Fernández-Llamazares Ana I, Spengler Jan, Albericio Fernando
Institute for Research in Biomedicine, Deparment of Chemistry and Molecular Pharmacology, Barcelona Science Park, Baldiri Reixac 10, Barcelona, 08028, Spain.
CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, Barcelona, 08028, Spain.
Biopolymers. 2015 Sep;104(5):435-52. doi: 10.1002/bip.22696.
Backbone N-substitution of peptides (N-Me and N-alkyl) has become of special interest as a chemical tool for peptide lead modification, either to improve biological activity or to optimize key pharmacokinetic characteristics. For the synthesis of backbone N-methylated peptides, many protocols have been developed already, yet some effort often has to be made to find appropriate conditions for the acylation of N-Me residues. Fewer examples are reported of peptides with other backbone N-substituents different than N-Me, and their synthesis is frequently reported as difficult. The synthesis of such peptides becomes more difficult as the size of the N-substituent increases. Coupling methods that work for the synthesis of N-methylated peptides were often found to fail when applied to peptides with larger N-substituents. This review addresses the challenges of the synthesis of backbone N-modified peptides, focusing on N-substituents larger than the N-Me group.
肽的主链N-取代（N-甲基和N-烷基）作为肽类先导物修饰的化学工具已引起特别关注，其目的要么是提高生物活性，要么是优化关键的药代动力学特性。对于主链N-甲基化肽的合成，已经开发了许多方法，但通常仍需努力寻找适合N-甲基残基酰化的条件。关于具有不同于N-甲基的其他主链N-取代基的肽的报道较少，并且它们的合成经常被报道为困难。随着N-取代基尺寸的增加，此类肽的合成变得更加困难。用于合成N-甲基化肽的偶联方法在应用于具有较大N-取代基的肽时常常失败。本综述探讨了主链N-修饰肽合成的挑战，重点关注大于N-甲基基团的N-取代基。
