Studies On Chiral Cyclic Dipeptide With Proline: Synthesis, Antimicrobial, Antineoplastic Activity And As Asymmetric Catalyst

Cyclic dipeptides (CDPs) are the smallest cyclic peptides known.They exist widely in nature.Recently CDPs have attracted attention due to their biological and pharmacological properties including antibacterial, antifungal, antineoplastic, antiviral activities.Bioactive CDPs have prospects on antibiotics and cancer inhibitors. It is important that design and synthesize CDPs compound libraries, study relationships between their antibacterial, antineoplastic activity and molecular structure in theory and practice.We designed a CDPs compound library based on L-Proline as the parent nucleus, other usual and unusual amino acid as ligand. And sixteen chiral cyclic dipeptides with Proline were synthesized which possessed bicyclo-rigid structure by improving synthetic route and their antibacterial and antineoplastic activity was also studied. In the test of the compounds for the inhibitory effect against bacterium and fungus, cyclic(L-Pro-L-Tyr), cyclic(L-Pro-L-Thr),cyclic(L-Pro-L-Ser) exhibited significant inhibitory effect against Staphylococcus aureus with MIC of 160,80,80μg/mL, respectively.And cyclic (L-Pro-L-Trp) showed inhibitory effect against Escherichia coli with MIC of 320μg/mL; cyclic (L-Pro-L-Phe) showed inhibitory effect against Candida albicans with MIC of 320μg/mL. Antineoplastic activity was tested using two cultured cell lines: MCF-7 and HeLa which were exposed to 2.5 mM CDPs. No obvious inhibitory activity could be detected, however, less than 10% growth inhibition of MCF-7 and Hela cells. CDPs have fascinated chemists on acting as asymmetric catalyst since Oku and Inoue published a pioneering study of CDPs as catalysts for the asymmetric addition of hydrogen cyanide to benzaldehyde.CDPs as small organic molecules catalysts have sdvantages of simple structure,easy synthesis and easy to build the relationship between structure and activity.But these catalysts have limitation in applicability to some extent.So design and synthesize CDPs catalysts which can be applied to asymmetric catalytic reactions is of great significance.Experiments were carried out by using sixteen synthetic chiral CDPs with Proline as catalyst for asymmetric addition of diethylzinc to benzaldehyde. Cyclic (L-Pro-L-Ser), cyclic (L-Pro-L-Thr), cyclic (L-Pro-L-His), cyclic (L-Pro-L-Trp), cyclic (L-Pro-D-His) and cyclic (L-Pro-D-Trp), which can form complexes with the zinc atom, have showed good asymmetric catalytic activity. The yield of product 1-phenyl-1-propanol was up to 41%, enantiomeric excess up to 21.3%. And it is found that the configuration of the product depended on the configuration of Proline.Additionly solvent, catalyst amount and temperature were studied.The experiment showed that 0℃, toluene as solvent and the CDP's amount of 10% benzaldehyde ware the optimal reaction conditions.Our study indicated that chiral cyclic dipeptides with Proline can asymmetric catalyze addition reaction of diethylzinc to benzaldehyde which made the foundation for further study.