Novel aminoglycosides and uses thereof in the treatment of genetic disorders

Abstract

A new class of paromomycin-derived aminoglycosides, which exhibit efficient stop-codon mutation suppression activity, low toxicity and high selectivity towards eukaryotic cells are provided. Also provided are chemical and chemo-enzymatic processes of preparing these paromomycin-derived aminoglycosides and intermediates thereof, as well as pharmaceutical compositions containing the same, and uses thereof in the treatment of genetic disorders.

What is claimed is: 
     
         1 . A compound having a general Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein:
 each of R 1 , R 2  and R 3  is independently a monosaccharide moiety, halide, hydroxyl, amine or an oligosaccharide moiety, 
 X is oxygen or sulfur; 
 R 4  is hydrogen or (S)-4-amino-2-hydroxybutyryl (AHB); 
 R 5  is hydroxyl or amine; 
 Y is hydrogen, alkyl or aryl; 
 the dashed line indicates an R configuration or an S configuration; 
 with the proviso that the compound is not selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         amikacin, apramycin, arbekacin, butirosin, dibekacin, fortimycin, G-418, gentamicin, hygromycin, habekacin, dibekacin, netlmicin, istamycin, isepamycin, kanamycin, lividomycin, neamine, neomycin, paromomycin, ribostamycin, sisomycin, spectinomycin, streptomycin and tobramycin. 
       
     
     
         2 . The compound of  claim 1 , being: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound having a general Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein:
 each of R 1 , R 2  and R 3  is independently a monosaccharide moiety, halide, hydroxyl, amine or an oligosaccharide moiety, 
 X is oxygen or sulfur; 
 R 4  is (S)-4-amino-2-hydroxybutyryl (AHB); 
 R 5  is hydroxyl or amine; 
 Y is hydrogen, alkyl or aryl; 
 the dashed line indicates an R configuration or an S configuration; 
 with the proviso that the compound is not selected from the group consisting of amikacin, arbekacin, butirosin, and isepamycin. 
 
     
     
         4 . The compound of  claim 3 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein X is oxygen. 
     
     
         6 . The compound of  claim 1 , wherein R 5  is hydroxyl. 
     
     
         7 . The compound of  claim 1 , wherein Y is hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein at least one of R 1 , R 2  and R 3  is a monosaccharide moiety. 
     
     
         9 . The compound of  claim 1 , wherein said monosaccharide moiety has the general Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         the dashed line indicates an R configuration or an S configuration; and 
         each of R 6 , R 7  and R 8  is independently selected from the group consisting of hydroxyl and amine. 
       
     
     
         10 . The compound of  claim 1 , wherein at least one of R 1 , R 2  and R 3  is an oligosaccharide moiety. 
     
     
         11 . The compound of  claim 10 , wherein said oligosaccharide moiety is a disaccharide moiety. 
     
     
         12 . The compound of  claim 11 , wherein said disaccharide moiety has the general Formula I*: 
       
         
           
           
               
               
           
         
         wherein:
 the dashed line indicates an R configuration or an S configuration; 
 each of R* 1 , R* 2  and R* 3  is independently a halide, hydroxyl, amine is linked to the compound having the general Formula I, whereas at least one of R* 1 , R* 2  and R* 3  is linked to the compound having the general Formula I above; 
 X* is oxygen or sulfur; 
 R* 4  is hydrogen or an (S)-4-amino-2-hydroxybutyryl (AHB) moiety; 
 R* 5  is hydroxyl or amine; and 
 Y* is hydrogen, alkyl or aryl. 
 
       
     
     
         13 . The compound of  claim 1 , wherein R 4  and Y are each hydrogen. 
     
     
         14 . The compound of  claim 1 , wherein R 5  is selected from the group consisting of hydroxyl and amine and Y is alkyl. 
     
     
         15 . The compound of  claim 3 , wherein R 5  is selected from the group consisting of hydroxyl and amine and Y is alkyl. 
     
     
         16 . The compound of  claim 1 , having selective activity towards eukaryotic cells over prokaryotic cells. 
     
     
         17 . The compound of  claim 16 , having no antibacterial activity. 
     
     
         18 . The compound of  claim 3 , having selective activity towards eukaryotic cells over prokaryotic cells. 
     
     
         19 . The compound of  claim 18 , having no antibacterial activity. 
     
     
         20 . A pharmaceutical composition comprising a compound having a general Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein:
 each of R 1 , R 2  and R 3  is independently a monosaccharide moiety, halide, hydroxyl, amine or an oligosaccharide moiety, 
 X is oxygen or sulfur; 
 R 4  is hydrogen or (S)-4-amino-2-hydroxybutyryl (AHB); 
 R 5  is hydroxyl or amine; 
 Y is hydrogen, alkyl or aryl; 
 the dashed line indicates an R configuration or an S configuration, and a pharmaceutically acceptable carrier, 
 with the proviso that the compound is not selected from the group consisting of amikacin, apramycin, arbekacin, butirosin, dibekacin, fortimycin, G-418, gentamicin, hygromycin, habekacin, dibekacin, netlmicin, istamycin, isepamycin, kanamycin, lividomycin, neamine, neomycin, paromomycin, ribostamycin, sisomycin, spectinomycin, streptomycin and tobramycin. 
 
     
     
         21 . The composition of  claim 20 , being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a genetic disorder. 
     
     
         22 . The composition of  claim 20 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The composition of  claim 20 , being formulated for oral administration. 
     
     
         24 . The composition of  claim 21 , wherein said genetic disorder comprises a protein having a truncation mutation. 
     
     
         25 . A method of treating a genetic disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a general Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
       
       wherein:
 each of R 1 , R 2  and R 3  is independently a monosaccharide moiety, halide, hydroxyl, amine or an oligosaccharide moiety, 
 X is oxygen or sulfur; 
 R 4  is hydrogen or (S)-4-amino-2-hydroxybutyryl (AHB); 
 R 5  is hydroxyl or amine; and 
 Y is hydrogen, alkyl or aryl; 
 the dashed line indicates an R configuration or an S configuration; 
 with the proviso that the compound is not selected from the group consisting of amikacin, apramycin, arbekacin, butirosin, dibekacin, fortimycin, G-418, gentamicin, hygromycin, habekacin, dibekacin, netlmicin, istamycin, isepamycin, kanamycin, lividomycin, neamine, neomycin, paromomycin, ribostamycin, sisomycin, spectinomycin, streptomycin and tobramycin. 
 
     
     
         26 . The method of  claim 25 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 25 , wherein said administering is effected orally. 
     
     
         28 . The method of  claim 25 , wherein the genetic disorder comprises a protein having a truncation mutation.