Anti-cancer compositions and methods

Abstract

Anti-cancer compositions and methods are described including one or more isothiocyanates and/or isoselenocyanates. Methods of treating a subject are provided according to embodiments of the present invention which include administering a therapeutically effective amount of a composition including an isothiocyanate and/or isoselenocyanate to a subject having a condition characterized by Akt dysregulation. Administering a therapeutically effective amount of a composition including an isothiocyanate and/or isoselenocyanate to a subject detectably increases apoptosis and/or decreases proliferation of cancer cells, particularly cancer cells characterized by Akt dysregulation.

1 . A composition comprising an isoselenocyanate having the structural formula:
 R—(CH 2 ) n —N═C═Se, where n is an integer in the range of 1-8, inclusive, and where R is selected from the group consisting of: an aromatic group and a non-aromatic organic group.   
     
     
         2 . The composition of  claim 1  where the isoselenocyanate has the structural formula: 
       
         
           
           
               
               
           
         
       
       where R′ is a substituted or unsubstituted, branched or straight chain, lower alkyl group, and where n is an integer in the range of 3-8, inclusive. 
     
     
         3 . The composition of  claim 2  wherein R′ is CH 3 . 
     
     
         4 . The composition of  claim 2 , where R′ is CH 3  and n is 4. 
     
     
         5 . A method for synthesis of an isoselenocyanate having the structural formula: R—(CH 2 ) n —N═C═Se, where n is an integer in the range of 1-8, inclusive, and where R is selected from the group consisting of: an unsubstituted aromatic group; an aromatic group substituted by one or more substituents selected from the group consisting of: F, Cl, Br, a lower alkyl group, a lower alkoxy group and a fluorinated lower alkyl group; R′—S(O), where R′ is a lower alkyl group, which may be substituted or unsubstituted, branched or straight chain; and CH 2 ═CH, comprising:
 formylation of a starting alkylamine compound having the structural formula: R—(CH 2 ) n —NH 2 , where n is an integer in the range of 1-8, inclusive, where R is selected from the group consisting of: an unsubstituted aromatic group; an aromatic group substituted by one or more substituents selected from the group consisting of: F, Cl, Br, a lower alkyl group, a lower alkoxy group and a fluorinated lower alkyl group; R′—S(O), where R′ is a lower alkyl group, which may be substituted or unsubstituted, branched or straight chain, to produce a formylated intermediate having the structural formula: R—(CH 2 ) n —NHCHO, where n and R are identical to R and n of the starting alkylamine;   contacting the formylated intermediate with triphosgene and selenium powder in the presence of triethylannine.   
     
     
         6 . The method of  claim 5 , wherein the formylated intermediate is contacted with triphosgene and selenium powder in the presence of triethylanine and in the presence of a solvent. 
     
     
         7 . A pharmaceutical composition, comprising:
 a compound having the structural formula:
 R—(CH 2 ) n —N═C═X, where n is an integer in the range of 1-8, inclusive, where X is S or Se, and where R is selected from the group consisting of: an aromatic group and a non-aromatic organic group. 
   
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the compound is selected from the group consisting of: a phenylalkyl isothiocyanate, a phenylalkyl isoselenocyanate, and a combination thereof. 
     
     
         9 . The pharmaceutical composition of  claim 7 , wherein the compound is an isoselenocyanate having the structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       where n is 4 or 6;
 and 
 
       
         
           
           
               
               
           
         
       
       where R′ is a substituted or unsubstituted, branched or straight chain, lower alkyl group, and where n is an integer in the range of 1-8, inclusive; and
 a pharmaceutically acceptable carrier. 
 
     
     
         10 . The composition of  claim 7 , further comprising a pharmaceutically acceptable carrier. 
     
     
         11 . The composition of  claim 7 , wherein the pharmaceutical composition is formulated for topical application. 
     
     
         12 . A method of treating a subject, comprising:
 administering a therapeutically effective amount of a composition comprising a compound having the structural formula:   R—(CH 2 ) n —N═C═X, where n is an integer in the range of 1-8, inclusive, where X is S or Se, and where R is selected from the group consisting of: an aromatic group and a non-aromatic organic group to a subject in need thereof.   
     
     
         13 . The method of  claim 12 , wherein the composition comprises a compound having the structural formula:
 phenyl-(CH 2 ) n —N═C═X, where n is an integer in the range of 1-8, inclusive, where X is S or Se.   
     
     
         14 . The method of  claim 12 , wherein the composition comprises an isoselenocyanate having the structural formula: 
       
         
           
           
               
               
           
         
       
       where R′ is a substituted or unsubstituted, branched or straight chain, lower alkyl group, and where n is an integer in the range of 3-8, inclusive. 
     
     
         15 . The method of  claim 14  wherein R′ is CH 3 . 
     
     
         16 . The method of  claim 12 , wherein the composition comprises a phenylalkyl isoselenocyanate having the structural formula: 
       
         
           
           
               
               
           
         
       
       where n is 4 or 6. 
     
     
         17 . The method of  claim 12  wherein the isoselenocyanate is selected from the group consisting of: an isoselenocyanate glutathione conjugate; an isoselenocyanate cysteine conjugate; and an isoselenocyanate N-acetylcysteine conjugate. 
     
     
         18 . The method of  claim 12  wherein the subject is human. 
     
     
         19 . The method of  claim 12  wherein the subject has or is at risk of having cancer. 
     
     
         20 . The method of  claim 19  wherein the cancer is a melanoma. 
     
     
         21 . The method of  claim 12  wherein the composition is formulated for topical application. 
     
     
         22 . The method of  claim 19  wherein the cancer is characterized by dysregulation of Akt. 
     
     
         23 . The method of  claim 19  wherein the cancer is characterized by dysregulation of Akt3. 
     
     
         24 . The method of  claim 19 , wherein administering the therapeutically effective amount of the composition to a subject detectably increases apoptosis and/or decreases proliferation of cells of the cancer. 
     
     
         25 . The method of  claim 19 , further comprising administration of an adjunct anti-cancer treatment. 
     
     
         26 . A method of modulating Akt dysregulation in a cell, comprising:
 contacting the cell with an effective amount of an isoselenocyanate having the structural formula: R—(CH 2 ) n —N═C═Se, where n is an integer in the range of 1-8, inclusive, and where R is selected from the group consisting of: an aromatic group and a non-aromatic organic group.   
     
     
         27 . The method of  claim 26  wherein contacting the cell decreases a component of an Akt signaling pathway selected from the group consisting of: an Akt1 signaling pathway; an Akt2 signaling pathway; an Akt3 signaling pathway; and a combination thereof.