Synthesis Of Cyclosporine A Derivatives

The compound cyclosporine A has been widely used since its introduction in the fields of organ transplantation and immunomodulation, and has brought a significant increase in the rate of success for transplantation procedures. Undesired side effects associated with cyclosporine, however, such as nephrotoxicity, have influenced its clinical practice. So it is important to search for its derivatives with high efficacy and low toxicity as new immunosuppressant.Structure-activity relationship (SAR) studies of cyclosporine A shows that the special amino acid (MeBmt) in position 1 of cyclosporine A plays a crucial role in immunosuppressive activities. Therefore synthetic modifications of the MeBmt are described in this study.The work is included as follows:1. Triphenylphosphonium bromide of acetyl cyclosporine A is synthesized by acetylation, bromation and the reaction with triphenylphosphine from cyclosporine A, and eight acetyl cyclosporine A derivatives are prepared by the Wittig reaction of Triphenylphosphonium bromide of acetyl cyclosporine A with different aldehydes. Finally seven cyclosporine A derivatives are gained by the deacetylation of eight acetyl cyclosporine A derivatives; A carboxylated cyclosporine A derivative is synthesized by the reaction of cyclosporine A with oxalyl chloride. The chemical structures of these sixteen new compounds are identified by MS and ~1H-NMR.2. The synthetic routes are modified to increase reaction yield. Acetyl cyclosporine A is prepared in 84.26% yields by the reaction of cyclosporine A with acetyl chloride, chloroform as solvent; Bromation of acetyl cyclosporine A is under protection of nitrogen; Triphenylphosphonium bromide of acetyl cyclosporine A is prepared in 73.7% yields under reflux heating reaction using acetonitrile as the solvent, and the ration of acetyl bromocyclosporine A and triphenylphosphine is 1:10; The best Wittig reaction conditions are listed as follows: the reaction temperature is 0℃, potassium hydroxide is the catalyst, the ration of triphenylphosphonium bromide of acetyl cyclosporine A and benzaldehyde is 1:10; The yield of carboxylated cyclosporine A derivative is 91% using a ration of 1:10 of cyclosporine A and oxalyl chloride.3. The immunosuppressive activities of six synthetic compounds are tested and the results show that immunosuppressive activities of cyclosporine A derivatives are lower than cyclosporine A.