02197nas a2200205   4500008004100000022001400041245011300055210006900168260000800237490000700245520142100252653001301673653002901686653002501715653003501740653003401775100002901809700002601838856012701864       2025                        eng d  a1433-785100aKetenimine multicomponent strategy for multifaceted amidine functionalization of peptides on the solid phase0 aKetenimine multicomponent strategy for multifaceted amidine func  cSEP0 v643 a<p>
	The amidine group and its derivatives serve as proteolytically stable bioisosteres of the peptide bond, and their selective incorporation into peptides attributes significant chemical and biological features. This study introduces an efficient synthesis of amidine-containing peptides by a copper-catalyzed, solid-phase-compatible multicomponent reaction (MCR), leveraging ketenimine intermediates that are generated in situ. Through the reaction of sulfonyl azides with terminal alkynes and a wide variety of amines, we establish the robust on-resin synthesis of delta/epsilon-amidine amino acids, arginine isologues, fluorescently labeled peptides, drug-peptide hybrids, and PEGylated derivatives. This strategy notably supports a wide range of peptide modifications, including side chain alteration, amine functionalization, and peptide macrocyclization through both backbone and side chain groups, as well as incorporating aromatic scaffolds into the peptide backbone. The methodology demonstrates broad substrate tolerance, compatibility with peptide chemistry protocols, and access to complex motifs, including pharmacophores and imaging tags, all within a single reaction platform. Our results underscore the synthetic versatility and functional applicability of ketenimine-based MCRs for advanced peptide modification, expanding the chemical space of peptide medicinal chemistry and therapeutics.</p>
10aAmidines10amulticomponent reactions10apeptide modification10aPeptide-small molecule hybrids10aSolid phase peptide synthesis1 aBodake, Supriya, Mahadev1 aMarelli, Udaya, Kiran  uhttp://library.ncl.res.in/content/ketenimine-multicomponent-strategy-multifaceted-amidine-functionalization-peptides-solid