The 1,2,3-triazole ring as a peptido- and olefinomimetic element: Discovery of click vanilloids and cannabinoids
The 1,2,3-triazole ring as a peptido- and olefinomimetic element: Discovery of click vanilloids and cannabinoids
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DOI：
10.1002/anie.200703590
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Di Marzo, Vincenzo
中科院分区：
文献类型：
--
作者：
Appendino, Giovanni;Bacchiega, Sara;Di Marzo, Vincenzo
在过去的几年里，叠氮化物和炔的1，3-偶极环加成反应已经成为一种重要的“缝合”操作，通过容易引入的永久连接来连接结构单元，具有无与伦比的化学和生物稳定性。[1]虽然表面上是代谢惰性的，但原则上，1，2，3-三唑环可以是生物学上可见的，因为它具有H-键供体和受体位点的组合，能够模拟氢键的酸碱性。[2]由于1，2，3-三唑环不易水解裂解或氧化还原修饰，[1]该系统相对于其他类型的肽模拟物存在潜在优势，并且已经报道了证明该问题系统性审查合理的初步证据。因此，结合到酰胺抑制剂安普那韦的HIV蛋白酶和结合到两个1，2，3-三唑类似物的相同蛋白酶的X-射线晶体学分析显示酰胺部分的结合模式与1，4-取代的三唑环的结合模式有极好的重叠。[3]类似地，海洋天然产物α-半乳糖基神经酰胺的类似物aGal-Cer的免疫刺激活性对用三唑单元替换酰胺部分相对不敏感。[4]关于安普那韦和aGal-Cer的三唑类似物的这些观察结果表明，酰胺键和1，2，3-三唑环具有潜在的生物等效性。然而，这些发现的意义是有点削弱了可用的信息的相关性酰胺键的生物活性的两个线索，和/或通过额外的修改进行其结构。此外，结构复杂的分子如安普那韦和aGal-Cer的多个识别结构域可以“稀释”电子等排修饰在与大分子靶标结合方面的作用。最后，还没有关于酰胺-三唑电子等排交换维持活性逆转或目标选择性调节的能力的报道，而三唑取代模式对其拟酰胺性质的影响尚未研究。为了阐明这些观点，我们研究了酰胺-三唑点突变在结构简单的化合物中的作用，这些化合物的肽键对活性至关重要。虽然解决这个问题的候选人并不短缺，但很少有人能在药效团的简单性（通过酰胺键连接到脂肪链的香草基）和靶标的多效性方面与辣椒素相媲美。[5]事实上，酰胺键与辣椒素（1a）的辛辣性的相关性是结构-活性关系领域中最古老的观察结果之一。在现代研究中，只有硫脲基团被确定为等效生物电子等排取代。[6]此外，某些脂肪酸衍生的辣椒素不仅可以与香草素受体（TRPV 1）[7]相互作用，还可以与内源性大麻素系统的蛋白质（主要是CB 2和FAAH）[8]相互作用，这一发现扩大了能够识别这些化合物的关键酰胺接头的已知生物分子的范围。由于酰胺连接基是辣椒素代谢不稳定性的主要位点，[9]用水解稳定基团取代它既可以改变它对识别辣椒素的大分子的活性，又可以显著改善它们的药代动力学特征。（合成辣椒素，1 B）[10]和TRPV 1拮抗剂6о-碘onivamide（1c）[11]与相应的1，4-和1，5-三唑类似物4a，B和5a，B的那些进行了比较。这些化合物…
Over the past few years, the 1, 3-dipolar cycloaddition of azides and alkynes has emerged as an important “stitching” maneuver to connect structural units through a readily introduced permanent link endowed with unparalleled chemical and biological stability.[1] Although apparently metabolically inert, the 1, 2, 3-triazole ring could, in principle, be biologically visible, as it features a combination of H-bond donor and acceptor sites capable of mimicking the hydrogenbonding acidity and basicity of a peptide bond.[2] As the 1, 2, 3-triazole ring is not susceptible to hydrolytic cleavage or redox modification,[1] potential advantages of this system over other types of peptidomimetics exist, and preliminary evidence to justify the systematic scrutiny of this issue has been reported. Thus, X-ray crystallographic analysis of the HIV protease bound to the amide inhibitor amprenavir and of the same protease bound to two 1, 2, 3-triazole analogues showed excellent overlap of the binding mode of the amide moiety with that of the 1, 4-substituted triazole ring.[3] Similarly, the immunostimulating activity of aGal-Cer, an analogue of the marine natural product a-galactosylceramide, was relatively insensitive to the replacement of the amide moiety with a triazole unit.[4] These observations with respect to the triazole analogues of amprenavir and aGal-Cer suggest that the amide bond and the 1, 2, 3-triazole ring are potentially bioequivalent. However, the significance of these findings is somewhat undermined by the paucity of information available on the relevance of the amide bond for the bioactivity of both leads, and/or by the additional modifications carried out on their structure. Furthermore, the multiple recognition domains of structurally complex molecules such as amprenavir and aGal-Cer could “dilute” the effect of the isosteric modification in terms of binding to a macromolecular target. Finally, no information has been reported on the ability of the amide-to-triazole isosteric exchange to sustain reversal of activity or modulation of target selectivity, while the effect of the triazole substitution pattern on its amidomimetic properties has not yet been investigated. To clarify these points, we investigated the effect of amide-to-triazole point mutations in structurally unsophisticated compounds whose peptide bond is critical for activity. Although there is no shortage of candidates to address this issue, few can rival capsaicinoids in terms of the simplicity of the pharmacophore (a vanillyl group linked to an aliphatic chain by an amide bond) and the pleiotropy of the target.[5] Indeed, the relevance of the amide bond for the pungency of capsaicin (1a) is one of the oldest observations in the realm of structure–activity relationships. Only the thiourea group has been identified in modern studies as an equipotent bioisosteric replacement.[6] Furthermore, the discovery that certain fatty-acid-derived capsaicinoids can interact not only with the vanilloid receptor (TRPV1)[7] but also with proteins of the endocannabinoid system (mainly CB2 and FAAH)[8] has expanded the range of known biomolecules capable of recognizing the key amide linker of these compounds. As the amide linker is a major site of metabolic lability of the capsaicinoids,[9] its replacement with hydrolytically stable groups could both alter its activity towards macromolecules that recognize capsaicinoids and dramatically improve their pharmacokinetic profile.Therefore, the vanilloid and cannabinoid profiles of the TRPV1 agonist nonivamide (synthetic capsaicin, 1b)[10] and the TRPV1 antagonist 6о-iodononivamide (1c)[11] were compared with those of the corresponding 1, 4-and 1, 5-triazole analogues 4a, b and 5a, b. These compounds …