Drug design for tubulin inhibitors, compositions, and methods of treatment thereof

Abstract

The present invention relates to a computer-assisted method of a designing of a tubulin inhibitor comprising: a) determining an interaction between a tubulin protein and a chemical known to bind the tubulin protein by evaluating a binding of the tubulin protein to the chemical known to bind the tubulin protein; b) based on the interaction, designing a candidate tubulin inhibitor; c) determining an interaction between the tubulin protein and the candidate tubulin inhibitor by evaluating a binding of the tubulin protein to the candidate tubulin inhibitor; and d) concluding that the candidate tubulin inhibitor inhibits the tubulin protein wherein the conclusion is based on the interaction of step c). The invention also provides compositions and methods of treatment of diseases with the candidate tubulin inhibitors.

1 . A computer-assisted method of a designing of a tubulin inhibitor comprising:
 a. determining an interaction between a tubulin protein and a chemical known to bind the tubulin protein by evaluating a binding of the tubulin protein to the chemical known to bind the tubulin protein;   b. based on the interaction, designing a candidate tubulin inhibitor;   c. determining an interaction between the tubulin protein and the candidate tubulin inhibitor by evaluating a binding of the tubulin protein to the candidate tubulin inhibitor; and   d. concluding that the candidate tubulin inhibitor inhibits the tubulin protein wherein the conclusion is based on the interaction of step c).   
   
   
       2 . The method of  claim 1 , wherein the tubulin protein is a three-dimensional structure comprising a binding domain of the tubulin protein. 
   
   
       3 . The method of  claim 2 , wherein the binding domain of the tubulin protein is selected from the group consisting of colchicine binding domain, vinblastine binding domain, and paclitaxel binding domain. 
   
   
       4 . The method of  claim 3 , wherein the binding domain of the tubulin protein is a colchicine binding domain. 
   
   
       5 . The method of  claim 1 , wherein the chemical known to bind the tubulin protein is a three-dimensional structure. 
   
   
       6 . The method of  claim 1 , wherein the tubulin protein is derived from a crystal of the tubulin protein. 
   
   
       7 . The method of  claim 1 , wherein the designing is performed in conjunction with a computer modeling. 
   
   
       8 . The method of  claim 2 , wherein the binding domain of the tubulin protein is an intradimer surface. 
   
   
       9 . The method of  claim 2 , wherein the binding domain of the tubulin protein is an interdimer surface. 
   
   
       10 . The method of  claim 2 , wherein the binding domain of the tubulin protein is a surface facing inside of a microtubule near an interprotofilament interface at a distance from any longitudinal interface. 
   
   
       11 . The method of  claim 10 , wherein the surface is a paclitaxel binding site. 
   
   
       12 . The method of  claim 1 , wherein the designing involves replacing a substituent on the chemical known to bind the tubulin protein with another substituent wherein the other substituent improves the binding of the candidate tubulin inhibitor with the tubulin protein. 
   
   
       13 . The method of  claim 1 , wherein the interaction is steric interaction, van der Waals interaction, electrostatic interaction, solvation interaction, charge interaction, covalent bonding interaction, non-covalent bonding interaction, entropically favorable interaction, enthalpically favorable interaction, or a combination thereof. 
   
   
       14 . The method of  claim 1 , wherein the candidate tubulin inhibitor is an analogue of the chemical known to bind the tubulin protein. 
   
   
       15 . The method of  claim 1 , wherein the chemical known to bind the tubulin protein is a ketone that is a thyroxine analogue. 
   
   
       16 . The method of  claim 1 , further comprising a step of chemically synthesizing the candidate tubulin inhibitor. 
   
   
       17 . The method of  claim 16 , further comprising evaluating a tubulin inhibitory activity of the candidate tubulin inhibitor and selecting the candidate tubulin inhibitor based on the evaluation. 
   
   
       18 . The method of  claim 17 , wherein the evaluating the tubulin inhibiting activity involves an assay technique. 
   
   
       19 . The method of  claim 1 , wherein the candidate tubulin inhibitor is a compound of formula I, its pharmaceutically acceptable salts, or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1  and R 5  are halogens; R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, ester, optionally substituted alkoxy, optionally substituted amine, phosphate, optionally substituted alkyl, and optionally substituted acetyl; and R 6 , R 7 , R 8 , R 9 , and R 10  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted alkoxy, optionally substituted amine, phosphate, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, nitroso, carboxyl, optionally substituted cycloalkyl, and optionally substituted heterocyclic. 
   
