Synthesis and biological activity of canavanine hydrazide derivatives

The canavanine derivatives L-canavanine hydrazide (CH), L-canavanine-bis-(2 -chloroethyl)hydrazide (CBCH) and L-canavanine phenylhydrazide (CPH) were s ynthesized and evaluated for biological activity in microorganisms, plants and tumor cells using canavanine as a positive control. (1) In microbial sy stems, the compounds exerted activity, as assessed in 14 bacterial strains. The effect of canavanine was easily removed by equimolar concentrations of arginine or ornithine, while the effect of CBCH or CPH was abolished by 10 -fold excess of arginine or 10- to 100-fold excess of ornithine. (2) In pla nts, the activity of CH and CBCH were relatively low, whereas the inhibitor y potential of CPH was comparable or even superior to that of canavanine, r esulting at 1 mM concentration in a nearly complete block of tomato cell gr owth, and reducing by up to 80% the length of radicles of cress, amaranth, cabbage and pumpkin. (3) In pumpkin seeds, CPH or canavanine induced the sy nthesis of four small heat shock proteins of hsp-17 family in the pH range of 6 to 7.5. The proteins exhibited in both cases a similar profile, but di ffered in the timing of their expression and/or accumulation. With canavani ne, the highest hsp-17 expression was found after 48h of drug treatment, wh ile with CPH this maximum was shifted to 24h. (4) CPH proved to be highly c ytotoxic against Friend leukemia cells in culture, exceeding by one order o f magnitude the cytotoxicity of canavanine. The effect of canavanine was co mpletely removed in the presence of equimolar amounts of arginine, while a 20-fold excess of arginine failed to abolish the cytotoxicity of CPH. Thus, a proper hydrazide modification of canavanine may lead to a significant in crease in its growth-inhibitory activity and to a change in the mode of act ion of the parent compound.