N-[3-methyl-1-[[3-oxo-3[(phenylmethyl)amino]propyl]diphenylsilyl]butyl]benzamide | 202743-40-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-[3-methyl-1-[[3-oxo-3[(phenylmethyl)amino]propyl]diphenylsilyl]butyl]benzamide
• 英文别名: n-[1-[Diphenyl[3-oxo-3-[(phenylmethyl)amino]propyl]silyl]-3-methyl-1-butyl]benzamide；N-[1-[[3-(benzylamino)-3-oxopropyl]-diphenylsilyl]-3-methylbutyl]benzamide
• CAS: 202743-40-6
• 化学式: C₃₄H₃₈N₂O₂Si
• 分子量: 534.773
• InChiKey: LGSGTEDLGNUQAP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.34
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  58.2
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N-[3-methyl-1-[[3-oxo-3[(phenylmethyl)amino]propyl]diphenylsilyl]butyl]benzamide 在 三氟甲磺酸 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.67h， 生成 2-[1-(benzoylamino)-3-methylbutyl]-1,1,1,5,5,5-hexamethyl-2-[[3-oxo-3-[(phenylmethyl)amino]propyl]silyl]trisiloxane
  参考文献：
  名称：

  Silicon-Based Metalloprotease Inhibitors:  Synthesis and Evaluation of Silanol and Silanediol Peptide Analogues as Inhibitors of Angiotensin-Converting Enzyme¹

  摘要：

  Silanols are best known as unstable precursors of siloxane (silicone) polymers, substances generally considered stable and inert, but have the potential to mimic a hydrated carbonyl and inhibit protease enzymes. While previous testing of simple silanediol and silanetriol species as inhibitors of hydrolase enzymes found them ineffective, this study reports polypeptide mimics with a central methylsilanol [SiMeOH] or silanediol [Si(OH)(2)] group and their assessment as effective transition state analogue inhibitors of the well-studied metalloprotease angiotensin-converting enzyme (ACE). Central to the synthesis strategy, phenylsilanes were employed as acid-hydrolyzable precursors of the silanol group. The N-benzoyl Leu[SiMeOH]-Gly benzyl amides proved to be stable and readily characterized. In contrast, the Leu-[Si(OH)(2)]Gly structure was difficult to characterize, possibly because of self-association. Capping the silanediol with chlorotrimethylsilane gave a well-defined trisiloxane, demonstrating that the silanediol was monomeric. The Leu-[Si]-Gly structures were converted to Leu-[Si]-Ala analogues by enolate alkylation. Coupling of the silanol precursors with proline tert-butyl ester gave N-benzoyl Leu-[Si]-Gly-Pro and N-benzoyl Leu[Si]-Ala-Pro tripeptide analogues. Treatment of these with triflic acid formed the corresponding methylsilanols and silanediols, all of which were monomeric. The silanediol tripeptide mimics inhibited ACE with IC50 values as low as 14 nM. Methylsilanols, in contrast, were poor inhibitors, with IC50 values above 3000 nM. These data, including comparisons with inhibition data from carbon analogues, are consistent with binding of the silanediols by chelation of the ACE active site zinc, whereas the methylsilanols ligate poorly.

  DOI：

  10.1021/ja026158w
• 作为产物：
  描述：

  苄胺 、 3-[[1-(benzoylamino)-1-(3-methylbutyl)]diphenylsilyl] propanoic acid 在 N-甲基吗啉 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以96 mg的产率得到N-[3-methyl-1-[[3-oxo-3[(phenylmethyl)amino]propyl]diphenylsilyl]butyl]benzamide
  参考文献：
  名称：

  Silicon-Based Metalloprotease Inhibitors:  Synthesis and Evaluation of Silanol and Silanediol Peptide Analogues as Inhibitors of Angiotensin-Converting Enzyme¹

  摘要：

  Silanols are best known as unstable precursors of siloxane (silicone) polymers, substances generally considered stable and inert, but have the potential to mimic a hydrated carbonyl and inhibit protease enzymes. While previous testing of simple silanediol and silanetriol species as inhibitors of hydrolase enzymes found them ineffective, this study reports polypeptide mimics with a central methylsilanol [SiMeOH] or silanediol [Si(OH)(2)] group and their assessment as effective transition state analogue inhibitors of the well-studied metalloprotease angiotensin-converting enzyme (ACE). Central to the synthesis strategy, phenylsilanes were employed as acid-hydrolyzable precursors of the silanol group. The N-benzoyl Leu[SiMeOH]-Gly benzyl amides proved to be stable and readily characterized. In contrast, the Leu-[Si(OH)(2)]Gly structure was difficult to characterize, possibly because of self-association. Capping the silanediol with chlorotrimethylsilane gave a well-defined trisiloxane, demonstrating that the silanediol was monomeric. The Leu-[Si]-Gly structures were converted to Leu-[Si]-Ala analogues by enolate alkylation. Coupling of the silanol precursors with proline tert-butyl ester gave N-benzoyl Leu-[Si]-Gly-Pro and N-benzoyl Leu[Si]-Ala-Pro tripeptide analogues. Treatment of these with triflic acid formed the corresponding methylsilanols and silanediols, all of which were monomeric. The silanediol tripeptide mimics inhibited ACE with IC50 values as low as 14 nM. Methylsilanols, in contrast, were poor inhibitors, with IC50 values above 3000 nM. These data, including comparisons with inhibition data from carbon analogues, are consistent with binding of the silanediols by chelation of the ACE active site zinc, whereas the methylsilanols ligate poorly.

