Histone deacetylase inhibitors

Abstract

Histone deacetylase is a metallo-enzyme with zinc at the active site. Compounds having a zinc-binding moiety, such as, for example, a hydroxamic acid group or a carboxylic acid group, can inhibit histone deacetylase. Histone deacetylase inhibition can repress gene expression, including expression of genes related to tumor suppression. Accordingly, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, e.g., hemoglobinopathies, and genetic related metabolic disorders, e.g., cystic fibrosis and adrenoleukodystrophy.

What is claimed is:  
     
         1 . A method of inhibiting histone deacetylase in cells comprising contacting the cells with an effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 A is phenyl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, or amino;  
 each of Y 1  and Y 2 , independently, is —CH 2 —, —O—, —S—, —N(R c )—, or a bond; where R c  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl;  
 L is a straight C 2-12  hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond; said hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, amino, nitro, cyano, C 3-5  cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, C 1-4  alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R e )—, —N(R e )—C(O)—O—, —O—C(O)—N(R e )—, —N(R e )—C(O)—N(R f )—, or —O—C(O)—O—; each of R e  and R f , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl;  
 X 1  is O or S; and  
 X 2  is —OR 1 , —SR 1 , —NR 3 —OR 1 , —NR 3 —SR 1 , —C(O)—OR 1 , —CHR 4 —OR 1 , —N═N—C(O)—N(R 3 ) 2 , or —O—CHR 4 —O—C(O)—R 5 ; where each of R 1 and R   2 , independently, is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group; R 3  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; R 4  is hydrogen, alkyl, hydroxylalkyl, or haloalkyl; R 5  is alkyl, hydroxylalkyl, or haloalkyl; and provided that when L is a C 2-3  hydrocarbon containing no double bonds and X 2  is —OR 1 , Y 1  is not a bond and Y 2  is not a bond;  
 or a salt thereof; and  
 determining whether the level of acetylated histones in the treated cells is higher than in untreated cells under the same conditions.  
 
     
     
         2 . The method of  claim 1 , wherein L is a saturated C 3-8  hydrocarbon chain substituted with C 1-2  alkyl, C 1-2  alkoxy, hydroxyl, —NH 2 , —NH(C 1-2  alkyl), or —N(C 1-2  alkyl) 2 .  
     
     
         3 . The method of  claim 2 , wherein X 1  is O; X 2  is —OR 1 , —NR 3 —OR 1 , —C(O)OR 1 , or —O—CHR 4 —O—C(O)—R 5 ; and each of Y 1  and Y 2 , independently, is —CH 2 —, —O—, —N(R a )—, or a bond.  
     
     
         4 . The method of  claim 1 , wherein L is an unsaturated C 4-8  hydrocarbon chain containing only double bonds, said unsaturated hydrocarbon chain optionally substituted with C 1-2  alkyl, C 1-2  alkoxy, hydroxyl, —NH 2 , —NH(C 1-2  alkyl), or —N(C 1-2  alkyl) 2 .  
     
     
         5 . The method of  claim 4 , wherein X 1  is O; X 2  is —OR 1 , —NR 3 —OR 1 , —C(O)OR 1 , or —O—CHR 4 —O—C(O)—R 5 ; and each of Y 1  and Y 2 , independently, is —CH 2 —, —O—, —N(R c )—, or a bond.  
     
     
         6 . The method of  claim 1 , wherein L is an unsaturated hydrocarbon chain containing at least one double bond and one triple bond, optionally substituted with C 1-2  alkyl, C 1-2  alkoxy, hydroxyl, —NH 2 , —NH(C 1-2  alkyl), or —N(C 1-2  alkyl) 2 .  
     
     
         7 . The method of  claim 6 , wherein X 1  is O; X 2  is —OR 1 , —NR 3 —OR 1 , —C(O)OR 1 , or —O—CHR 4 —O—C(O)—R 5 ; and each of Y 1  and Y 2 , independently, is —CH 2 —, —O—, —N(R c )—, or a bond.