Synthesis of Multiply Substituted Cyclosporine Analogs

• Main Author: 楊福助
• Other Authors: 胡明寬
• Format: Others
• Language: zh-TW
• Published: 1997
• Online Access: http://ndltd.ncl.edu.tw/handle/66236975452094456363

碩士 === 國防醫學院 === 藥學研究所 === 85 === 　　Cyclosporin A (CsA, Figure 1) is a naturally occurring cyclo-undecapeptide which is currently an important important immunosuppressive drug for preventing graft rejection during tissue transplantation. In addition, CsA also displays blockade of P-glycoprotein-meidated multidrug resistance in tur or cells and inhibits replication of human immunodeficiency virus in vitro. 　　Recently, Sandoz reported that SDZ NIM 811 [(MeIle4)CsA], a 4-position-modified CsA analogure strogue strongly inhibited replication of HIV-1 in vitro with different mechanism of actions, showed a non-immunosuppressive activity and lower toxicity. Furthermore, PSC 833 [(3-Oxo-MeBmt1, Val2)CsA]was demonstrated to block multidrug resistance in tumor cells. 　　In our laboratory, we modified CsA at the 1, 2, 4 or 6-positions with stretegies regards with conformational constraint and multiple substitutions. A series of coupling reagents such as BOP, PyBrOP, PyBOP and BOP-Cl were compared for the couplings peptide fragments and amino-acids. We found that PyBOP was also a suitable coupling reagent for steric-hindered amino acid derivatives in some cases. New CsA derivatives: [(MePhe1)CsA], [(MePhe1, MeIle4)CsA], [(MePhe1, MeIle6)CsA], [(MePhe1, MeIle4, MeIle6)CsA], [(MePhe1, MeVal6)CsA], [(MePhe1, Leu4, MeIle6)CsA] were obtained and their structures were determined with HR-FABMS and NMR spectra. The relative pharmacological tests of these products were evaluated for future study.