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4-Methyl-5-amino-1-formylisoquinoline Thiosemicarbazone, a Second-Generation Antineoplastic Agent of the -(N)-Heterocyclic Carboxaldehyde Thiosemicarbazone Series¹

Department of Pharmacology and Section of Developmental Therapeutics, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510 [K. C. A., P. D. M., J. B. S., H. D., A. C. S.]; Department of Biochemistry, The University of Texas Cancer Center, M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030 [E. C. M.]; and Arthur D. Little, Inc., Acorn Park, Cambridge, Massachusetts 02140 [I. W.]

4-Methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIQ-1) was studied to determine its potential for clinical trial as a second-generation antineoplastic agent of the -(N)-heterocyclic carboxaldehyde thiosemicarbazone class. MAIQ-1 was shown to be among the most potent known inhibitors of the major target for the expression of antineoplastic activity by this class of agents, the enzyme ribonucleoside diphosphate reductase, requiring only 0.06 µM for 50% inhibition. This potency at the enzymatic level was consistent with its antineoplastic activity against the murine neoplasms Sarcoma 180, Leukemia L1210, Leukemia P388, and the B16 melanoma. The acetylation of the 5-amino group of the model substrate 5-amino-1,4-dimethylisoquinoline was lower than that of 5-amino-1-methylisoquinoline when incubated with acetyl-coenzyme A and rat liver homogenate. This finding suggests that the presence of the 4-methyl function offers steric hinderance to enzymatic substitution of the adjacent 5-amino group. In vivo metabolism of MAIQ-1 in mice, studied with [3'-¹⁴C]MAIQ-1, showed that relatively slow excretion of this agent occurred, since the cumulative urinary excretion of radioactivity was only 35% in 48 hr. About 51% of excreted urinary radioactivity was present in chromatograms in an area corresponding to the iron chelate of MAIQ-1, and only a minor quantity of material migrating like acetylated MAIQ-1 was present in urine, a finding consistent with enzymatic data with liver homogenates. The results indicate that MAIQ-1 has the antineoplastic activity, enzyme inhibitory potency, and relative resistance to metabolic inactivation required of an agent of this class for clinical trials.

¹ This research was supported in part by USPHS Research Grants CA-02817, GM-17021, CA-04464, and CA-16359 and Contract CM-53765 from the National Cancer Institute.

² Present address: Department of Pharmacology, Tulane University School of Medicine, New Orleans, La. 70112.

³ Present address: Pathology-Anatomy Institute, University of Vienna, Vienna, Austria.

⁴ Present address: School of Osteopathic Medicine and Surgery, Oklahoma College, Tulsa, Okla. 74119.

Received 12/ 6/76. Accepted 3/14/77.