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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 239 results

1)  Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS.
DNA deaminating ability and genotoxicity of nitric oxide and its progenitors.
Science. 254: 1001-3, 1991. [Journal]

2)  Maragos CM, Morley D, Wink DA, Dunams TM, Saavedra JE, Hoffman A, Bove AA, Isaac L, Hrabie JA, Keefer LK.
Complexes of .NO with nucleophiles as agents for the controlled biological release of nitric oxide. Vasorelaxant effects.
J. Med. Chem. 34: 3242-7, 1991. [Journal]

3)  Hrabie JA, Klose JR, Wink DA, Keefer LK.
New nitric oxide-releasing zwitterions derived from polyamines.
Journal of Organic Chemistry. 58: 1472-1476, 1993. [Journal]

4)  Saavedra JE, Billiar TR, Williams DL, Kim YM, Watkins SC, Keefer LK.
Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver.
J. Med. Chem. 40: 1947-54, 1997. [Journal]

5)  Keefer LK, Roller PP.
N-nitrosation by nitrite ion in neutral and basic medium.
Science. 181: 1245-7, 1973. [Journal]

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