Semi-synthesis of cyclosporins

• Published in: Biochimica et biophysica acta Vol. 1850; no. 10; pp. 2121 - 2144
• Main Authors: Peel, Michael, Scribner, Andrew
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2015
• Subjects: amino acids; anions; bioactive properties; biologists; catalysts; Cyclic peptide; Cyclophilin; Cyclosporine; Cyclosporins - chemical synthesis; Cyclosporins - chemistry; Humans; olefin; Semi-synthesis; stereochemistry; T-lymphocytes; Cyclic peptide; Cyclosporine; Cyclophilin; Semi-synthesis
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2015.02.008

Since its isolation in 1970, and discovery of its potent inhibitory activity on T-cell proliferation, cyclosporin A (CsA) has been shown to play a significant role in diverse fields of biology. Furthermore, chemical modification of CsA has led to analogs with distinct biological activities associated with its protein receptor family, cyclophilins. This review systematically collates the synthetic chemistry performed at each of the eleven amino acids, and provides examples of the utility of such transformations. The various modifications of CsA are traced from early, modest chemistry performed at the unique Bmt residue, through the remarkable use of a polyanion enolate that can be stereoselectively manipulated, and onto application of more recently developed olefin metathesis chemistry to prepare new CsA derivatives with unexpected biological activity. The myriad biological activities of CsA and its synthetic derivatives have inspired the development of new approaches to modify the CsA ring. In turn, these new CsA derivatives have served as tools in the discovery of new roles for cyclophilins. This review provides information on the types of cyclosporin derivatives that are available to the many biologists working in this field, and should be of value to the medicinal chemist trying to discover drugs based on CsA. This article is part of a Special Issue entitled Proline-directed foldases: Cell signaling catalysts and drug targets. •A review of cyclosporine compounds available for biological investigation•Overview of the biological activity of modified cyclosporins•A systematic review of chemistry applied to cyclosporine A