tert-butyl N-(N-(tert-butoxycarbonyl)-S-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-L-cysteinyl)-O-(tert-butyl)-L-serinate | 1234451-22-9

• 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: tert-butyl N-(N-(tert-butoxycarbonyl)-S-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-L-cysteinyl)-O-(tert-butyl)-L-serinate
• 英文别名: (S)-tert-butyl 3-tert-butoxy-2-((R)-(tert-butoxycarbonylamino)-3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methylthio)propanamido)propanoate；(S)-tert-butyl 3-(tert-butoxy)-2-((R)-2-(tert-butoxycarbonyl)amino-3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methylthio)propanamido)propanoate；tert-butyl (2S)-2-[[(2R)-3-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methylsulfanyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-3-[(2-methylpropan-2-yl)oxy]propanoate
• CAS: 1234451-22-9
• 化学式: C₂₅H₄₆N₂O₈S
• 分子量: 534.715
• InChiKey: BPNVJAXMCGWVMF-SQNIBIBYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  36
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  147
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tert-butyl N-(N-(tert-butoxycarbonyl)-S-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-L-cysteinyl)-O-(tert-butyl)-L-serinate 在 4-二甲氨基吡啶 、 溶剂黄146 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 18.5h， 生成 (R)-3-(((R)-2-((tert-butoxycarbonyl)amino)-(((S)-1,3-di-tert-butoxy-1-oxopropan-2-yl)amino)-3-oxopropyl)thio)-2-hydroxypropyl palmitate
  参考文献：
  名称：

  Structure–Activity Relationships in Toll-Like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides

  摘要：

  Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cystein-yl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C-16) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood,

  DOI：

  10.1021/jm201071e
• 作为产物：
  描述：

  N,N'-双(叔丁氧羰基)-L-胱氨酸 在 三丁基膦 、 potassium carbonate 、 1-羟基苯并三唑 、 三乙胺 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.0h， 生成 tert-butyl N-(N-(tert-butoxycarbonyl)-S-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-L-cysteinyl)-O-(tert-butyl)-L-serinate
  参考文献：
  名称：

  一种有效且可扩展的强效 TLR2 激动剂 PAM2CSK4 合成†

  摘要：

  二酰化 PAM 2 CSK 4是一种非常昂贵的脂肽，具有理想的水溶性和广谱的细胞因子/趋化因子诱导作用，是一种最有效的双重（人和鼠）Toll-Like Receptor-2 (TLR2) 激动剂。除了这些令人兴奋的特性外，它的合成过程在文献中也没有报道。本报告描述了一种高效且可扩展的 20 步 PAM 2 CSK 4合成方法，收率良好（所有步骤 > 60%），并清楚地描述了每个步骤中采用的障碍和简单的解决方案。总体而言，采用了收敛合成方法，包括合成适当保护的起始材料、合成关键骨架骨架 PAM 2CS，四赖氨酸片段的合成和最终偶联产生PAM 2 CSK 4。在许多步骤中大规模避免了繁琐的柱层析。

  DOI：

  10.1039/c8ra01387j

文献信息

• Structure−Activity Relationships in Toll-like Receptor-2 Agonistic Diacylthioglycerol Lipopeptides
  作者：Wenyan Wu、Rongti Li、Subbalakshmi S. Malladi、Hemamali J. Warshakoon、Matthew R. Kimbrell、Michael W. Amolins、Rehman Ukani、Apurba Datta、Sunil A. David

  DOI：10.1021/jm901839g

  日期：2010.4.22

  The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2) and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure activity relationships in such lipopeptides have largely been obtained using murine cells, and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-Diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity.
• An efficient and scalable synthesis of potent TLR2 agonistic PAM₂CSK₄
  作者：Arshpreet Kaur、Poonam Poonam、Madhuri T. Patil、Surinder K. Mehta、Deepak B. Salunke

  DOI：10.1039/c8ra01387j

  日期：——

  present report describes an efficient and scalable 20 step synthesis of PAM2CSK4 in good yield (all steps > 60%) along with a clear description of the hindrances and easy solutions adopted in each step. Overall, a convergent synthetic approach was adopted involving synthesis of appropriately protected starting materials, synthesis of a key backbone skeleton PAM2CS, synthesis of a tetralysine fragment

  二酰化 PAM 2 CSK 4是一种非常昂贵的脂肽，具有理想的水溶性和广谱的细胞因子/趋化因子诱导作用，是一种最有效的双重（人和鼠）Toll-Like Receptor-2 (TLR2) 激动剂。除了这些令人兴奋的特性外，它的合成过程在文献中也没有报道。本报告描述了一种高效且可扩展的 20 步 PAM 2 CSK 4合成方法，收率良好（所有步骤 > 60%），并清楚地描述了每个步骤中采用的障碍和简单的解决方案。总体而言，采用了收敛合成方法，包括合成适当保护的起始材料、合成关键骨架骨架 PAM 2CS，四赖氨酸片段的合成和最终偶联产生PAM 2 CSK 4。在许多步骤中大规模避免了繁琐的柱层析。
• Structure–Activity Relationships in Toll-Like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides
  作者：Geetanjali Agnihotri、Breanna M. Crall、Tyler C. Lewis、Timothy P. Day、Rajalakshmi Balakrishna、Hemamali J. Warshakoon、Subbalakshmi S. Malladi、Sunil A. David

  DOI：10.1021/jm201071e

  日期：2011.12.8

  Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cystein-yl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C-16) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood,