Catalytic antioxidants and methods of use

Abstract

The invention provides small molecules that act as catalytic antioxidants and methods of use thereof. The compounds can repeatedly bind and destroy reactive oxygen species by serving as substrates for enzymes of the methionine sulfoxide reductase (Msr) class. Some embodiments of the catalytic antioxidant compounds are derived from drugs with anti-inflammatory activity due to inhibition of cyclooxygenase enzymes.

1 - 2 . (canceled) 
   
   
       3 . A compound having formula 6, or a pharmaceutically acceptable salt thereof; 
     
       
         
         
             
             
         
       
     
     wherein:
 the aromatic ring includes one or more nitrogen atoms; the aromatic carboxyl group is oriented ortho, meta, orpara to the methionine-based moiety; R 1  is CH of either t or S configuration; R 2  is a normal or branched alkyl or fluoroalkyl group having 1 to 6 carbons; R 3  is methyl or ethyl or a fluorinated derivative thereof; R 4  is a hydrogen or a normal or branched alkyl group having 1 to 6 carbons; R 5  is a nitrogen with substituent R 4  as defined herein, an oxygen, or a sulfur; and X is S or Se in any oxidation state. 
 
   
   
       4 . The compound of  claim 3  having formula 6a, or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
   
   
       5 . (canceled) 
   
   
       6 . A compound having formula 7a, or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
   
   
       7 . (canceled) 
   
   
       8 . A compound having formula 8a, or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
   
   
       9 - 13 . (canceled) 
   
   
       14 . A method for reducing, preventing or reversing oxidative damage in a cell, the method comprising the steps of:
 (a) providing a non-naturally occurring compound comprising at least one methyl sulfide or methyl sulfoxide moiety, the compound being a substrate for at least one Msr enzyme;   (b) providing a cell expressing at least one Msr enzyme, said cell comprising or being exposed to reactive oxygen species; and   (c) contacting the cell with an amount of the compound sufficient to reduce, prevent, or reverse oxidative damage in the cell by said reactive oxygen species.   
   
   
       15 . The method of  claim 14 , wherein the cell is within an animal subject. 
   
   
       16 . The method of  claim 14 , wherein the animal subject has a condition or disorder associated with oxidative damage. 
   
   
       17 . The method of  claim 14 , wherein the disorder involves degeneration of a nerve cell. 
   
   
       18 . The method of  claim 14 , wherein the condition is age-related. 
   
   
       19 . A method for extending the lifespan of an animal comprising administering to the animal a therapeutically effective amount of a non-naturally occurring compound according to any one of  claims 3 ,  4 ,  6 , or  8 . 
   
   
       20 . A method of treating a disease related to oxidative damage in a cell consisting essentially of administering to a patient in need thereof, a compound according to any one of  claims 3 ,  4 ,  6 , or  8 , wherein said disease is selected from: smokers, emphysema, reperfusion damage, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ASL), heart attacks and stroke.