Trimethyl-(2-methyl-5-methylsulfanyl-5-oxopent-3-yn-2-yl)azanium;iodide

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: Trimethyl-(2-methyl-5-methylsulfanyl-5-oxopent-3-yn-2-yl)azanium;iodide
• 化学式: C₁₀H₁₈NOS*I
• 分子量: 327.23
• InChiKey: KUVKVRWKDQSNKM-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -1.63
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  42.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  (1,1-dimethylprop-2-ynyl)dimethylamine 在 正丁基锂 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 99.5h， 生成 Trimethyl-(2-methyl-5-methylsulfanyl-5-oxopent-3-yn-2-yl)azanium;iodide
  参考文献：
  名称：

  Novel competitive irreversible inhibitors of aldehyde dehydrogenase (ALDH1): restoration of chemosensitivity of L1210 cells overexpressing ALDH1 and induction of apoptosis in BAF3 cells overexpressing bcl2

  摘要：

  4-Amino-4-methyl-pent-2-ynthioc acid S-methyl ester (ampal thiolester: ATE) was used as a lead compound to synthesise new aminosubstituted derivatives of alpha,beta acetylenic thiolester compounds as inhibitors of aldehyde dehydrogenase 1, (ALDH1). Of these compounds, the dimethyl derivative (DIMATE) was a competitive irreversible inhibitor (K-i similar to 280 muM) of baker's yeast ALDH1 in vitro showing 80% inhibition at 400 muM when preincubated with the enzyme for 30 min, whereas the trimethyl ammonium and the morpholine derivatives showed only 15% inhibition at 600 muM even after 60 min preincubation. ATE inhibited ALDH1 activity in ALDH1-transfected L1210 T cells resistant to hydroperoxycyclophosphamide (HCPA) and inhibited growth synergistically in the presence of HCPA. In non-transfected L1210 counterparts ATE did not potentiate growth inhibition by HCPA. DIMATE was a 30-100-fold more effective growth inhibitor than ATE. Endogenous ALDH1 activities of BAF(3) cells over-expressing different levels of bcl(2) (0-100%) were similar (16-20 mU/mg protein) and were all inhibited by DIMATE, reaching 20-30% at 4 muM. Up to 4 muM no apoptosis, as measured by DNA-fragmentation was observed, but at 8 and 10 muM DIMATE, DNA-fragmentation increased concomitantly with ALDH1 inhibition. No DNA-fragmentation was observed with ALDH1 irreversible inhibitors devoid of a thiolester group or with thiolesters which were not inhibitors of ALDH1. It was seen only with competitive irreversible inhibitors having the methanethiol and enzyme-inhibitory moieties. The methanethiol putatively released from DIMATE by ALDH1 esterase activity plays a role, albeit undefined, in lowering intramitochondrial glutathione levels which decreased by 47% as DNA-fragmentation increased. (C) 2002 Elsevier Science Inc. All rights reserved.

  DOI：

  10.1016/s0006-2952(02)01294-7

文献信息

• Aldehyde dehydrogenase inhibitors: α,β-Acetylenic N-substituted aminothiolesters are reversible growth inhibitors of normal epithelial but irreversible apoptogens for cancer epithelial cells from human prostate in culture
  作者：Gerard Quash、Guy Fournet、Charlotte Courvoisier、Rosa M. Martinez、Jacqueline Chantepie、Marie Julie Paret、Julie Pharaboz、Marie Odile Joly-Pharaboz、Jacques Goré、Jean André

