Molecular Pharmacology, Vol 6, 93-96, Copyright © 1970 by the American Society for Pharmacology and Experimental Therapeutics

Inactivation by Mouse Serum of a Tightly Bound Inhibitor of Dihydrofolate Reductase

¹ Departments of Pharmacology and Medicine, Yale University School of Medicine, New Haven, Connecticut 06510

A potent inhibitor of dihydrofolate reductase, a substituted 4,6-diaminotriazine (NSC 113,423; a 1:1 compound of 4-[p-(4,6-diamino-2,2-dimethyl-s-triazine-1(2H)-yl)hydrocinnamido]-o-toluenesulfonyl fluoride and ethanesulfonic acid), was found to be rapidly inactivated by mouse serum. Preliminary studies on the mechanism of this inactivation indicate that a mouse serum protein hydrolyzes the sulfonyl fluoride group. However, this triazine inhibitor was not inactivated by the sera of other species, including rat, dog, and man. It is suggested that NSC 113,423 and related compounds may still be valuable chemotherapeutic agents against tumors occurring in man.

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ACKNOWLEDGMENTS NSC 113,423 and 117,664 were obtained from Dr. Florence White of the Cancer Chemotherapy Service Center, and from Dr. B. R. Baker, who also generously supplied the sulfonic acid derivative of NSC 117,664 as well as valuable advice. The expert technical assistance of Mrs. Inger-Anne Skjeltorp is also acknowledged.