Compositions and methods comprising osmium for the treatment of cancers

Abstract

Compositions and methods comprising osmium are provided. In some embodiments, the osmium compounds comprise a bidentate ligand. In some embodiments, the osmium compounds are used in method for treating cancer.

What is claimed is: 
     
         1 . A compound comprising Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 4   X 5  is a bidentate ligand, wherein X 4  and X 5  are the same or different and are selected from the group consisting of N, O, S, and P; 
 X 1 , X 2 , and X 3  are the same or different and are selected from the group consisting of halo, —CN, —OR′, —OCN, —SeCN, —SR′, —SCN, —OCOR′, —OSO 2 , and —OPO 31 3 R′ 2 ; and 
 each R′ is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl. 
 
     
     
         2 . The compound of any preceding claim, wherein X 4  and X 5  are N. 
     
     
         3 . The compound of any preceding claim, wherein X 4  and X 5  are O. 
     
     
         4 . The compound of any preceding claim, wherein X 4  and X 5  are S. 
     
     
         5 . The compound of any preceding claim, wherein X 4  and X 5  are P. 
     
     
         6 . The compound of any preceding claim, wherein the compound of Formula I comprises Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 N N is a bidentate ligand; 
 X 1 , X 2 , and X 3  are the same or different and are selected from the group consisting of halo, —CN, —OR′, —OCN, —SeCN, —SR′, —SCN, —OCOR′, —OSO 2 , and —OPO 31 3 R′ 2 ; and 
 each R′ is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl. 
 
     
     
         7 . The compound of any preceding claim, wherein N N comprises the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 each Z is independently —NR″—, —CR″═, —CR″ 2 —, —O—, or —S—; 
 T 1  and T 2  are independently —NR″—, —CR″═, —CR″ 2 —, —O—, or —S—, or optionally, T 1  and T 2  may be joined together to form a ring; 
 T 3  and T 4  are independently —N— or —CR″—, or optionally, T 3  and T 4  may be joined together to form a ring; 
 each R″ is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally, any two R″ may be joined to form a ring; and 
 each m is independently 1 or 2. 
 
     
     
         8 . The compound of any preceding claim, wherein N N comprises the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 each R 1  is independently —CN, —OR 3 , —SR 3 , —COOR 3 , —OCOR 3 , —N(R 3 ) 2 , —NO 2 , halo, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloheteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally any two R 1  may be joined to form a ring; 
 each R 2  is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy; 
 each R 3  is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 each e is independently 0, 1, 2, 3, 4, or 5; 
 each n is independently 0, 1, 2, 3, or 4; 
 each p is independently 0, 1, 2, or 3; and 
 each a is independently 0, 1, or 2. 
 
     
     
         9 . The compound of any preceding claim, wherein N N comprises the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1  is independently —CN, —OR 3 , —SR 3 , —COOR S , —OCOR 3 , —N(R 3 ) 2 , —NO 2 , halo, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloheteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally any two R 1  may be joined to form a ring; 
 each R 3  is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 each e is independently 0, 1, 2, 3, 4, or 5; 
 each n is independently 0, 1, 2, 3, or 4; 
 each p is independently 0, 1, 2, or 3; and 
 each a is independently 0, 1, or 2. 
 
     
     
         10 . The compound of any preceding claim, wherein N N comprises the structure: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of any preceding claim, wherein at least one R 1  is substituted with -Q, wherein -Q is a targeting moiety. 
     
     
         12 . The compound of any preceding claim, wherein at least one R 1  is substituted with -L-Q, wherein L is a linking moiety and Q is a targeting moiety. 
     
     
         13 . The compound of any preceding claim, wherein N N comprises the structure: 
       
         
           
           
               
               
           
         
         wherein L is a linking moiety and Q is a targeting moiety. 
       
     
     
         14 . The compound of any preceding claim, wherein X 1 , X 2 , and X 3  are halo. 
     
     
         15 . The compound of any preceding claim, wherein X 1 , X 2 , and X 3  are chloro. 
     
     
         16 . The compound of any preceding claim, wherein R′ is optionally substituted alkyl or optionally substituted aryl. 
     
     
         17 . The compound of any preceding claim, wherein L is three hydrophobic amino acids, each independently selected from the group consisting of alanine, valine, isoleucine phenylalanine, tryptophan, and tyrosine. 
     
     
         18 . The compound of any preceding claim, wherein Q is a peptide. 
     
     
         19 . The compound of any preceding claim, wherein the compound causes at least a two-fold increase in cell death in a cancer cell compared to a non-cancer cell. 
     
     
         20 . The compound of any preceding claim, wherein the compound causes at least a two-fold increase in cell death in cancer stem cells compared to non-cancer cells. 
     
     
         21 . The compound of any preceding claim, wherein the compound causes at least a two-fold increase in cell death in cancer stem cells compared to cancer cells. 
     
     
         22 . A pharmaceutical composition, comprising:
 a compound of any preceding claim, or a pharmaceutically acceptable salt thereof; and   one or more pharmaceutically acceptable carriers, additives, and/or diluents.   
     
     
         23 . A kit for the treatment of cancer, comprising:
 a compound of any preceding claim; and   instructions for use of the composition for treatment of cancer.   
     
     
         24 . A method of treating cancer in a patient in need of treatment for cancer, comprising:
 administering a compound of any preceding claim to the patient.   
     
     
         25 . The compound of any preceding claim, wherein the compound has a log P greater than or equal to about 1.7.