   
       20 . The method of  claim 19 , wherein the candidate tubulin inhibitor is a compound of formula II or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
     wherein: R, R′, R 2 , R 4 , R 6 , R 7 , R 9 , and R 10  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted alkoxy, optionally substituted amine, phosphate, optionally substituted alkyl, and optionally substituted acetyl. 
   
   
       21 . The method of  claim 20 , wherein the candidate tubulin inhibitor is a compound of formula III or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
     wherein: R, R 7 , R 9 , and R 10  are independently selected from the group consisting of hydrogen, hydroxyl, optionally substituted amine, phosphate, and optionally substituted alkyl. 
   
   
       22 . The method of  claim 21 , wherein the candidate tubulin inhibitor is a compound of formula IIIA or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
   
   
       23 . The method of  claim 21 , wherein the candidate tubulin inhibitor is a compound of formula IIIB or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
   
   
       24 . The method of  claim 21 , wherein the candidate tubulin inhibitor is a compound of formula IIIC or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
   
   
       25 . The method of  claim 21 , wherein the candidate tubulin inhibitor is a compound of formula IIID or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
   
   
       26 . The method of  claim 21 , wherein the optionally substituted alkyl is substituted with an optionally substituted heterocyclic. 
   
   
       27 . The method of  claim 26 , wherein the optionally substituted heterocyclic is selected from a group consisting of azeridine, azetidine, pyrrole, dihydropyrrole, pyrrolidene, pyrazole, pyrazoline, pyrazolidine, imidazole, benzimidazole, triazole, tetrazole, oxazole, isoxazole, benzoxazole, oxadiazole, oxazoline, oxazolidine, thiazole, isothiazole, pyridine, dihydropyridine, tetrahydropyridine, quinazoline, pyrazine, pyrimidine, pyridazine, quinoline, isoquinoline, triazine, tetrazine, and piperazine. 
   
   
       28 . The method of  claim 27 , wherein the candidate tubulin inhibitor is a compound of formula IIIE or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
   
   
       29 . A computer system containing a set of information to perform a design of a tubulin inhibitor having a user interface comprising a display unit, the set of information comprising:
 a. logic for inputting an information regarding a binding of a tubulin protein to a chemical known to bind tubulin protein;   b. logic for designing a candidate tubulin inhibitor based on the binding of the tubulin protein to the chemical known to bind tubulin protein;   c. logic for determining an information regarding a binding of the tubulin protein to the candidate tubulin inhibitor; and   d. logic for making a conclusion regarding a tubulin inhibitory properties of the candidate tubulin inhibitor based on the determination of step c).   
   
   
       30 . A computer-readable storage medium containing a set of information for a general purpose computer having a user interface comprising, a display unit, the set of information comprising:
 a. logic for inputting an information regarding a binding of a tubulin protein to a chemical known to bind tubulin protein;   b. logic for designing a candidate tubulin inhibitor based on the binding of the tubulin protein to the chemical known to bind tubulin protein;   c. logic for determining an information regarding a binding of the tubulin protein to the candidate tubulin inhibitor; and   d. logic for making a conclusion regarding a tubulin inhibitory properties of the candidate tubulin inhibitor based on the determination of step c).   
   
   
       31 . The system of  claim 29 , wherein the chemical is a ketone which is a thyroxine analogue. 
   
   
       32 . The computer readable media of  claim 30 , wherein the chemical is a ketone which is a thyroxine analogue. 
   
   
       33 . An electronic signal or carrier wave that is propagated over the internet between computers comprising a set of information for a general purpose computer having a user interface comprising a display unit, the set of information comprising a computer-readable storage medium containing a set of information for a general purpose computer having a user interface comprising a display unit, the set of information comprising:
 a. logic for inputting an information regarding a binding of a tubulin protein to a chemical known to bind tubulin protein;   b. logic for designing a candidate tubulin inhibitor based on the binding of the tubulin protein to the chemical known to bind tubulin protein;   c. logic for determining an information regarding a binding of the tubulin protein to the candidate tubulin inhibitor; and   d. logic for making a conclusion regarding a tubulin inhibitory properties of the candidate tubulin inhibitor based on the determination of step c).   
   
