Using Glutathione Transferase to Generate Nitric Oxide in MDR Breast Tumors
Final rept. 15 Aug 2004-14 Aug 2005
MARYLAND UNIV BALTIMORE COUNTY BALTIMORE MD
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The objective of the proposed research is to develop a novel class of prodrugs for delivering nitric oxide into multidrug resistant MDR tumors overexpressing the pi isoform of glutathione transferase GSTP1-1. The MDR phenotype is due, in part, to the overexpression of the pi isozyme of glutathione GSH-transferase GSTP1-1, which catalyzes the addition of GSH to electrophilic antitumor agents followed by the active export of the conjugate from tumor cells. Two recent observations suggest a novel strategy for overcoming the MDR phenotype. The first is the discovery that GSTP1-1 catalyzes the Michael addition of GSH to 2-crtonyloxymethyl-2-cyclohexenone COMC6 causing the displacement of crotonic acid. The second is the recent finding that nitric oxide has the ability to cause tumors to undergo differentiation and apoptosis. We will take advantage of these two observations by synthesizing a new class of 2-dialkyloxymethyldiazene- 2-cyclohexenone DOC6 derivatives, which will undergo a GSTP1-1-catalyzed addition of GSH resulting in the displacement of dialklydiazeniumdiolate salts by a mechanism analogous to that for the GSTP-1-catalyzed displacement of crotonate from COMC6. Since the dialkyldiazeniumdiolate salts are known to spontaneously decompose to nitric oxide under neutral conditions, DOC6 should selectively deliver high concentrations of nitric oxide to MDR tumors overexpressing GSTP1-1.
- Medicine and Medical Research
- Inorganic Chemistry