Review D. Macmillan et al. Scheme 9. Head to tail cyclization of sequence H–CRKFFARIRGGRGC–OH via N!S acyl transfer followed by NCL.[32b] Figure 3. Serum sensitivity assays of linear (light grey) and the S- carboxamidomethyl (dark grey) derivative of ent-10 against P. aeru- ginosa strain PAO1 and S. aureus strain ATCC 25923. The results of this study confirmed that several pep- tides, equipped simply with an N-terminal Cys and an ap- propriate C-terminal Xaa–Cys motif, are able to undergo head-to-tail cyclization, and that this process is likely ap- plicable to many cyclic peptides of biological or medicinal interest. 4. 4.1. Synthesis of Post-Translationally Modified Peptide Thioesters via N!S Acyl Transfer Relying on heating peptide samples to 60 8C at mildly acidic pH could certainly raise concern that this method could not be applied to peptides decorated with non-pep- tide appendages such as carbohydrates. For example, the acetal linkages present in glycopeptides, linking the car- bohydrate to the peptide backbone in O-linked glycosyla- tion, or those present in interglycosidic linkages, are well known to be susceptible to acid hydrolysis. In a typical example, benzylidene acetal protected sugars can be cleaved in heated 80 % v/v acetic acid. However, in the case of non-benzylic acetals, catalytic quantities of miner- al acids are usually employed to cleave glycosides or ace- tonides efficiently. Considering that proteins that have undergone post-translational modification (PTM) are of increasing interest for their regulatory and targeting roles in biological systems, it is important that they can be ac- cessed using N!S acyl transfer. Most PTM occurs on specific amino acid residue side- chains, and two of the most predominant forms of PTM 894 www.ijc.wiley-vch.de 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Isr. J. Chem. 2011, 51, 885 – 899