dimethyl 2,2′-(((2R,2′R)-3,3′-disulfanediylbis(2-((tertbutoxycarbonyl)amino)propanoyl))bis(azanediyl))(2S,2′S)-bis(3-(tert-butoxy)propanoate) | 1346422-41-0

• 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: dimethyl 2,2′-(((2R,2′R)-3,3′-disulfanediylbis(2-((tertbutoxycarbonyl)amino)propanoyl))bis(azanediyl))(2S,2′S)-bis(3-(tert-butoxy)propanoate)
• 英文别名: Boc-Cys(1)-Ser(tBu)-OMe.Boc-Cys(1)-Ser(tBu)-OMe；methyl (2S)-2-[[(2R)-3-[[(2R)-3-[[(2S)-1-methoxy-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]disulfanyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-3-[(2-methylpropan-2-yl)oxy]propanoate
• CAS: 1346422-41-0
• 化学式: C₃₂H₅₈N₄O₁₂S₂
• 分子量: 754.964
• InChiKey: SLTQJVCOKPDPHL-CMOCDZPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  50
• 可旋转键数：
  25
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  257
• 氢给体数：
  4
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  dimethyl 2,2′-(((2R,2′R)-3,3′-disulfanediylbis(2-((tertbutoxycarbonyl)amino)propanoyl))bis(azanediyl))(2S,2′S)-bis(3-(tert-butoxy)propanoate) 在 4-二甲氨基吡啶 、 三丁基膦 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.17h， 生成 2-(((R)-2-amino-3-(((S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)amino)-3-oxopropyl)-thio)ethyl palmitate
  参考文献：
  名称：

  Structure–Activity Relationships in Human Toll-like Receptor 2-Specific Monoacyl Lipopeptides

  摘要：

  Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. We had previously determined that at least one acyl group of optimal length (C-16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. We now show that these structurally simpler analogues display agonistic activities with human, but not murine, TLR2. SAR studies on the monoacyl derivatives show that the optimal acyl chain length is C-16, and aryl substituents are not tolerated. A variety of alkyl and acyl substituents on the cysteine amine were examined. All N-alkyl derivatives were inactive. In contradistinction, short-chain N-acyl analogues were found to be highly active, with a clear dependence on the chain length. A cysteine N-acetyl analogue was found to be the most potent (EC50: 1 nM), followed by the N-butyryl analogue. The N-acetyl analogue is human TLR2-specific, with its potency comparable to that of PAM(2)CS.

  DOI：

  10.1021/jm3000533
• 作为产物：
  描述：

  L-胱氨酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 dimethyl 2,2′-(((2R,2′R)-3,3′-disulfanediylbis(2-((tertbutoxycarbonyl)amino)propanoyl))bis(azanediyl))(2S,2′S)-bis(3-(tert-butoxy)propanoate)
  参考文献：
  名称：

  Design and Development of Stable, Water-Soluble, Human Toll-like Receptor 2 Specific Monoacyl Lipopeptides as Candidate Vaccine Adjuvants

  摘要：

  Antigens in modern subunit vaccines are largely soluble and poorly immunogenic proteins inducing relatively short-lived immune responses. Appropriate adjuvants initiate early innate immune responses, amplifying subsequent adaptive immune responses. Agonists of Toll-like receptor 2 (TLR2) are devoid of significant proinflammatory activity in ex vivo human blood models and yet are potently adjuvantic, suggesting that this chemotype may be a safe and effective adjuvant. Our earlier work on the monoacyl lipopeptide class of TLR2 agonists led to the design of a highly potent lead but with negligible aqueous solubility, necessitating the reintroduction of aqueous solubility. We explored several strategies of introducing ionizable groups on the lipopeptide, as well as the systematic evaluation of chemically stable bioisosteres of the ester-linked palmitoyl group. These studies have led to a fully optimized, chemically stable, and highly water-soluble human TLR2-specific agonist, which was found to have an excellent safety profile and displayed prominent adjuvantic activities in rabbit models.

  DOI：

  10.1021/jm400620g

文献信息

• 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,
• Synthesis, evaluation and molecular dynamics study of human toll-like receptor 2/6 specific monoacyl lipopeptides as candidate immunostimulants
  作者：Yueyue Zhu、Bo Liu、Zonglong Chen、Xianyang Wang、Yujie Wang、Wenhong Zhang、Sen Wang、Mingming Zhang、Yingxia Li

  DOI：10.1016/j.bioorg.2023.106823

  日期：2023.12
• Design and Development of Stable, Water-Soluble, Human Toll-like Receptor 2 Specific Monoacyl Lipopeptides as Candidate Vaccine Adjuvants
  作者：Deepak B. Salunke、Seth W. Connelly、Nikunj M. Shukla、Alec R. Hermanson、Lauren M. Fox、Sunil A. David

  DOI：10.1021/jm400620g

  日期：2013.7.25

  Antigens in modern subunit vaccines are largely soluble and poorly immunogenic proteins inducing relatively short-lived immune responses. Appropriate adjuvants initiate early innate immune responses, amplifying subsequent adaptive immune responses. Agonists of Toll-like receptor 2 (TLR2) are devoid of significant proinflammatory activity in ex vivo human blood models and yet are potently adjuvantic, suggesting that this chemotype may be a safe and effective adjuvant. Our earlier work on the monoacyl lipopeptide class of TLR2 agonists led to the design of a highly potent lead but with negligible aqueous solubility, necessitating the reintroduction of aqueous solubility. We explored several strategies of introducing ionizable groups on the lipopeptide, as well as the systematic evaluation of chemically stable bioisosteres of the ester-linked palmitoyl group. These studies have led to a fully optimized, chemically stable, and highly water-soluble human TLR2-specific agonist, which was found to have an excellent safety profile and displayed prominent adjuvantic activities in rabbit models.
• Structure–Activity Relationships in Human Toll-like Receptor 2-Specific Monoacyl Lipopeptides
  作者：Deepak B. Salunke、Nikunj M. Shukla、Euna Yoo、Breanna M. Crall、Rajalakshmi Balakrishna、Subbalakshmi S. Malladi、Sunil A. David

  DOI：10.1021/jm3000533

  日期：2012.4.12

  Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. We had previously determined that at least one acyl group of optimal length (C-16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. We now show that these structurally simpler analogues display agonistic activities with human, but not murine, TLR2. SAR studies on the monoacyl derivatives show that the optimal acyl chain length is C-16, and aryl substituents are not tolerated. A variety of alkyl and acyl substituents on the cysteine amine were examined. All N-alkyl derivatives were inactive. In contradistinction, short-chain N-acyl analogues were found to be highly active, with a clear dependence on the chain length. A cysteine N-acetyl analogue was found to be the most potent (EC50: 1 nM), followed by the N-butyryl analogue. The N-acetyl analogue is human TLR2-specific, with its potency comparable to that of PAM(2)CS.