Design, Synthesis And Kinetic Study Of The Optical Activity Of Carboxypeptidase-a Inhibitors

Compounds A,B,were designed as irreversible inhibitor to explore the interactionsof the active site of CPA according to the latest research progresses and themechanism of CPA. Both enantiomers of 2-benzyl-5-bromo-4-oxopentanoic acid Aand 2-benzyl-4-oxopentanoic acid B were prepared utilizing the diazo ketones as thekey intermediates and all of them assayed for inhibitory activity againstcarboxypeptidase A to find that the (R)-forms are more potent than theircorresponding enantiomers, i.e., 260-fold for A and 11-fold for B, respectively. Thefinding that the (R)-A which belongs to the L-series is mostly responsible for theinhibitory activity accords with the explanation that it is a transition state analoginhibitor. In the other hand, the more than 120-fold weak inhibition ofcarboxypeptidase A by (R)-B suggested that the non-halogenated ketone should be asubstrate analog inhibitor of carboxypeptidase A. These results further disclosed thatthe introduction of bromo group at the a-position of ketones could significantlyenhance the electrophilicity of the carbonyl group and the generated gem-diol form ofA in situ, which mimics the transition state in the catalytic process, should beresponsible for the potent inhibition of carboxypeptidase A.The antifungal activities of Juglone and its derivative,5,8-dihydroxy-1,4-naphtho- quinine, were tested against 12 pathogenic fungi. Bothcompounds shown the higher inhibition effects on the growth of mycelial ofRhizoctonia pathogeny compared to the case of Fusarium. oxysporum f. sp.. The EC₅₀values of Juglone and 5,8-dihydroxy-1,4-naphthoquinine against three fungi ofRhizoctonia pathogeny were 10.63-15.88mg/L and 9.79-14.69mg/L, respectively.Both of them exhibited the highest inhibitory effects on conidial germination toBipolaris maydis and, which were determined as 60% at the concentrations of 12.5mg/L. For conidial germination of the four kinds of pathogenic fungi ofFusarium.oxysporum f. sp., their inhibitory rate can be about 60 % at the dosage of 50mg/L.