Synthesis And Biological Activities Of Cyclosporin H Derivatives

Recent studies have showed that cyclosporin H(CsH) displays more potent inhibition for human FPR(Formyl-peptid receptor) than most of other antagonists. Besides, CsH has other biological activities such as reversing MDR(multidrug resistance), anti-parasite and anti-virus activities. Structrue-activity relationship (SAR) studies of cyclosporins show that the special amino acid -- MeBmt in 1-position of cyclosporins plays a crucial role in their biological activities. Therefore MeBmt can act as an important modification site in the semi-synthesis of cyclosporins derivatives. CsH derivatives were synthesized and some of their biological activities were tested for further understanding mechanisms, SAR of CsH and their derivatives.1. Twelve new CsH derivatives(including a pair of optic isomer) were synthesized and the synthetic routes were modified to increase reaction yields and simplify procedure.2. 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, HPLC-MS and IR.3. Antagonistic activities for FPR were tested. Primarily results showed that all of the 12 synthetic CsH derivatives exhibited inhibitory effects on fMLF-induced calcium mobilization, but not exceeded CsH.4. Inhibiting effects on the growth of edlworm C.elegans in vitro were tested and the results showed that the effects were very weak.5. Antifungal activities of these synthetic compounds were investigated. Experimental data indicate that only some specific fungi were inhibited by some of the compounds.6. The immunosuppressive activities of these synthetic compounds were tested and the results showed that immunosuppressive activities of CsH and their derivatives were lower than that of cyclosporin A. But remarkable changes were observed in the immunosuppressive if specific modifications happed on some functional groups of CsH.