  DOI：

  10.1021/ja026158w

文献信息

• Silanol enzyme inhibitors
  申请人：Sieburth McN. Scott

  公开号：US20050171059A1

  公开（公告）日：2005-08-04

  Compounds of formula (I, II, or III), wherein X is OH; Y is OH, H, lower alkyl of one to six carbons or heteroatoms or F; Z and Z′ are independently H, lower alkyl or Q 3 Si where Q is lower alkyl or aryl; n is 3-50; n′ is 2-50; A and B are independently a) alkyl of one to ten carbons or heteroatoms, b) aryl of four to ten carbons or heteroatoms, c) cyclic of three to ten carbons or heteroatoms, or moieties of the formulas (d, e, or f); R 1 -R 11 groups are each independently hydrogen, alkyl of one to ten carbons or heteroatoms, aryl of 4 to 14 carbons or heteroatoms, arylalkyl of five to twenty carbons or heteroatoms; unsubstituted carbonyl or substituted carbonyl. Heteroatoms are nitrogen, oxygen, silicon or sulfur. At least one of A or B, or both A and B are d), e), or f). The compounds of formula (I) inhibit protease enzymes and can be used as pharmaceuticals.

  式(I, II或III)的复合物，其中X为OH; Y为OH，H，1-6个碳原子或杂原子的低烷基或F; Z和Z'独立地为H，低烷基或Q3Si，其中Q为低烷基或芳基; n为3-50; n'为2-50; A和B独立地为a) 1-10个碳原子或杂原子的烷基，b) 4-10个碳原子或杂原子的芳基，c) 3-10个碳原子或杂原子的环状结构，或公式(d，e或f)的基团; R1-R11基团各自独立地为氢，1-10个碳原子或杂原子的烷基，4-14个碳原子或杂原子的芳基，5-20个碳原子或杂原子的芳基烷基; 未取代的羰基或取代的羰基。杂原子为氮、氧、硅或硫。 A或B中至少有一个，或A和B都是d，e或f。式(I)的化合物抑制蛋白酶酶，可用作药物。
• Silicon-Based Metalloprotease Inhibitors:  Synthesis and Evaluation of Silanol and Silanediol Peptide Analogues as Inhibitors of Angiotensin-Converting Enzyme¹
  作者：Mwangi wa Mutahi、Thomas Nittoli、Luxuan Guo、Scott McN. Sieburth

  DOI：10.1021/ja026158w

  日期：2002.6.1

  Silanols are best known as unstable precursors of siloxane (silicone) polymers, substances generally considered stable and inert, but have the potential to mimic a hydrated carbonyl and inhibit protease enzymes. While previous testing of simple silanediol and silanetriol species as inhibitors of hydrolase enzymes found them ineffective, this study reports polypeptide mimics with a central methylsilanol [SiMeOH] or silanediol [Si(OH)(2)] group and their assessment as effective transition state analogue inhibitors of the well-studied metalloprotease angiotensin-converting enzyme (ACE). Central to the synthesis strategy, phenylsilanes were employed as acid-hydrolyzable precursors of the silanol group. The N-benzoyl Leu[SiMeOH]-Gly benzyl amides proved to be stable and readily characterized. In contrast, the Leu-[Si(OH)(2)]Gly structure was difficult to characterize, possibly because of self-association. Capping the silanediol with chlorotrimethylsilane gave a well-defined trisiloxane, demonstrating that the silanediol was monomeric. The Leu-[Si]-Gly structures were converted to Leu-[Si]-Ala analogues by enolate alkylation. Coupling of the silanol precursors with proline tert-butyl ester gave N-benzoyl Leu-[Si]-Gly-Pro and N-benzoyl Leu[Si]-Ala-Pro tripeptide analogues. Treatment of these with triflic acid formed the corresponding methylsilanols and silanediols, all of which were monomeric. The silanediol tripeptide mimics inhibited ACE with IC50 values as low as 14 nM. Methylsilanols, in contrast, were poor inhibitors, with IC50 values above 3000 nM. These data, including comparisons with inhibition data from carbon analogues, are consistent with binding of the silanediols by chelation of the ACE active site zinc, whereas the methylsilanols ligate poorly.