Anticancer drug candidates

Abstract

Enediyne compounds having a structure according to formula (I), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and X are defined herein.

What is claimed is: 
     
         1 .- 13 . (canceled) 
     
     
         14 . A compound having a structure represented by formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  and R 2  are each independently H, OH, or OR′; 
 R 3  is OH; 
 R 4  is H or CH 3 ; 
 R 5  is C(O)R; 
 R′ and R are independently H, CH 3 , or C 1 -C 10 alkyl and, 
 X is N. 
 
     
     
         15 . The compound of  claim 14 , further comprising a ligand, the ligand comprising: antibodies, antibody fragments, aptamers, peptides, polypeptides, carbohydrates, oligonucleotides, polynucleotides or small molecular weight (MW) compounds. 
     
     
         16 . The compound of  claim 15 , wherein the ligand specifically binds a tumor antigen or a target molecule or cell associated with a disease. 
     
     
         17 . An antibody-drug conjugate comprising a compound according to  claim 14 , wherein the compound is conjugated to an antibody, wherein the antibody is specific for a tumor antigen or a target molecule or cell associated with a disease. 
     
     
         18 . A targeting ligand-drug conjugate comprising a structure represented by formula (IV)
   (A) x L   
       wherein:
 L is a targeting ligand, 
 x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and 
 A is selected from the group consisting of compounds having a general structure represented by formula (III). 
 
     
     
         19 . The targeting ligand-drug conjugate of  claim 18 , further comprising one or more linking moieties comprising a structure represented by formula (V):
   (A) x (M) y L z      
       wherein:
 M is a linking moiety; and, 
 y and z are independently 0, 1, 2 or 3. 
 
     
     
         20 .- 22 . (canceled) 
     
     
         23 . A pharmaceutical composition comprising a compound according to any one of  claims 14 ,  17 ,  18 , or  19 . 
     
     
         24 . A compound according to any one of  claims 14 ,  17 ,  18 , or  19 , wherein the compound comprises a detectable label. 
     
     
         25 . A cell comprising a compound according to any one of  claims 14 ,  17 ,  18 , or  19 . 
     
     
         26 . A liposome comprising a compound according to any one of  claims 14 ,  17 ,  18 ,  19 ,  23  or  24 . 
     
     
         27 . A method of producing a compound according to any one of  claims 14 ,  17 ,  18 , or  19 , comprising: mutating a nucleic acid sequence in a cell, the cell producing native enediyne compounds, comparing metabolite profiles of the enediyne native producing cell to mutated cells and recombinant cells; selecting mutant and recombinant cells expressing the mutated nucleic acid sequences; and screening for enediyne compounds produced by the mutated nucleic acid sequence as compared to a native enediyne compound. 
     
     
         28 . A method of producing a compound according to any one of  claims 14 ,  17 ,  18 , or  19 , comprising: providing an expression vector encoding a mutated nucleic acid sequence; transfecting a cell with the expression vector; and, screening for enediyne compounds produced by a mutated nucleic acid sequence as compared to a native enediyne compound. 
     
     
         29 . A method of treating a subject diagnosed with cancer, comprising administering to the subject a therapeutically effective amount of a compound according to any one of  claims 14 ,  17 ,  18 ,  19 ,  23  or  24 . 
     
     
         30 . The method of  claim 29 , wherein the compound is conjugated to a targeting ligand. 
     
     
         31 . The method of  claim 30 , wherein the targeting ligand comprises: antibodies, antibody fragments, aptamers, peptides, polypeptides, carbohydrates, integrins, oligonucleotides or small molecular weight (MW) compounds. 
     
     
         32 . The method of  claim 31 , wherein the targeting ligand specifically binds to a tumor antigen.