Synthesis And Biological Activities Of Cyclosporin A Derivatives

Cyclosporin A ( CsA ) as an important immunosuppressive agent has been widely used in organ transplantation. It has other biological activities such as antifungal, anti-parasite and anti-virus activities and so on. Structrue-activity relationship ( SAR ) studies of CsA show that the special amino acid---( 2S, 3R, 4R, 6E )-3-hydroxy- 4-methyl-2-methylamino-6-octenoic acid ( MeBmt ) in position 1 of CsA plays a crucial role in immunosuppressive and other biological activities. Therefore MeBmt can be chosen as an important modifing target in the semi-synthesis of CsA derivatives. CsA derivatives with chemical modifications on the MeBmt were synthesized and some of their biological activities were tested. The work was included in the followings:1.Twelve new CsA derivatives were synthesized and the synthetic routes were modified to increase reaction yield and simplify procedure.2.Silica gel column chromatograph, HPLC, HSCCC (high-speed countercurrent chromatography) and other isolation and purification methods were established for the efficient separation of synthetic compounds. The chemical structures of these compounds were identified by spectrometric methods such as MS, IR and NMR.3.The immunosuppressive activities of these synthetic compounds were tested and the results showed that immunosuppressive activities of CsA derivatives were lower than CsA . But remarkable changes were observed in the immunosuppressive if specific modifications happened on some functional groups of CsA.4.Antifungal activities of these synthetic compounds were investigated. Experimental data indicated that only some specific fungi were inhibited by some of the compounds.