Synthesis And Bioactivity Study Of DOPA-Containing Cyclo-Dipeptides

Cyclodipeptides,made from two amino acids connecting head-to-tail with each other,are structurally stable with high possibility to become new drugs.Cyclodipeptides can be found in human and many organisms.Some of them demonstrates good properties in antibacterial,bioinformation messaging,antitumor,neuron protection,and etc.L-DOPA,a naturally-occuring,rare amino acid,is the most efficacious drug for Parkinson's disease,regarded as the "gold standard".Unfortunately,due to its extremely low bioavailability,a large amount of dosage should be taken by the patients and this frequently results in many serious adverse effects.Up to now,only four L-DOPA containing cyclodipetides have been published in the literature and no work on cyclodipeptides made from L-DOPA and the remaining 16 common amino acids has been even reported.L-DOPA-containing cyclodipeptides are very stable under physiological condition,highly resistant to degradation,and can enter the blood circulation through oligopeptide channels in the intestine membrane.This thesis explored a new strategy to synthesize L-DOPA-containing cyclodipeptides and investigated their stability in liver homogenate and applications in antibacterial and neuron protection.L-DOPA-containing cyclopeptides were synthesize in three steps.First,lab-synthesize Fmoc-DOPA(Acetonide)-OH was reacted with commercially available methyl ester of common amino acids to produce a linear dipeptide derivative Fmoc-DOPA(Acetonide)-AA-OMe,or commercially available Fmoc-AA-OH was reacted with lab-synthesized H-DOPA(Acetonide)-OMe to produce Fmoc-AA-DOPA(Acetonide)-OMe.Second,the synthesized dipeptide was stirred in 20%piperidine solution to remove the Fmoc protection and facilitate intramolecular cyclization to yield L-DOPA-containing cyclodipeptides in protected form.The obtained cyclodipeptide derivatives are very stable,ready to be purified and stored for future application.Third,the protection of side chains of the synthesized cyclodipeptides was removed with trifluoroacetic acid to give the target,free cyclodipeptides.Anti-bacterial experiments showed that cyclo(DOPA-Trp)and cyclo(DOPA-D-Glu)had slight antibacterial property against E.coli and S.aureus while Cyclo-(DOPA-Ala)and Cyclo(DOPA-Gln)had some degree of protection for them in acetic acid/DMSO solution.Live homogenate experiments showed that among those tested,cyclo(DOPA-Ala)was most stable with a t1/2 of 3419 min while cyclo(DOPA-Lys)was the least with a t1/2 of 502 min,near that of H-DOPA-Glu-OH at 448min.Future work is to complete the syntheses of all L-DOPA-containing cyclodipeptides and investigate their various bioactivities in antibacterial,antiparasites,antitumor,and neuroprotection.