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首页> 外文期刊>Chemistry: A European journal >Rapid Total Synthesis of Cyclic Lipodepsipeptides as a Premise to Investigate their Self-Assembly and Biological Activity
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Rapid Total Synthesis of Cyclic Lipodepsipeptides as a Premise to Investigate their Self-Assembly and Biological Activity

机译：快速总合成环脂肽多肽作为研究其自组装和生物活性的前提。

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摘要

A rapid and efficient total synthesis is reported for the cyclic lipodepsipeptide pseudodesmin A. This member of the Pseudomonas viscosin group is active against Grampositive bacteria and features self-assembling properties. A conserved serine residue within the lactone macrocycle is exploited for initial immobilization on 2-chlorotrityl chloride resin through ether formation with the side-chain alcohol. Subsequent elongation proceeds through Fmoc solid-phase peptide synthesis, including automated incorporation of the enantioselectively synthesized (R)-3-hydroxydecanoic acid lipid tail. Following esterification to generate the incipient lactone bond, the macrocycle is formed by on-resin head-totail macrolactamization and cleaved from the resin to give the desired compound in good purity. The short and efficient synthesis route allows rapid generation of analogues by facile variation of both the peptide and lipid moieties with good control of epimerization while maximizing automation. Synthesis of the pseudodesmin A enantiomer yields identical self-assembly and biological activity to that observed for the natural compound, showing that activity is not mediated by chiral interactions. A d-Asn8 analogue developed en route retains self-assembly, but loses activity. The synthesis strategy should be generally applicable for the rapid generation of analogues from various cyclic lipodepsipeptide groups, allowing an investigation of their self-assembling properties and structure-activity relationships.
机译：据报道，快速高效的环状脂二肽假拟蛋白A的总合成。假单胞菌粘蛋白素组的这一成员对革兰氏阳性细菌具有活性，并具有自组装特性。内酯大环中保守的丝氨酸残基被用于通过与侧链醇形成醚而初步固定在2-氯三苯甲基氯树脂上。随后的延伸通过Fmoc固相肽合成进行，包括对映选择性合成的（R）-3-羟基癸酸脂尾的自动引入。酯化生成初始内酯键后，通过树脂头尾大内酰胺化形成大环，并从树脂上裂解，得到纯度高的所需化合物。短而有效的合成途径可通过肽和脂质部分的易变而快速产生类似物，同时很好地控制差向异构化，同时最大限度地提高自动化程度。假结蛋白A对映异构体的合成产生与天然化合物相同的自组装和生物活性，表明该活性不是由手性相互作用介导的。在途中开发的d-Asn8类似物保留了自组装性，但失去了活性。合成策略通常应适用于从各种环状脂肽基团快速生成类似物，从而可以研究其自组装性质和构效关系。

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