Synthesis of novel tubulin polymerization inhibitors: benzoylphenylurea (bpu) sulfur analogs

Abstract

A novel series of BPU analogues were synthesized and evaluated for antitumor activity. In particular, BPU sulfur analogues 6n and 7d were shown to possess up to 10-fold increased potency, when compared to compound 1, against cancer cell lines. 6n was more effective than compound 1 in causing apoptosis of MCF-7 cells. When compared to other drugs with a similar mechanism of action, 6n retained significant ability to inhibit tubulin assembly, with an IC50 of 2.1 μM.

1 . A method of inhibiting tubulin polymerization in a cell, comprising contacting said cell with a composition comprising 1 nM to 10 microM of a compound represented by either of the following formulas: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       2 . The method of  claim 1 , wherein said cell is a cancerous cell. 
   
   
       3 . (canceled) 
   
   
       4 . (canceled) 
   
   
       5 . A process for the preparation of 1-[4-(5-Bromopyrimidin-2-ylsulfanyl)phenyl]-3-(2-nitrobenzoyl)-urea comprising the steps of:
 (a) preparing a solution comprising of 5-bromo-2-chloropyrimidine and 4-aminothiophenol and heating said solution to yield 4-(5-bromopyrimidin-2-ylsulfanyl)phenylamine; and   (b) mixing a solution of said 4-(5-bromopyrimidin-2-ylsulfanyl)phenylamine of step (a) with a solution of 2-nitrobenzoyl isocyanate to yield 1-[4-(5-Bromopyrimidin-2-ylsulfanyl)phenyl]-3-(2-nitrobenzoyl)-urea.   
   
   
       6 . The process of  claim 5 , wherein the solvent of said solution of step (a) is a dry or an anhydrous solvent. 
   
   
       7 . The process of  claim 6 , wherein said solvent is a dry dimethylsulfoxide. 
   
   
       8 . (canceled) 
   
   
       9 . The process of  claim 5 , wherein said solution of step (a) further comprises a base. 
   
   
       10 . The process of  claim 9 , wherein said base is potassium carbonate. 
   
   
       11 . The process of  claim 5 , wherein said 4-(5-bromopyrimidin-2-ylsulfanyl)phenylamine of step (a) is isolated. 
   
   
       12 . (canceled) 
   
   
       13 . The process of  claim 5 , wherein the solvent of said solution comprising 4-(5-bromopyrimidin-2-ylsulfanyl)phenylamine of step (b) is a dry or an anhydrous solvent. 
   
   
       14 . The process of  claim 13 , wherein said solvent is dioxane. 
   
   
       15 . The process of  claim 1 , wherein the solvent of said solution of 2-nitrobenzoyl isocyanate of step (b) is a dry or an anhydrous solvent. 
   
   
       16 . The process of  claim 15 , wherein said solvent is dioxane. 
   
   
       17 . (canceled) 
   
   
       18 . A process for the preparation of 1-(2-Aminobenzoyl)-3-[4-(5-bromopyrimidin-2-ylsulfanyl)phenyl]urea comprising the steps of:
 (a) preparing a solution comprising of 5-bromo-2-chloropyrimidine and 4-aminothiophenol and heating said solution to yield 4-(5-bromopyrimidin-2-ylsulfanyl)phenyl amine;   (b) mixing a solution of said 4-(5-bromopyrimidin-2-ylsulfanyl)phenylamine of step (a) with a solution of 2-nitrobenzoyl isocyanate to yield 1-[4-(5-Bromopyrimidin-2-ylsulfanyl)phenyl]-3-(2-nitrobenzoyl)-urea; and   (c) reduction of 1-[4-(5-Bromopyrimidin-2-ylsulfanyl)phenyl]-3-(2-nitrobenzoyl)-urea, to yield 1-(2-Aminobenzoyl)-3-[4-(5-bromopyrimidin-2-ylsulfanyl)phenyl]urea.   
   
   
       19 . The process of  claim 18 , wherein the solvent of said solution of step (a) is a dry or an anhydrous solvent. 
   
   
       20 . The process of  claim 19 , wherein said solvent is dry dimethylsulfoxide. 
   
   
       21 . (canceled) 
   
   
       22 . The process of  claim 18 , wherein said solution of step (a) further comprises a base. 
   
   
       23 . The process of  claim 22 , wherein said base is potassium carbonate. 
   
   
       24 . The process of  claim 18 , wherein said 4-(5-bromopyrimidin-2-ylsulfanyl)phenylamine of step (a) is isolated. 
   
   
       25 . The process of  claim 24 , wherein said isolated is by extraction with ethyl acetate and water. 
   
   
       26 . The process of  claim 18 , wherein the solvent of said solution of 4-(5-bromopyrimidin-2-ylsulfanyl)phenylamine of step (b) is a dry or an anhydrous solvent. 
   
   
       27 . The process of  claim 26 , wherein said solvent is dioxane. 
   
   
       28 . The process of  claim 18 , wherein the solvent of said solution of 2-nitrobenzoyl isocyanate of step (b) is a dry or an anhydrous solvent. 
   
   
       29 . The process of  claim 28 , wherein said solvent is dioxane. 
   
   
       30 . (canceled) 
   
   
       31 . The process of  claim 18 , wherein said reduction is performed using iron (Fe) to obtain the 2-NH 2  derivative.