Biological activity and mode of action of some dihydroorotic and dihydroazaorotic acid derivatives.
The conversion of six dihydroorotate analogues by the dihydroorotate dehydrogenase (DHO-DH) of plant and animal mitochondria was studied. In the case of plant DHO-DH the dehydrogenation of analogues was as follows: Dihydroorotic acid (DHO) (control, 100%), DHO-hydrazide (40%), azaDHO (13%), azaDHO-ethyl ester (23%), azaDHO-hydrazide (11%), dihydrouracil (0%), dihydrothymine (0%). When animal DHO-DH was used the analogues were practically not dehydrogenated. These compounds were also tested as inhibitors of DHO-dehydrogenation. AzaDHO, azaDHO-hydrazide and azaDHO-ethylester inhibited this reaction by 75, 70% and 60%, respectively, for plant DHO-DH. AzaDHO and azaDHO-ethylester inhibited this reaction to 90% and 70%, respectively, for animal enzyme. The other analogues had no effect. The compounds showed a moderate antibacterial activity. AzaDHO was more active than azaDHO-ethyl ester and azaDHO-hydrazide. A considerable inhibitory effect of azaDHO and azaDHO-ethyl ester was observed on the growth of St. aureus mutant UV-2 and S. lutea. The analogues were little active against the experimental mouse tumors leukemia L 1210, Lewis lung carcinoma (LLC) and B-16 melanoma. AzaDHO-ethyl ester and azaDHO-hydrazide inhibited the growth of LLC by 59% and 56%, respectively. In addition, the effect of analogues on the growth of plant cells was studied. AzaDHO and azaDHO-ethyl ester inhibited the growth of tomato cells in suspension culture by 10% and 41%, respectively.
Miersch
J
J
Department of Biosciences, University of Halle-Wittenberg, GDR.
Grancharov
K
K
Krauss
G J
GJ
Spassovska
N
N
Karamanov
G
G
Maneva
L
L
Mladenova
J
J
Golovinsky
E
E
D000818:Animals; D002478:Cells, Cultured; D000090722:Dihydroorotate Dehydrogenase; D004354:Drug Screening Assays, Antitumor; D008826:Microbial Sensitivity Tests; D008930:Mitochondria, Liver / Q000201:enzymology; D009963:Orotic Acid / Q000031:analogs & derivatives*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D063245:Plant Development; D010944:Plants / Q000187:drug effects / Q000201:enzymology; D051381:Rats
D000090722:Dihydroorotate Dehydrogenase; D009963:Orotic Acid; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors