BACKGROUND: 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.
SCOPE OF REVIEW: 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.
MAJOR CONCLUSIONS: 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.
GENERAL SIGNIFICANCE: 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.