Aldolase-inhibiting aromatic compounds

Abstract

The invention relates to novel aldolase-inhibiting compounds that can be advantageously used as medicaments (in therapeutic doses), especially for treating certain cancers, due to the inhibition efficacy thereof. An inventive compound corresponds to general formula (I) wherein the aldehyde group (—CHO) and the phenol group (—OH) are linked to two carbon atoms adjacent to the same aromatic chain, i.e., the first aromatic chain, and R is a phosphate group or a phosphate group mimetic linked to a carbon atom of the second aromatic chain.

1 . A method of inhibiting an extracellular or intracellular aldolase, other than an intracellular aldolase of non-isolated living cells from a human or animal body, or a human embryo, said method comprising contacting said aldolase with an aromatic compound comprising an aldehyde group, a phenol group, and a phosphate group or a mimetic thereof, wherein:
 the aromatic nucleus of said aromatic compound comprises two aromatic benzene chains,   said aromatic compound having a structure according to the following general formula:   
     
       
         
         
             
             
         
       
     
     where:
 the aldehyde group (—CHO) and the phenol group (—OH) are linked to two adjacent carbon atoms from the same aromatic chain, known as the first aromatic chain, 
 and linked to a carbon atom in a second aromatic chain is R, wherein R is a phosphate group or a phosphate group mimetic selected from the group consisting of:
 an enzymolabile protecting group adapted to allow said aromatic compound to pass through a cell and/or parasite membrane system passively, and to be able to generate, once inside the cell or parasite, the formation of a phosphate group or a stable phosphate group analogue; and 
 a stable phosphate group analogue adapted to prevent spontaneous or enzyme-mediated dephosphorylation of the aromatic compound; and 
 
 
     wherein said contacting is with an amount of said aromatic compound sufficient to inhibit said aldolase. 
   
   
       2 . A method of treating cancer, said method comprising contacting an extracellular or intracellular aldolase in a patient having cancer with an aromatic compound comprising an aldehyde group, a phenol group, and a phosphate group or a mimetic thereof, wherein:
 the aromatic nucleus of said aromatic compound comprises two aromatic benzene chains,   said aromatic compound having a structure according to the following general formula:   
     
       
         
         
             
             
         
       
     
     where:
 the aldehyde group (—CHO) and the phenol group (—OH) are linked to two adjacent carbon atoms from the same aromatic chain, known as the first aromatic chain, 
 and linked to a carbon atom in a second aromatic chain is R, wherein R is a phosphate group or a phosphate group mimetic selected from the group consisting of:
 an enzymolabile protecting group adapted to allow said aromatic compound to pass through a cell and/or parasite membrane system passively, and to be able to generate, once inside the cell or parasite, the formation of a phosphate group or a stable phosphate group analogue; and 
 a stable phosphate group analogue adapted to prevent spontaneous or enzyme-mediated dephosphorylation of the aromatic compound; and 
 
 
     wherein said contacting is with an amount of said aromatic compound sufficient to inhibit said aldolase in said patient. 
   
   
       3 . The method of  claim 1  or  2 , wherein said aromatic compound has the general formula: 
     
       
         
         
             
             
         
       
     
     where R 1  is a phosphate group or a phosphate group mimetic. 
   
   
       4 . The method of  claim 1  or  2 , wherein said enzymolabile protecting group is a group capable of being deprotected by one or more intracellular esterases. 
   
   
       5 . The method of  claim 4 , wherein the enzymolabile protecting group has the following general formula: 
     
       
         
         
             
             
         
       
     
     where R′ is selected from group (IV) or group (V) shown below: 
     
       
         
         
             
             
         
       
     
   
   
       6 . The method of  claim 4 , wherein the enzymolabile protecting group has the following general formula: 
     
       
         
         
             
             
         
       
     
     where R″ is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       7 . The method of  claim 4 , wherein the enzymolabile protecting group has the following general formula: 
     
       
         
         
             
             
         
       
     
     where R′″ is: 
     
       
         
         
             
             
         
       
     
   
   
       8 . The method of  claim 1  or  2 , wherein the stable phosphate group analogue is selected from the group consisting of:
 methylenephosphonate;   difluoromethylenephosphonate; and   monofluoromethylenephosphonate.   
   
   
       9 . The method of  claim 1  or  2 , wherein, in said aromatic compound, a hydrogen atom from at least one carbon atom from at least one of said first or said second aromatic chains is substituted by a hydrophobic substituent, said hydrophobic substituent being adapted to improve the global hydrophobicity of the aromatic compound. 
   
   
       10 . The method of  claim 9 , wherein the hydrophobic substituent is one of the alkyl groups of the principal chain comprising a maximum of three carbon atoms. 
   
   
       11 . The method of  claim 1  or  2 , wherein said aromatic compound inhibits class I aldolase activity. 
   
   
       12 . The method of  claim 11 , wherein said aromatic compound inhibits class I aldolase activity with an inhibition constant K i  of less than 25 μM. 
   
   
       13 . The method of  claim 12 , wherein said K i  is less than 50 nM. 
   
   
       14 . The method of  claim 12 , wherein said K i  is about 25 nM. 
   
   
       15 . The method of  claim 1 , said aromatic compound inhibits at least one aldolase irreversibly or virtually irreversibly. 
   
   
       16 . The method of  claim 2 , wherein said inhibiting extracellular or intracellular aldolases inhibits glycolysis in a cell. 
   
   
       17 . The method of  claim 2 , wherein said method further comprises administering glycerol to said patient.