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Mechanism of Action of 2-Amino-1,3,4-thiadiazole (NSC 4728)¹

Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205

The synthesis and isolation of two derivatives of 2-amino-1,3,4-thiadiazole(aminothiadiazole) are described. The derivatives are a nicotinamide adenine dinucleotide (NAD) analog prepared by an exchange reaction with NAD in the presence of nicotinamide adenine dinucleotide glycohydrolase and a presumed aminothiadiazole mononucleotide prepared by treatment of the NAD analog with nucleotide pyrophosphatase. Both derivatives are potent inhibitors of inosine 5'-phosphate (IMP) dehydrogenase obtained from leukemia L1210 cells. The NAD analog is a pseudoirreversible inhibitor of the enzyme, noncompetitive with either IMP or NAD. The aminothiadiazole mononucleotide has a K_i of about 0.1 µM, is competitive with IMP, and is uncompetitive with NAD; the inhibition appears to be reversible by Ackermann-Potter analysis. A metabolite of [5-¹⁴C]aminothiadiazole is formed in L1210 cells in vivo to a level of 0.3 nmole/10⁹ cells. Retention volume of the metabolite on a high-pressure liquid chromatography system is the same as that of the aminothiadiazole mononucleotide prepared as described above. These results suggest that IMP dehydrogenase is the site of action for aminothiadiazole metabolites as was indicated by earlier observations.

There is no evidence that the NAD analog is formed in vivo. Nicotinamide prevented formation of the mononucleotide in vivo. Therefore, since formation and cleavage of the NAD analog apparently are not the route to the thiadiazole nucleotide, some other pathway for the metabolism of nicotinamide may be involved such as the action of a phosphoribosyltransferase or the sequential action of a nucleoside phosphorylase and a nucleoside kinase.

¹ Supported by Contract NO1-CM-43784 from the Division of Cancer Treatment, National Cancer Institute, NIH, Department of Health, Education and Welfare.

² Present address: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77550.

³ To whom requests for reprints should be sent.

Received 8/ 2/76. Accepted 10/ 7/76.

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