O2-Arylated or O2-Glycosylated 1-Substituted Diazen-1-ium-1,2-diolates and O2-Substituted 1-[(2-Carboxylato)Pyrolidin-1-yl] Diazen-1-ium-1,2-diolates
Description of Invention:
Diazeniumdiolates are compounds that contain an N2O2 functional group. These compounds are potentially useful as prodrugs because they generate nitric oxide upon degradation. Nitric oxide (NO) plays a role in regulation of blood pressure, inflammation, neurotransmission, macrophage-induced cytostasis, and cytotoxicity. NO is also important in the protection of the gastric mucosa, relaxation of smooth muscle, and control of the aggregation state of blood cells. Derivatives of diazeniumdiolates have been produced that degrade under differing environmental conditions, allowing for selective delivery of nitric oxide in a manner dependent on environment. A new series of diazeniumdiolate derivatives has been synthesized that are stable in neutral to acidic environments and generate nitric oxide in basic or nucleophilic environments. These derivatives are potentially suited to the delivery of nitric oxide to basic or nucleophilic compartments within the body. They may be useful for inactivating proteins to prevent detoxification of chemotherapeutic agents or disruption of proteins active in tumor formation, infection, or regulatory activities. The compounds are stable in an aqueous environment but can be activated by enzymatic action to release nitric oxide that is believed to be useful in treating fulminant liver failure, respiratory problems, impotence, and a variety of cardiovascular/hematologic disorders. The diazeniumdiolates have also been derivatized by their incorporation into polymers. These compounds may allow for site specific delivery of nitric oxide. Overall, these compounds appear to be applicable toward the wide variety of processes involving nitric oxide.
Inventors:
Joseph E. Saavedra (NCI) Larry K. Keefer (NCI) Aloka Srinivasan (NCI) Christian Bogdan William G. Rice (NCI) Xinhua Ji (NCI)
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Portfolios: Internal Medicine
Internal Medicine-Therapeutics
For Additional Information Please Contact: Norbert J. Pontzer PhD JD
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: (301) 435-5502
Email: pontzern@mail.nih.gov
Fax: (301) 402-0220
