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ORGANIC LETTERS

Synthesis of Monolysyl Advanced Glycation Endproducts and Their Incorporation into Collagen Model Peptides
Tom M. Woods,† Meder Kamalov,† Paul W. R. Harris,† Garth J. S. Cooper,‡ and Margaret Brimble*,†
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand, and Centre for Advanced Discovery and Experimental Therapeutics (CADET),Central Manchester University Hospitals NHS Foundation Trust, and School of Biomedicine, The University of Manchester and Manchester Academic Health Sciences Centre, Manchester, U.K. m.brimble@auckland.ac.nz
Received October 4, 2012

2012 Vol. 14, No. 22 5740–5743

ABSTRACT

The synthesis of advanced glycation endproducts (AGEs), CML, CEL, and pyrraline and their incorporation into collagenmodel peptides is reported. AGEs are modified amino acids that form on proteins such as collagen and are thought to play a significant role in the pathogenesis of many diseases, particularly diabetes. The synthesis and incorporation of these compounds into synthetic peptides is a key step in developing model systems with which to investigate AGE-modified proteins.

Advanced glycation endproducts(AGEs) are a group of compounds that are formed by nonenzymatic reactions between reducing sugars and amino acid side-chain residues in proteins. These post-translational modifications mainly involve reactions at lysine and arginine residues and give rise to a large number of structurally diverse compounds ranging from simple alkylations to more complex heterocycles and cross-linked structures.1The formation and accumulation of AGEs in the body is thought to play a significant role in the pathogenesis of many debilitating diseases including diabetes2 and age-related neurodegenerative diseases,
The University of Auckland. The University of Manchester and Manchester Academic Health Sciences Centre. (1) (a) Rabbani, N.; Thornalley, P. J. Amino Acids 2012, 29, 313. (b) Ledl, F.; Schleicher,E. Angew. Chem., Int. Ed. 1990, 29, 565. (2) (a) Ahmed, N.; Thornalley, P. J. Diabetes Obes. Metab. 2007, 9, 233. (b) Stitt, A. W. Br. J. Ophthalmol. 2001, 85, 746. (c) Peppa, M.; Vlasarra, H. Hormones 2005, 4, 28. (3) M€nch, G.; Westcott, B.; Menini, T.; Gugliucci, A. Amino Acids u 2012, 42, 1221.
‡ †

such as Alzheimer’s disease.3 AGE formation and accumulation is most problematic onlong-lived proteins such as collagen and lens-crystallins,4 and these are the most relevant proteins to study when investigating AGEs. However, the precise molecular mechanisms by which AGEs influence the progression of these diseases are not clear, and there remains a need to develop new chemical tools to investigate them. A key step to achieve this is the site-specific incorporation of AGEs intosynthetic peptide sequences using solid phase peptide synthesis (SPPS). This will enable access to synthetic AGE-modified peptides that will facilitate the development of suitable model systems to undertake future detailed molecular studies. The initial step required to address these fundamental questions is the development of
(4) (a) Verzijl, N.; DeGroot, J.; Oldehinkel, E.; Bank, R. A.; Thorpe, S. R.;Baynes, J. W.; Bayliss, M. T.; Bijlsma, J. W. J.; Lafeber, F. P. J. G.; TeKoppele, J. M. Biochem. J. 2000, 350, 381. (b) Verzijl, N.; DeGroot, J.; Thorpe, S. R.; Bank, R. A.; Shaw, J. N.; Lyons, T. J.; Bijlsma, J. W. J.; Lafeber, F. P. J. G.; Baynes, J. W.; TeKoppele, J. M. J. Biol. Chem. 2000, 275, 39027.

10.1021/ol302745f r 2012 American Chemical Society Published on Web 11/01/2012practical and efficient synthetic strategies for the preparation of suitably protected AGE building blocks for incorporation into SPPS. Here we report the synthesis of the three monolysyl AGEs, Nε-(carboxymethyl)lysine (1) (CML), Nε-(carboxyethyl)lysine (2) (CEL), and pyrraline (3) (Figure 1) as both Fmocprotected building blocks suitable for SPPS and as free amino acids. Furthermore, the AGE building...