Prodrugs of Short-Chain Fatty Acids and Treatment Methods

Abstract

Prodrugs made up of biologically-active short-chain fatty acids or derivatives thereof conjugated to neutral or cationic amino acids capable of intracellular transport by ATB 0 , + are provided. The short-chain fatty acid or derivative thereof can be attached to the amino acid through a hydroxyl group of the amino acid to form a fatty acid ester of the amino acid, or it can be attached through the amino group of the amino acid to form a fatty-acid amide of the amino acid. Serine butyrate (O-butyryl serine) is a preferred prodrug. These prodrugs are useful for treatment of colon cancer, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lung cancer, cervical cancer, and cancers resulting from metastases from primary colon cancer sites. Methods of delivering biologically-active short-chain fatty acids or derivatives thereof to cells in need of these molecules and methods of treating diseases using the prodrugs of this invention are also provided.

1 . A prodrug of a biologically active anticancer drug, short-chain fatty acid or derivative thereof, wherein:
 said prodrug is capable of intracellular transport by ATB 0,+ ; and   said prodrug comprises an amino acid or derivative thereof capable of intracellular transport by ATB 0,+  attached to said anticancer drug, short-chain fatty acid or derivative thereof;   and pharmaceutically acceptable salts of said prodrug.   
     
     
         2 . The prodrug of  claim 1  wherein said short-chain fatty acid or derivative thereof is selected from the group consisting of acetate, propionate, pyruvate, and butyrate. 
     
     
         3 . The prodrug of  claim 1  wherein said prodrug is a prodrug of butyrate. 
     
     
         4 . The prodrug of  claim 1  wherein said prodrug is a prodrug of pyruvate. 
     
     
         5 . The prodrug of  claim 1  wherein said prodrug is a prodrug of 3-bromopyruvate. 
     
     
         6 . The prodrug of  claim 1  wherein said prodrug is a prodrug of an anticancer drug. 
     
     
         7 . The prodrug of  claim 6  wherein said anticancer drug is a nucleoside drug conjugated to an amino acid. 
     
     
         8 . The prodrug of  claim 1  wherein said amino acid is selected from the group consisting neutral and cationic L- and D-amino acids. 
     
     
         9 . The prodrug of  claim 1  wherein said amino acid is selected from the group consisting of the L-enantiomers of alanine, serine, methionine, leucine, tryptophan, threonine, histidine, phenylalanine, glutamine, asparagine, lysine, arginine, valine and isoleucine and the D-enantiomers of alanine, serine, methionine, leucine, and tryptophan. 
     
     
         10 . The prodrug of  claim 1  wherein said amino acid is selected from the group consisting of the L-enantiomers of serine, threonine and tyrosine. 
     
     
         11 . The prodrug of  claim 1  wherein said short-chain fatty acid or derivative thereof is attached to said amino acid through a hydroxyl group of said amino acid to form a fatty acid ester of said amino acid. 
     
     
         12 . The prodrug of  claim 1  which is serine butyrate. 
     
     
         13 . The prodrug of  claim 1  wherein said amino acid is a modified amino acid modified to comprise a hydroxyl group, and said short-chain fatty acid or derivative thereof is attached to said modified amino acid through said hydroxyl group to form a fatty acid ester of said modified amino acid. 
     
     
         14 . The prodrug of  claim 1  wherein said short-chain fatty acid or derivative thereof is attached to said amino acid through the amino group of said amino acid to form a fatty acid amide of said amino acid. 
     
     
         15 . The prodrug of  claim 1  in a pharmaceutically acceptable carrier. 
     
     
         16 . The prodrug of  claim 15  wherein said pharmaceutically acceptable carrier is selected from the group consisting of an oral delivery carrier, a suppository delivery carrier, an intravenous delivery carrier, and an aerosol carrier. 
     
     
         17 . A method for treating a disease condition characterized by upregulation of ATB O,+  comprising administering to a patient having said disease a therapeutically effective amount of a prodrug of a biologically active anticancer drug, short-chain fatty acid or derivative thereof, and pharmaceutically acceptable salts of said prodrug, wherein:
 said prodrug is capable of intracellular transport by ATB 0,+ ; and   said prodrug comprises an amino acid or derivative thereof capable of intracellular transport by ATB 0,+  attached to said anticancer drug, short-chain fatty acid or derivative thereof.   
     
     
         18 . The method of  claim 17  wherein said disease condition is characterized by downregulation of SLC5A8. 
     
     
         19 . The method of  claim 17  wherein said disease condition is selected from the group consisting of colon cancer, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lung cancer, cervical cancer, and cancers resulting from metastases from primary colon cancer sites. 
     
     
         20 . The method of  claim 17  wherein said disease condition is colon cancer. 
     
     
         21 . The method of  claim 17  wherein said prodrug comprises a short-chain fatty acid conjugated to an amino acid. 
     
     
         22 . The method of  claim 21  wherein the prodrug is an amino acid butyrate. 
     
     
         23 . The method of  claim 22  wherein the prodrug is serine butyrate. 
     
     
         24 . The method of  claim 23  wherein the prodrug is an amino acid pyruvate. 
     
     
         25 . The method of  claim 17  wherein said prodrug comprises an anticancer drug conjugated to an amino acid. 
     
     
         26 . The method of  claim 17  wherein said prodrug is administered in a pharmaceutically acceptable carrier selected from the group consisting of an oral delivery carrier, a suppository delivery carrier, an intravenous delivery carrier, and an aerosol carrier. 
     
     
         27 . A method for delivering a biologically-active short-chain fatty acid or derivative thereof to a patient in which the short-chain fatty acid or derivative thereof can exhibit biological activity comprising:
 attaching a fatty acid or derivative thereof to an amino acid capable of being transported by ATB 0,+  to form a prodrug of a biologically active short-chain fatty acid or derivative thereof, wherein:
 said prodrug is capable of intracellular transport by ATB 0,+ ; and 
 said prodrug comprises an amino acid or derivative thereof capable of intracellular transport by ATB 0,+  attached to said short-chain fatty acid or derivative thereof; and 
   administering an effective amount of said prodrug and pharmaceutically acceptable salts of said prodrug to said patient.   
     
     
         28 . The method of  claim 27  wherein said prodrug is an amino acid acetate, serine butyrate, serine pyruvate or serine propionate. 
     
     
         29 . The method of  claim 28  wherein said prodrug is serine acetate, serine butyrate, serine pyruvate or serine propionate. 
     
     
         30 . A method for targeting a biologically-active short-chain fatty acid or derivative thereof to cancer cells in a patient in which the short-chain fatty acid or derivative thereof can exhibit biological activity comprising:
 attaching fatty acid or derivative thereof to an amino acid capable of being transported by ATB 0,+  to form a prodrug of  claim 1 ; and   administering an effective amount of said prodrug to said patient.   
     
     
         31 . The method of  claim 30  wherein said prodrug is an amino acid butyrate or an amino acid pyruvate. 
     
     
         32 . The method of  claim 31  wherein said prodrug is serine butyrate or serine pyruvate.