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 synthesized and evaluated for biological activity in microorganisms, plants and tumor cells using canavanine as a positive control. (1) In microbial systems, 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 plants, the activity of CH and CBCH were relatively low, whereas the inhibitory potential of CPH was comparable or even superior to that of canavanine, resulting at 1 mM concentration in a nearly complete block of tomato cell growth, 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 synthesis 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 differed in the timing of their expression and/or accumulation. With canavanine, the highest hsp-17 expression was found after 48 h of drug treatment, while with CPH this maximum was shifted to 24 h. (4) CPH proved to be highly cytotoxic against Friend leukemia cells in culture, exceeding by one order of magnitude the cytotoxicity of canavanine. The effect of canavanine was completely 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 increase in its growth-inhibitory activity and to a change in the mode of action of the parent compound.
Miersch
J
J
Institute of Biochemistry, Martin-Luther-University, Halle, Federal Republic of Germany. miersch@biochemtech.uni-halle.de
Grancharov
K
K
Pajpanova
T
T
Tabakova
S
S
Stoev
S
S
Krauss
G J
GJ
Golovinsky
E
E
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism; D001419:Bacteria / Q000187:drug effects; D002172:Canavanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D005622:Friend murine leukemia virus / Q000378:metabolism; D006834:Hydrazines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007942:Leukemia, Experimental / Q000378:metabolism; D018551:Solanum lycopersicum / Q000187:drug effects; D051379:Mice; D010944:Plants / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D006834:Hydrazines; C410363:canavanine phenylhydrazide; C410362:canavanine-bis-(2-chloroethyl)hydrazide; D002172:Canavanine