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Toxicity and Antileukemic Effectiveness of Pyridine Derivatives and 1,3,4-Thiadiazole Derivatives in Mice. Relationship to Nicotinamide Antagonism

Laboratory of Chemical Pharmacology, National Cancer Institute, National Institutes of Health, Public Health Service, U. S. Department of Health, Education, and Welfare Bethesda, Maryland
Graduate Department of Biochemistry, Brandeis University,¹ Waltham, Massachusetts
Microbiological Associates, Inc., ^,2 Bethesda, Maryland

Detailed data are presented on the toxicology and antileukemic (L-1210) effectiveness of pyridine derivatives and thiadiazole derivatives with reference to their metabolite-antagonist relationships with nicotinamide. The data are related to previous biochemical findings and discussed with reference to their possible significance to antitumor chemotherapy.

Most of the pyridine derivatives employed undergo an exchange reaction with the nicotinamide moiety of diphosphopyridine nucleotide (DPN), forming analog of DPN in vitro (18). Since the exchange reaction may occur in vivo (5,22), the formation of fraudulent DPN has been suggested as a possible mechanism of their toxic effects (22).

In the current studies, nicotinamide was found to protect against the toxicity of 3-acetylpyridine (3-AP) or its reduction product, pyridyl-3-methylcarbinol, Nicotinamide did not protect against the toxicity of pyridyl-3-carbinol, pyridyl-3-aldehyde, 3-methylpyridine (ß-picoline) or pyridine.

Nicotinamide also protected against the toxicity of 6-aminonicotinamide, 2-amino-1,3,4-thiadiazole (ATDA), and 2-ethylamino-1,3,4-thiadiazole (EATDA).

Protection against 3-AP toxicity was afforded by N-methylnicotinamide, N-ethylnicotinamide, and nicotinhydroxamic acid. These pyridine bases are known to form DPN (14,23). DPN also protected against 3-AP toxicity. The failure of N,N-diethylnicotinamide to reverse 3-AP toxicity may have arisen from the acute toxicity of N,N-diethylnicotinamide itself.

Nicotinamide protected well against 3-AP toxicity when given at various times ranging from 4 hours prior to 3-AP to 2 hours after 3-AP. When nicotinamide was given 9 hours prior to 3-AP, protection by the metabolite was reduced. Previous biochemical findings had indicated that liver DPN synthesis reaches a peak in 8 to 12 hours after nicotinamide injection and is increased approximately 9-fold in about 9 hours (23). The current data indicate that the protection by nicotinamide against 3-AP toxicity resulted from direct competition between nicotinamide and 3-AP and is not attributable primarily to biosynthesized DPN.

A wide range of antileukemic (L-1210) activity was found among the nicotinamide antagonists tested. The thiadiazole derivatives, ATDA and EATDA, displayed a high degree of activity. 6-Aminonicotinamide was moderately active. 3-AP and other pyridine derivatives were relatively inactive. The antileukemic activities of the thiadiazole derivatives and 6-aminonicotinamide were reversible by nicotinamide.

N,N-Diethylnicotinamide (Coramine), although failing to protect against 3-AP toxicity, reversed the antileukemic activity of ATDA. Similarly, nicotinic acid reversed the antileukemic activity of ATDA but did not protect against 3-AP toxicity.

¹ Aided by grants from the National Cancer Institute, National Institutes of Health (Grant No. CY-3611), and the American Cancer Society, Massachusetts Division.

Publication No. 147 of the Graduate Department of Biochemistry, Brandeis University.

² National Institutes of Health Contract No. SA-43-ph-2371.