   
       34 . A method of treating a disease comprising administering to a patient in need thereof an effective amount of at least one compound of formula I, its pharmaceutically acceptable salts, or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1  and R 5  are halogens;
 R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, ester, optionally substituted alkoxy, optionally substituted amine, phosphate, optionally substituted alkyl, and optionally substituted acetyl; and 
 R 6 , R 7 , R 8 , R 9 , and R 10  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted alkoxy, optionally substituted amine, phosphate, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, nitroso, carboxyl, optionally substituted cycloalkyl, and optionally substituted heterocyclic. 
 
   
   
       35 . The method of  claim 34 , wherein the compound is of formula II or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
     wherein: R, R′, R 2 , R 4 , R 6 , R 7 , R 9 , and R 10  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted alkoxy, optionally substituted amine, phosphate, optionally substituted alkyl, and optionally substituted acetyl. 
   
   
       36 . The method of  claim 35 , wherein the compound is of formula III or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
     wherein: R 6 , R 7 , R 9 , and R 10  are independently selected from the group consisting of hydrogen, hydroxyl, optionally substituted amine, phosphate, and optionally substituted alkyl. 
   
   
       37 . The method of  claim 35 , wherein the compound is of formula IIIA or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
   
   
       38 . The method of  claim 35 , wherein the compound is of formula IIIB or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
   
   
       39 . The method of  claim 35 , wherein the compound is of formula IIIC or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
   
   
       40 . The method of  claim 35 , wherein the compound is of formula IIID or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
   
   
       41 . The method of  claim 36 , wherein the optionally substituted alkyl is substituted with an optionally substituted heterocyclic. 
   
   
       42 . The method of  claim 41 , wherein the optionally substituted heterocyclic is selected from a group consisting of azeridine, azetidine, pyrrole, dihydropyrrole, pyrrolidene, pyrazole, pyrazoline, pyrazolidine, imidazole, benzimidazole, triazole, tetrazole, oxazole, isoxazole, benzoxazole, oxadiazole, oxazoline, oxazolidine, thiazole, isothiazole, pyridine, dihydropyridine, tetrahydropyridine, quinazoline, pyrazine, pyrimidine, pyridazine, quinoline, isoquinoline, triazine, tetrazine, and piperazine. 
   
   
       43 . The method of  claim 42 , wherein the candidate tubulin inhibitor is a compound of formula IIIE or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
   
   
       44 . The method of  claim 34 , wherein the treating comprises inhibiting tubulin protein function. 
   
   
       45 . The method of  claim 34 , wherein the disease is selected from the group consisting of cancer, inflammation, metabolic disease, gout, CVS disease, CNS disease, disorder of the hematolymphoid system, disorder of endocrine and neuroendocrine, disorder of urinary tract, disorder of respiratory system, disorder of female genital system, and disorder of male genital system. 
   
   
       46 . A process of manufacturing a compound of formula IIIB or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
     
     comprising:
 (a) nitrating 1-(3,5-diiodo-4-(4-methoxyphenoxy)phenyl)ethanone to form as an intermediate 1-(3,5-diiodo-4-(4-methoxy-3-nitrophenoxy)phenyl)ethanone; and 
 (b) reducing the intermediate of step (a) to form the compound of formula IIIB. 
 
   
   
       47 . The process of  claim 46 , wherein the nitrating is carried out in the presence of nitric acid and concentrated sulfuric acid in an organic solvent. 
   
   
       48 . The process of  claim 47 , wherein the organic solvent is methylene chloride. 
   
   
       49 . The process of  claim 46 , wherein the reducing is carried out in the presence of tin(II) chloride. 
   
   
       50 . A process of manufacturing a compound of formula IIIA or its pharmaceutically acceptable salts or prodrugs: 
     
       
         
         
             
             
         
       
       comprising:
 (a) reacting a compound of formula IIIB: 
 
     
     
       
         
         
             
             
         
       
       
         with a metal nitrate in the presence of a strong acid to form a diazonium intermediate; and 
         (b) refluxing the diazonium intermediate in the presence of a strong acid to form the compound of formula IIIA. 
       
     
   
   
       51 . The process of  claim 50 , wherein the metal nitrate is sodium nitrate. 
   
   
       52 . The process of  claim 50 , wherein the strong acid of step (a) is sulfuric acid. 
   
   
       53 . The process of  claim 50 , wherein the strong acid of step (b) is sulfuric acid. 
   
   
       54 . The process of  claim 50 , wherein the strong acid of step (a) and step (b) is sulfuric acid.