Synthesis of Elastin Crosslinker Desmosines

Desmosine (1) and isodesmosine (2) are 1,3,4,5-and 1,2,3,5tetrasubstituted pyridiniums and exist only in the extracellular matrix protein elastin as major crosslinking amino acids.They are formed by the condensation and cyclization of one lysine and three allysines, generated from lysine by lysyl oxidase.Since the discovery of desmosines in 1964, there have been no reports on their chemical synthesis for decades.The first total synthesis of 1 was reported in 2012 and since then, isodesmosine (2), desmopyridine (3), isodesmopyridine (4), neodesmosine (5), and merodesmosine (6) have been synthesized.Isotopically labeled desmosines have also been synthesized for the precise analysis of desmosines using isotope-dilution LC-MS/MS analysis.Synthesis of conjugates with desmosines and carrier proteins was achieved for antibody production.This review summarizes a series of desmosine syntheses based on cross-coupling reactions and Chichibabin pyridinium synthesis as synthesis methodologies.The obtained results would help in the development of novel diagnostic and therapeutic methodologies for elastin-degradation-related diseases.CONTENTS 2.3 Sonogashira and Negishi Cross-Coupling Reactions 2.4 Synthesis of Isotopically Labeled Desmosine-dn 3. Synthesis of Isodesmosine 3.1 Synthesis Strategy 3.2 Sonogashira and Negishi Cross-Coupling Reactions 4. Synthesis of Neodesmosine and Merodesmosine 4.1 Synthesis of Neodesmosine 4.2 Synthesis of Merodesmosine 5. Synthesis of Desmosines via Chichibabin/isoChichibabin Pyridinium Synthesis 5.1 Background 5.2 Chichibabin/isoChichibabin Pyridinium Synthesis 5.3 Synthesis of [ 13 C3, 15 N1]-Labeled Desmosine/Isodesmosine 5.4 Mechanistic Insights 6. Synthesis of Carrier Protein Conjugate 6.1 Synthesis of Desmosine-BSA/KLH Conjugate 6.2 Synthesis of Isodesmosine-KLH Conjugate 7. Conclusion 1100