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Saturday, 11 June 2016

Dr. Larry Keefer

Dr. Larry Keefer
Drug Design
Dr. Keefer received his Ph.D. in organic chemistry from the University of New Hampshire in 1966 and held research positions at the Chicago Medical School and the University of Nebraska College of Medicine before joining the NCI staff in 1971.
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Dr. Larry Keefer

Dr. Larry Keefer
Drug Design

Research Summary

Link to Diazeniumdiolate Chemistry Database

Chemistry and Biology of Nitric Oxide

Nitric oxide (NO) is a potent and multifaceted bioregulatory agent. This project is aimed at finding ways to target NO to specific sites in the body for important research and/or therapeutic applications.

Our strategy in pursuing this goal is to begin by characterizing the fundamental chemistry of the NO-releasing diazeniumdiolates (compounds containing the [N(O)NO] functional group). We then attempt to exploit our accumulating knowledge in this area as a platform for solving problems in biomedical research and clinical medicine. We are currently pursuing basic research investigations into the structure, spectra, dissociation to NO and/or HNO, alkylation, arylation, photodegradation, and general reactivity of the diazeniumdiolate functional group with an eye toward designing prodrugs that are stable at physiological pH but that can be activated to generate NO or HNO by enzymatic action. An example is AcOM-PYRRO/NO, an esterase-sensitive diazeniumdiolate that penetrates the cell and generates NO within the cytoplasm on esterase-induced hydrolysis; AcOM-PYRRO/NO has proved to be two orders of magnitude more potent as an inducer of apoptosis in HL-60 leukemia cells in culture than the spontaneously dissociating parent ion, PYRRO/NO. Other achievements include the design of agents that can be activated for NO release by enzymes of the glutathione S-transferase, glycosidase, and cytochrome P450 families. Other recently introduced diazeniumdiolates have been designed to target nitric oxide delivery to macrophages for antimicrobial activity. Proof-of-concept studies that underscore the substantial clinical promise of these compounds include: inhibition of restenosis after angioplasty; preparation of thromboresistant medical devices; and inhibition of tumor growth in in vivo models. The results of the animal experiments suggest that a variety of problems in clinical medicine might be solved by mining the extensive library of possible diazeniumdiolate structures.

Current collaborators in these efforts include: Sonia Donzelli, Univ. of Hamburg-Eppendorf, Hamburg, Germany; Astrid Weyerbrock, Uni-Klinik Freiburg, Germany; Stefan Chlopicki, Jagellionian Center for Experimental Therapeutics, Krakow, Poland; Jeffrey Deschamps, Naval Research Laboratory; Xinhua Ji, NIH; Melina Kibbe, Northwestern University; Paul Shami, University of Utah; David Wink, NIH; and Regina Ziegler, NIH.
1 - 5 of 242 results
1)  Biswas D, Hrabie JA, Saavedra JE, Cao Z, Keefer LK, Ivanic J, Holland RJ.
Aminolysis of an N-Diazeniumdiolated Amidine as an Approach to Diazeniumdiolated Ammonia.
J. Org. Chem. 79: 4512-4516, 2014. [Journal]
2)  Bharadwaj G, Benini PG, Basudhar D, Ramos-Colon CN, Johnson GM, Larriva MM, Keefer LK, Andrei D, Miranda KM.
Analysis of the HNO and NO donating properties of alicyclic amine diazeniumdiolates.
Nitric Oxide. 42: 70-8, 2014. [Journal]
3)  Fuhrman BJ, Xu X, Falk RT, Dallal CM, Veenstra TD, Keefer LK, Graubard BI, Brinton LA, Ziegler RG, Gierach GL.
Assay reproducibility and interindividual variation for 15 serum estrogens and estrogen metabolites measured by liquid chromatography-tandem mass spectrometry.
Cancer Epidemiol. Biomarkers Prev. 23: 2649-57, 2014. [Journal]
4)  Holland RJ, Klose JR, Deschamps JR, Cao Z, Keefer LK, Saavedra JE.
Direct reaction of amides with nitric oxide to form diazeniumdiolates.
J. Org. Chem. 79: 9389-93, 2014. [Journal]
5)  Kaczmarek MZ, Holland RJ, Lavanier SA, Troxler JA, Fesenkova VI, Hanson CA, Cmarik JL, Saavedra JE, Keefer LK, Ruscetti SK.
Mechanism of action for the cytotoxic effects of the nitric oxide prodrug JS-K in murine erythroleukemia cells.
Leuk. Res. 38: 377-82, 2014. [Journal]

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