The Synthesis, Structural Analysis And Biological Activity Of Sansalvamide A Cyclopentapepide Analogues

Sansalvamide A is a cyclic depsipeptide which was isolated from marine fungus of genus Fusarium and exhibits anti-cancer bioactivity. On this basis, the corresponding Sansalvamide A cyclic peptides analogs(cyclic pentapeptides)have been synthesized and showed more potent than Sansalvamide A as a cytotoxic agent. In this paper, using Sansalvamide A cyclic peptide as lead, compound a series of novel Sansalvamide A cyclic peptides analogues, which contains different unnatural animo acides and/or substitute leucine with proline, are synthesized, and their activity against five different human cancer cell lines also evaluated. Objective It is to explore the effect of different amino acids on antitumor activitieswere explored, which is benefit for developing new antitumor drugs.1. Recent progress of the synthesis bioactive study of marine cyclic peptides and Sansalvamide A analogues are reviewed.2. Using Sansalvamide A cyclic peptides as the template, series of Sansalvamide A cyclic peptides analogues are designed by structural improvement and modification according to the principle of hybridization and bioisosteric replacement.3. Five unnatural L-Aryl alanine and their enantiomer are prepared by nucleophilic substitution, nitrosification oximation, reduction and chemical resolution from chloromethyl of bromometnyl aromatic ring. Optimum synthesis conditions is explored; A new synthetic method is obtained. Their structures are characterized by 1HNMR,IR and elemental analysis;The single crystal of intermediates (3-phenyl acetone oximino methyl esters) is obtained and its structure is determined by X-ray Single Crystal Diffraction4. Eighteen dipeptides, four tripeptides and one tetrapeptide are synthesized via solution-phase synthesis utilizing Boc strategy; Ninteen chain-pentapeptides possessing different group benzene ring, different aromatic ring, different configuration and substitution leucine with proline, are obtained by step wise method and convergent approach, respectively; The condensation agent and activation agent are selected in chain-peptide synthetical process;1H NNR,IR spectra is analysized and their structures are confirmed; The resolution of racemic dipeptides are tried by chemical methods, giving crystal of Boc-L-Leu-D-3-(2-naphthyl) alanine methyl esters and Boc-D-Leu-L-3-(2-naphthyl) alanine methyl esters, and X-Ray analysis is used for two crystals so that the real conformations and configurations of compounds are shown directly.5. Ninteen sansalvamide A cyclic peptides analogues have been synthesized by cyclization of chain peptides using HBTU and PyBop as condensation agent under solution phase condition. The effects of concentration, condensation agent, temperature and solvent on cyclization reaction are investigated, and cyclization conditions are explored. The peak assignment of 1H NMR spectra is given, furthermore, the strucures are confirmed by high-resolution MS6. Proliferating inhibitory activities of cyclic peptides analogues against MDA-MB231,HT-29,HCT-15,K562,A549 cell lines are evaluated. The effects of different group in benzene ring, different aromatic ring, different configuration and substitution leucine with proline on antitumor activities are discussed. The results have shown that TM-5, TM-10,T M-23 and TM-19 have higher biological activities against five cancer cell lines.