Substituted Phenyl Aziridine Precursor Analogs for Inhibiting Androgen-Independent Cancer Cell Growth

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 .- 6 . (canceled) 
     
     
         7 . The method of  claim 25 , wherein the compound is 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride. 
     
     
         8 . The method of  claim 25 , wherein the compound sensitizes prostate cancer cells to the apoptotic effect of TNF-α. 
     
     
         9 . The method of  claim 25 , wherein the compound sensitizes DU145 to the apoptotic effect of TNF-α. 
     
     
         10 . The method of  claim 25 , wherein the compound binds to a glucocorticoid receptor. 
     
     
         11 .- 20 . (canceled) 
     
     
         21 . The method of  claim 25 , further comprising administering an effective amount of a pro-apoptotic stimuli. 
     
     
         22 . The method of  claim 21 , wherein the pro-apoptotic stimuli is selected from a group consisting of lonidamine, arsenite, PK 11195, LY294002, STI-571, PS-341, UCN-01, and flavopiridol. 
     
     
         23 . The method of  claim 25 , further comprising assessing expression of a marker selected from the group consisting of hespin, α-methylacyl-CoA racemase, and maspin in the patient prior to administering to the patient the therapeutically effective amount of the compound. 
     
     
         24 . The method of  claim 25 , further comprising assessing expression of a marker selected from the group consisting of hespin, α-methylacyl-CoA racemase, and maspin in the patient after administering to the patient the therapeutically effective amount of the compound. 
     
     
         25 . 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 or a pharmaceutically acceptable salt thereof, the compound having a formula: 
       
         
           
           
               
               
           
         
         wherein R is hydrogen or —C(O)—CH 3 , and X is a hydrogen or halogen. 
       
     
     
         26 . 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 or a pharmaceutically acceptable salt thereof, the compound having a formula: 
       
         
           
           
               
               
           
         
         wherein R is hydrogen or —C(O)—CH 3 , and X is a hydrogen or halogen. 
       
     
     
         27 . The method of  claim 26 , wherein the compound sensitizes prostate cancer cells to the apoptotic effect of TNF-α. 
     
     
         28 . The method of  claim 26 , wherein the compound sensitizes DU145 to the apoptotic effect of TNF-α. 
     
     
         29 . The method of  claim 26 , wherein the compound binds to glucocorticoid receptor. 
     
     
         30 . The method of  claim 26 , further comprising administering an effective amount of a pro-apoptotic stimuli. 
     
     
         31 . The method of  claim 30 , wherein the pro-apoptotic stimuli is selected from a group consisting of lonidamine, arsenite, PK 11195, LY294002, STI-571, PS-341, UCN-01, and flavopiridol. 
     
     
         32 . The method of  claim 26 , further comprising assessing expression of a marker selected from the group consisting of hespin, α-methylacyl-CoA racemase, and maspin in the patient prior to administering to the patient the therapeutically effective amount of the compound. 
     
     
         33 . The method of  claim 26 , further comprising assessing expression of a marker selected from the group consisting of hespin, α-methylacyl-CoA racemase, and maspin in the patient after administering to the patient the therapeutically effective amount of the compound. 
     
     
         34 . 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 or a pharmaceutically acceptable salt thereof, the compound having a formula: 
       
         
           
           
               
               
           
         
         wherein R is hydrogen or —C(O)—CH 3 .