The Design And Synthesis Of Anti-HIV Cyclic Pentapeptide

Scientists have been isolated a series of antiviral natural cyclodepsipeptides from various marine sponges,including callipetin A,papuamides A,B,theopapuamide B,neamphamide A,mirabamide A-D.Some residues in the class peptides are essential for anti-HIV activity via structure-activity relationship studies.These pharmacophores include?-methoxy tyrosine,N-terminal fatty acid moiety,L-homoproline,2,3-diaminobutanoic acid,3,4-dimethyl-L-glutamine and so on.The antiviral activities of the compounds belonged to have cytoprotective activity against HIV-1 in vitro by inhibitin gviral entry.Compared with other anti-HIV agents,the side effect of these cyclodepsipeptides acting at the early steps of HIV-1 infection is reduced greatly.The current studies revealed that the virus,and not the cell,is the target of papuamide A's action.In this paper,some critical residues were incorporated into the structure of sansalvamide A and we hope this modification exhibiting anti-HIV activity.A series of target molecules were designed by changing sansalvamide A.The leucine was replaced with proline.The phenylalanine was substituted by?-methoxyarylalanine.The process of synthesis:?1?The preparation of?-methoxyarylalanines:Ethyl benzoylacetate was used as starting material,ethyl?±?-erythro-N-acetyl-?-phenylserinate were obtained through oximation,reduction and acylation.?2S,3S?and?2R,3R?-?-Phenylserine with high enantiomeric excess?100%ee?were obtained via the hydrolysis of erythro-N-acetyl-?-phenylserine by L or D-aminoacylase.Furthermore,the condition of methylation of the remaining?-hydroxyl group was explored.Asymmetric hydrolysis of erythro-N-acetyl-?-methoxy phenylalanine by L-aminoacylase affored?2S,3S?-?-methoxy phenylalanine.?2S,3S?and?2R,3R?-?-methoxy-?-p-methoxyphenyalanine with high enantiomeric excess?100%ee?could be prepared via this process too.Compared with the methods in the literature,the specific rotation of every isomers have approximately the same value.?2?The preparation of cyclopeptides:The pentapeptides were synthesized by reaction of Boc-?2S,3S?-?-methoxyphenylalanine and Boc-?2S,3S?-?-methoxy-?-p-methoxy phenyalanine as starting material with tetrapeptide?Leu-Val-Leu-Leu?.At last,two target molecules were obtained through cycliczation of the linear pentapeptides respectively.The preparation of unnature amino acid and the synthesis of chain peptide and cyclic peptide had been studied in this paper.The unnature amino acids were prepared.The linear peptide and the cyclic peptide were purified by recrystallization and column chromatography.The structure of the intermediates and the target molecules were deter mined by IR,¹H NMR,¹³C NMR,MS.