METABOLIC CLEAVAGE OF FRANGUFOLINE IN RODENTS - IN-VITRO AND IN-VIVO STUDY

Frangufoline, a sedative 14-membered frangulanine-type cyclopeptide al kaloid, was found to be rapidly converted, via enzymatic process, in v itro and in vivo in rodents to M1 -(2S,3S)-3-[(p-formylphenoxy)leucyl] -(S)-leucine), which is a substituted linear tripeptide. The reaction did not require low molecular weight cofactors, and mammalian serum fa iled to catalyze the reaction. Structure-reactivity study of cyclopept ide alkaloid analogs suggested that the enamide bond is the site being cleaved, and the reaction was inhibited by organophosphorus esters su ch as BPNP and by eserine at higher concentrations but not by eserine at lower concentrations or by EDTA and PCMB. On the basis of these res ults, a possible mechanism for metabolic conversion of frangufoline to M1 was proposed,in which oxidation of the vinyl group and enzyme-cata lyzed hydrolysis of the adjacent amide bond, possibly by B-esterase-Li ke enzyme, proceed in a concerted manner.