Substituted Phenyl Aziridine Precursor Analogs as Modulators of Steroid Receptor Activities

Abstract

Disclosed are methods and pharmaceutical compositions for modulating one or more steroidal receptor activities. The methods typically utilize and the pharmaceutical compositions typically include one or more substituted phenyl aziridine precursors, their respective aziridines, analogs thereof, derivatives thereof, or pharmaceutically acceptable salts thereof such as CpdA. The methods and compositions may be used for treating diseases, disorders, and conditions associated with glucocorticoid receptor activity, androgen receptor activity, or both, such as cancers, acne vulgaris, and alopecia.

1 . A method of inhibiting prostate cancer cell growth in a patient having androgen-independent prostate cancer, the method comprising administering to the patient a therapeutically effective amount of a compound having formula (I), 
     
       
         
         
             
             
         
       
     
     or aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof: wherein R is a hydrogen or —C(O)-Z, and Z is a branched or straight chain C 1 -C 6  alkyl group; 
     X is a hydrogen, hydroxyl, halogen, or a leaving group; and 
     Y is a hydrogen or a branched or straight chain C 1 -C 6  alkyl group. 
   
   
       2 . The method of  claim 1 , wherein R is acetyl. 
   
   
       3 . The method of  claim 1 , wherein X is a halogen. 
   
   
       4 . The method of  claim 3 , wherein the halogen is chloride, bromide, or fluoride. 
   
   
       5 . The method of  claim 1 , wherein Y is methyl, ethyl, propyl, or butyl. 
   
   
       6 . The method of  claim 5 , wherein Y is methyl. 
   
   
       7 . The method of  claim 1 , wherein the compound having formula (I), or aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof is CpdA. 
   
   
       8 . The method of  claim 1 , wherein the compound sensitizes prostate cancer cells to the apoptotic effect of TNF-α. 
   
   
       9 . The method of  claim 1 , wherein the compound sensitizes DU145 to the apoptotic effect of TNF-α. 
   
   
       10 . The method of  claim 1 , wherein the compound binds to glucocorticoid receptor. 
   
   
       11 . The method of  claim 1 , wherein the compound inhibits androgen receptor transcriptional activity in prostate cancer cells. 
   
   
       12 . The method of  claim 1 , wherein the compound inhibits androgen receptor transcriptional activity in LNCaP cells. 
   
   
       13 . A method of sensitizing prostate cancer cells to apoptosis comprising administering:
 (a) an effective amount of a compound having formula (I),   
     
       
         
         
             
             
         
       
       
         or aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof: 
         wherein R is a hydrogen or —C(O)-Z, and Z is a branched or straight chain C 1 -C 6  alkyl group; 
         X is a hydrogen, hydroxyl, halogen, or leaving group; and 
         Y is a hydrogen or a branched or straight chain C 1 -C 6  alkyl group; and 
       
       (b) an effective amount of a pro-apoptotic stimuli. 
     
   
   
       14 . The method of  claim 13 , wherein the compound having formula (I), or aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof is CpdA. 
   
   
       15 . A method of treating prostate cancer in a patient in need thereof comprising:
 (a) assessing expression of a marker selected from the group consisting of hespin, α-methylacyl-CoA racemase, and maspin; and   (b) based on the assessed expression administering an effective amount of a compound having formula (I)   
     
       
         
         
             
             
         
       
       
         or aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof: 
         wherein R is a hydrogen or —C(O)-Z, and Z is a branched or straight chain C 1 -C 6  alkyl group; 
         X is a hydrogen, hydroxyl, halogens or leaving group; and 
         Y is a hydrogen or a branched or straight chain C 1 -C 6  alkyl group. 
       
     
   
   
       16 . The method of  claim 15 , wherein the compound having formula (I), or aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof is CpdA. 
   
   
       17 . A method of treating prostate cancer in a patient in need thereof and assessing the treatment, the method comprising:
 (a) administering an effective amount of a compound having formula (I)   
     
       
         
         
             
             
         
       
       
         or aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof: 
         wherein R is a hydrogen or —C(O)-Z, and Z is a branched or straight chain C 1 -C 6  alkyl group; 
         X is a hydrogen, hydroxyl, halogen, or leaving group; and 
         Y is a hydrogen or a branched or straight chain C 1 -C 6  alkyl group; and 
       
       (b) assessing expression of a marker selected from the group consisting of hespin, α-methylacyl-CoA racemase, and maspin, thereby assessing the therapeutic effect of the compound. 
     
   
   
       18 . A method of treating benign prostate hyperplasia in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound having formula (I) 
     
       
         
         
             
             
         
       
     
     or aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof:
 wherein R is a hydrogen or —C(O)-Z, and Z is a branched or straight chain C 1 -C 6  alkyl group; 
 X is a hydrogen, hydroxyl, halogen, or leaving group; and 
 Y is a branched or straight chain C 1 -C 6  alkyl group. 
 
   
   
       19 . A method of treating acne vulgaris in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound having formula (I) 
     
       
         
         
             
             
         
       
     
     or aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof:
 wherein R is a hydrogen or —C(O)-Z, and Z is a branched or straight chain C 1 -C 6  alkyl group; 
 X is a hydrogen, hydroxyl, halogen, or leaving group; and 
 Y is a hydrogen or a branched or straight chain C 1 -C 6  alkyl group. 
 
   
   
       20 . A method of treating androgenetic alopecia in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound having formula (I) 
     
       
         
         
             
             
         
       
     
     or aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof
 wherein R is a hydrogen or —C(O)-Z, and Z is a branched or straight chain C 1 -C 6  alkyl group; 
 X is a hydrogen, hydroxyl, halogen, or leaving group; and 
 Y is a hydrogen or a branched or straight chain C 1 I-C 6  alkyl group.