Spacers acid-labile linkers

In order to facilitate the generation of peptide thioesters, several groupst have developed generalized versions of the thioester linker pioneered by Hojo and Aimoto.f A 3-sulfanylpropanoic acid residue is generated on an acid-labile linker such as Boc-Leu-PAM-resin or Boc-Leu-MBHA-resin. It is important to have a one-residue spacer between the MBHA linker and the thiol for optimal acid stability of the amide bond.f All twenty Boc-protected amino acids can be coupled to this thiol on the solid support to generate the thioester.Despite the potential reactivity of the thioester to the amino terminus, the formation of a dioxopiperazine is not generally observed when using in situ neutralization protocols. However, when the sequence was Leu-Tyr-Arg-Ala-Pro, 20% of a dipeptide deletion product, Leu-Tyr-Arg, was observed. It is likely that sequences such as C-terminal Pro-Gly would also be subject to this side reaction.t ... 

Nicolaou [57] has reported the synthesis of a dodecasaccharide employing a p-hydroxybenzoic acid spacer group connected via a photo labile linker [3- (hydroxymethyl) -4-nitrophenol] to the resin (Scheme 20.16). Sugar mono- or oligomers... 

Linker hydrolysis there is presence of acid-labile linkages between the pol5mier and drug in the pol5mier backbone or side-chain. Presence of these acid-sensitive spacers between drug and polymer enables release of drug either in relatively acidic extracellular fluids in a tumor, or after endocytosis in the... 

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