Structural aspects of N-hydroxy-N'-aminoguanidine derivatives as inhibitors of L1210 cell growth and ribonucleotide reductase activity.

Abstract

Previous studies have shown that N-hydroxy-N'-aminoguanidine (HAG) derivatives [RCH = NNHC(= NH)NHOH-tosylate] inhibit ribonucleotide reductase activity and block the growth of leukemia L1210 cells and human colon carcinoma, HT-29, cells in culture. In the current studies, the role of the side chains and the location of the bond of the side chain moiety to HAG were investigated using a new series of HAG derivatives which contained as the R-group--cyclohexyl, phenyl-, pyridyl- or napthyl moieties. The effects of these compounds as inhibitors of L1210 cell growth and ribonucleotide reductase activity were compared with the parent compound. N-hydroxy-N'-aminoguanidine was less inhibitory to ribonucleotide reductase activity and L1210 cell growth than hydroxyurea. The phenyl-HAG compounds which included 1-benzyloxybenzylidene- and 4-cyclohexylmethoxybenzylidene-HAG inhibited CDP reductase with IC50s which ranged from 50-110 microM. 1-Naphthylmethylene-HAG was more inhibitory than 2-naphthylmethylene-HAG and more inhibitory than the phenyl-HAG compounds. 2-Pyridylmethylene-HAG was more inhibitory than 3-pyridylmethylene- or 4-pyridylmethylene-HAG. While HAG inhibited CDP and ADP reductase activities essentially to the same extent, the HAG-derivatives inhibited ADP reductase activity to a greater extent than CDP reductase activity. Cyclohexylmethylene-HAG did not inhibit either L1210 cell growth or ribonucleotide reductase activity. There was good correlation between the inhibition of ribonucleotide reductase activity and L1210 cell growth by these HAG-derivatives. These data indicate that not only is the nature of the side chain substitution important, but also the location of the HAG-moiety on the ring position.

• Authors: J G Cory, A H Cory, N K Raber, A Narayanan, S W Schneller
• Journal: Advances in enzyme regulation (Adv Enzyme Regul) Vol. 33 Pg. 129-40 ( 1993) ISSN: 0065-2571 [Print] England
• PMID: 8356905 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Guanidines
• N-hydroxy-N'-aminoguanidine
• Ribonucleotide Reductases

Topics

• Animals
• Cell Division (drug effects)
• Guanidines (chemistry, pharmacology)
• Leukemia L1210 (drug therapy, pathology)
• Mice
• Ribonucleotide Reductases (antagonists & inhibitors)
• Structure-Activity Relationship
• Tumor Cells, Cultured (drug effects, enzymology, pathology)