Smmr (small molecule metabolite reporters) for use as in vivo glucose biosensors

Abstract

Small Molecule Metabolite Reporters (SMMRs) for use as in vivo glucose biosensors, sensor compositions, and methods of use, are described. The SMMRs include boronic acid-containing xanthene, coumarin, carbostyril and phenalene-based small molecules which are used for monitoring glucose in vivo, advantageously on the skin.

1 . A small molecule metabolite reporter compound of the following formula: 
       
         
           
           
               
               
           
         
         wherein
 D is a heteroatom; 
 R 1  and R 2  are different and are selected from the group consisting of H, OH, NH 2 , NO 2 , OCH 3 , N(CH 3 ) 2 , A, or, R 1  and R 2 , taken together with the ring to which they are attached, form R 7 ; 
 R 3  and R 4  are different and are selected from the group consisting of H, 
 
       
       
         
           
           
               
               
           
         
         
            OH, B(OH) 2 , M, or R 3  and R 4 , taken together with the ring to which they are attached, form R 8 ; 
           R 5  and R 6  are different and are selected from the group consisting of H or 
         
       
       
         
           
           
               
               
           
         
         
            wherein Q is H, COOH, B(OH) 2 , or M; 
           A is OH, NH 3 , 
         
       
       
         
           
           
               
               
           
         
         
           R 7  is 
         
       
       
         
           
           
               
               
           
         
         
           R 8  is 
         
       
       
         
           
           
               
               
           
         
         
           M is 
         
       
       
         
           
           
               
               
           
         
         
           L, when present, is an amino-containing linking moiety; 
           R 1  and R 2 , and R 3  and R 4 , are adjacent to each other on the rings on which they reside; and 
           at least one boronic acid moiety is present; and salts thereof. 
         
       
     
     
         2 . The reporter compound of  claim 1 , wherein D is N or O. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . A small molecule metabolite reporter compound of the following formula: 
       
         
           
           
               
               
           
         
         M is 
       
       
         
           
           
               
               
           
         
          and 
         L, when present, is an amino-containing linking moiety; and salts thereof. 
       
     
     
         6 . (canceled) 
     
     
         7 . A topical sensor composition comprising a compound of  claim 1  and a carrier or binder. 
     
     
         8 . A method of measuring a compound or metabolite thereof, comprising contacting a reporter compound of the following formula: 
       
         
           
           
               
               
           
         
         wherein
 D is a heteroatom; 
 R 1  and R 2  are different and are selected from the group consisting of H, OH, NH 2 , NO 2 , OCH 3 , N(CH 3 ) 2 , A, or, R 1  and R 2 , taken together with the ring to which they are attached, form R 7 ; 
 R 3  and R 4  are different and are selected from the group consisting of H,  , OH, B(OH) 2 , M, or R 3  and R 4 , taken together with the ring to which they are attached, form R 8 ; 
 R 5  and R 6  are different and are selected from the group consisting of H or 
 
       
       
         
           
           
               
               
           
         
         
            wherein Q is H, COOH, B(OH) 2 , or M; 
           A is OH, NH 3 , 
         
       
       
         
           
           
               
               
           
         
         
           R 7  is 
         
       
       
         
           
           
               
               
           
         
         
           R 8  is 
         
       
       
         
           
           
               
               
           
         
         
           M is 
         
       
       
         
           
           
               
               
           
         
         
           L, when present, is an amino-containing linking moiety; and 
           R 1  and R 2 , and R 3  and R 4 , are adjacent to each other on the rings on which they reside; and 
           at least one boronic acid moiety is present; and salts thereof; which reporter compound is sensitive to the presence of said compound or metabolite thereof, with an area of the body where said metabolites may be found, and detecting a photometric change in said reporter compound indicative of said metabolite. 
         
       
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 8 , wherein said area of the body is skin. 
     
     
         12 . The method of  claim 8 , wherein said area of the body is the layer of the skin known as stratum corneum. 
     
     
         13 . The method of  claim 8 , wherein said area of the body is the layer of the skin known as epidermis. 
     
     
         14 . The method of  claim 8 , wherein said area of the body is the layer of the skin known as dermis. 
     
     
         15 . The method of  claim 8 , wherein said compound is glucose.