  DOI：10.1016/j.ejmech.2007.06.004

  日期：2008.5

  The pharmacomodulation of the N atom of alpha,beta-acetylenic aminothiolesters or the replacement of the thiolester moiety by more electroplfflic groups did not permit any clear rationale to be established for improving the selective growth-inhibitory activity of this family of compounds over that of the previously synthesized alpha,beta-acetylenic aminothiolesters DIMATE and MATE [G. Quash, G. Fournet, J. Chantepie, J. Gore, C. Ardiet, D. Ardail, Y. Michal, U. Reichert, Biochem Phannacol 64 (2002) 1279-92]. Hence DIMATE and MATE were investigated more thoroughly for selectivity and growth-inhibitory activity using human prostate epithelial normal cells (HPENC) on the one hand and human prostate epithelial cancer cells (DU145) on the other. Unequivocal evidence was obtained showing that both compounds were reversible growth inhibitors of HPENC but irreversible growth inhibitors of DU145. Growth-inhibition of DU145 was due to the induction of early apoptosis as revealed by the flow cytometric analytical profile of inhibitor-treated cells, of the decrease in the redox potential and increase in superoxide anion content of their mitochondria. Of the two intracellular enzymes: aldehyde dehydrogenases 1 and 3 (ALDH1 and ALDH3) targeted by DIMATE and MATE, ALDH3 was inhibited to the same extent by both compounds whereas ALDH1 was less susceptible to inhibition by MATE. As the induction of ALDH3 by xenobiotics is hormone-dependent, MATE, the more selective of the two inhibitors, is a useful tool not only for examining the role of the ALDH3 isoform in hormone-sensitive and resistant prostate cancer cells in culture but also for investigating if it can inhibit the growth of xenografts of prostate cancer in immunodeficient mice. (C) 2007 Elsevier Masson SAS. All rights reserved.
• Novel competitive irreversible inhibitors of aldehyde dehydrogenase (ALDH1): restoration of chemosensitivity of L1210 cells overexpressing ALDH1 and induction of apoptosis in BAF3 cells overexpressing bcl2
  作者：Gerard Quash、Guy Fournet、Jacqueline Chantepie、Jacques Gore、Claude Ardiet、Dominique Ardail、Yvonne Michal、Uwe Reichert

  DOI：10.1016/s0006-2952(02)01294-7

  日期：2002.10

  4-Amino-4-methyl-pent-2-ynthioc acid S-methyl ester (ampal thiolester: ATE) was used as a lead compound to synthesise new aminosubstituted derivatives of alpha,beta acetylenic thiolester compounds as inhibitors of aldehyde dehydrogenase 1, (ALDH1). Of these compounds, the dimethyl derivative (DIMATE) was a competitive irreversible inhibitor (K-i similar to 280 muM) of baker's yeast ALDH1 in vitro showing 80% inhibition at 400 muM when preincubated with the enzyme for 30 min, whereas the trimethyl ammonium and the morpholine derivatives showed only 15% inhibition at 600 muM even after 60 min preincubation. ATE inhibited ALDH1 activity in ALDH1-transfected L1210 T cells resistant to hydroperoxycyclophosphamide (HCPA) and inhibited growth synergistically in the presence of HCPA. In non-transfected L1210 counterparts ATE did not potentiate growth inhibition by HCPA. DIMATE was a 30-100-fold more effective growth inhibitor than ATE. Endogenous ALDH1 activities of BAF(3) cells over-expressing different levels of bcl(2) (0-100%) were similar (16-20 mU/mg protein) and were all inhibited by DIMATE, reaching 20-30% at 4 muM. Up to 4 muM no apoptosis, as measured by DNA-fragmentation was observed, but at 8 and 10 muM DIMATE, DNA-fragmentation increased concomitantly with ALDH1 inhibition. No DNA-fragmentation was observed with ALDH1 irreversible inhibitors devoid of a thiolester group or with thiolesters which were not inhibitors of ALDH1. It was seen only with competitive irreversible inhibitors having the methanethiol and enzyme-inhibitory moieties. The methanethiol putatively released from DIMATE by ALDH1 esterase activity plays a role, albeit undefined, in lowering intramitochondrial glutathione levels which decreased by 47% as DNA-fragmentation increased. (C) 2002 Elsevier Science Inc. All rights reserved.