6-Diazo-5-oxo-L-norleucine (DON), an unconventional amino acid having a structure similar to that of L-glutamine, was first isolated in the 1950’s from Streptomyces bacteria.1 DON broadly blocks glutamine utilizing reactions in cancer cells, and has shown robust efficacy in both preclinical cancer models and exploratory clinical studies. However, the clinical development of DON was halted, in part due to gastrointestinal toxicities,2 as the GI system is highly glutamine utilizing. Given DON’s promising efficacy in treating “glutamine-addicted” tumors, JHDD worked with chemists at the Institute of Organic Chemistry and Biochemistry in Prague to create DON prodrugs which deliver DON selectively to the tumor while minimizing its peripheral toxicity. Our novel tumor-targeted prodrugs of DON circulate intact and inert in plasma and are preferentially biotransformed to DON in tumor cells, permitting significant dose reduction and improved therapeutic index. Taking advantage of the elevated activities of specific tumor associated proteases, we have identified prodrugs that are stable in the gut but preferentially release DON in tumors. Furthermore, development of prodrugs designed to deliver DON preferentially to the brain is currently under way as a treatment for brain cancers and other neurological and psychiatric disorders.3
(a) DeWald, H. A.; Moore, A. M., 6-Diazo-5-oxo-L-norleucine, a New Tumor-inhibitory Substance. 1a Preparation of L-, D-and DL-Forms1b. Journal of the American Chemical Society 1958, 80 (15), 3941-3945; (b) Nawrat, C. C.; Moody, C. J., Natural products containing a diazo group. Natural product reports 2011, 28 (8), 1426-1444.
(a) Magill, G. B.; Myers, W. P.; Reilly, H. C.; Putnam, R. C.; Magill, J. W.; Sykes, M. P.; Escher, G. C.; Karnofsky, D. A.; Burchenal, J. H., Pharmacological and initial therapeutic observations on 6-diazo-5-oxo-1-norleucine (DON) in human neoplastic disease. Cancer 1957, 10 (6), 1138-50; (b) Earhart, R. H.; Amato, D. J.; Chang, A. Y.; Borden, E. C.; Shiraki, M.; Dowd, M. E.; Comis, R. L.; Davis, T. E.; Smith, T. J., Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas. Investigational new drugs 1990, 8 (1), 113-9; (c) Rahman, A.; Smith, F. P.; Luc, P. T.; Woolley, P. V., Phase I study and clinical pharmacology of 6-diazo-5-oxo-L-norleucine (DON). Investigational new drugs 1985, 3 (4), 369-74.
Rais, R.; Jancarik, A.; Tenora, L. s.; Nedelcovych, M.; Alt, J.; Englert, J.; Rojas, C.; Le, A.; Elgogary, A.; Tan, J., Discovery of 6-Diazo-5-oxo-L-norleucine (DON) prodrugs with enhanced CSF delivery in monkeys: a potential treatment for glioblastoma. Journal of medicinal chemistry 2016, 59 (18), 8621-8633.