dehydrogenases to about 40-60%. It was concluded that although clofibrate protects against the toxic effects of hypoglycin, some enzyme inhibitions as indicated by dicarboxylic aciduria are only partly prevented.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

...氯贝丁酯饲养显然保护了动物免受低血糖素的有毒、降糖和降体温的影响...并完全防止了低血糖素引起的超微结构损害。在低血糖素给药后，肝脏线粒体丁酰辅酶A脱氢酶活性被抑制了超过90%，令人惊讶的是，所研究的过氧化物酶活性在很大程度上得到了保留。当低血糖素给予食用含有氯贝丁酯饮食的大鼠时，单独低血糖素治疗后不完整的癸酰肉碱氧化，在解耦线粒体中仍然不完整，但在耦合线粒体中变得明显完整。在后一种情况下，在氧气摄取脉冲的最后四分之一期间，速率有所减慢。此外，氯贝丁酯饲养的动物中，丁酰辅酶A脱氢酶活性受到低血糖素的影响要小得多。...

...Clofibrate feeding apparently protected the animals against the toxic, hypoglycemic and hypothermic effects of hypoglycin...and completely prevented the ultrastructural damage caused by hypoglycin. After hypoglycin administration, hepatic mitochondrial butyryl-CoA dehydrogenase activity was inhibited by more than 90% and, surprisingly, the activity of the peroxisomal enzymes studied was largely preserved. When hypoglycin was given to rats fed on a clofibrate-containing diet, the oxidation of decanoylcarnitine, which was incomplete after hypoglycin treatment alone, remained incomplete with uncoupled mitochondria, but became apparently complete with coupled mitochondria. In the latter condition, there was a slowing of the rate during the last quarter of the pulse of oxygen uptake. Further, butyryl-CoA dehydrogenase activity was much less affected by hypoglycin in clofibrate-fed animals. ...

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  (2S,4S)-hypoglycin A 生成 (S)-3-甲基戊酸
  参考文献：
  名称：

  艾伦。第十九部分。（±）-高血糖素A的合成和天然异构体的构型

  摘要：

  描述了通过Simmons-Smith甲基化通过烯丙基中间体1-乙基甲酰基氨基戊3,4-二烯-1,1-二羧酸二乙酯合成次糖苷A的方法。用丁酸2，3-二烯丙酸乙酯和烯丙基（甲酰氨基）丙二酸二乙酯进行模型实验，得到亚甲基环丙烷甲酸乙酯，水解和脱羧后，得到2-氨基-3-环丙基丙酸。降糖素A降解为已知（S）-构型的（+）-3-甲基戊酸将其构型确定为（+）-（2 S：4 S）-2-氨基-4,5-甲基己基-5-烯酸。

  DOI：

  10.1039/j39680000288
• 作为产物：
  描述：

  (R)-(+)-Methylenecyclopropylmethanol 在 吡啶 、 盐酸 、 lithium hydroxide 、 正丁基锂 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 94.5h， 生成 (2S,4S)-hypoglycin A
  参考文献：
  名称：

  低血糖素A的各个非对映异构体的不对称全合成

  摘要：

  利用Sharpless环氧化法合成了构成非寻常的含有α-氨基酸次糖苷A的不寻常的亚甲基环丙烷的各个非对映异构体，以允许不对称的亚甲基环丙烷的合成。

  DOI：

  10.1039/c39920001249

文献信息

• Asymmetric total synthesis of the individual diastereoisomers of hypoglycin A.
  作者：Jack E. Baldwin、Robert M. Adlington、David Bebbington、Andrew T. Russell

  DOI：10.1016/s0040-4020(01)89313-3

  日期：1994.1

  The individual diastereoisomers that constitute the unusual methylenecyclopropane containing α-amino acid hypoglycin A have been synthesised utilising the Sharpless epoxidation to permit an asymmetric methylenecyclopropane synthesis.

  利用Sharpless环氧化法合成了构成非寻常的含有α-氨基酸次糖苷A的不寻常的亚甲基环丙烷的各个非对映异构体，以允许不对称的亚甲基环丙烷的合成。