4-Sulfur Substituted Podophyllotoxin Derivative and Preparation Method Therefor and Use Thereof

Abstract

Disclosed are a 4-sulfur substituted podophyllotoxin derivative and a synthetic method therefor and the use thereof. In the present invention, introducing heteroaromatic compounds with rigidity, such as 4-trifluoromethylpyridin-2-thiol, 4-trifluoromethyl-2-mercaptopyrimidine, and para-fluorothiophenol, respectively as substituent groups to position 4 of C ring of a podophyllotoxin or 4′-demethylepipodophyllotoxin, obtaining a podophyllotoxin derivative as shown in formula (V) with a significantly improved antitumour activity and reduced toxic side effects. Experiments of in vitro tumour cell activity inhibition indicate that the antitumour activity of the compound as shown in formula (V) of the present invention is significantly improved compared to that of the podophyllotoxin or 4′-demethylepipodophyllotoxin.

1 . A compound of formula (V) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         Wherein R 1  is selected from 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 2  is hydrogen or —CH 3 . 
       
     
     
         2 . A method for preparing the compound of  claim 1 , characterized by comprising the steps of:
 introducing a reaction monomer into position-4 of the C ring in podophyllotoxin or 4′-demethylepipodophyllotoxin through a nucleophilic substitution reaction, wherein the reaction monomer may be selected from the group consisting of 4-trifluoromethylpyridin-2-thiol, 4-trifluoromethyl-2-mercaptopyrimidine, para-fluorothiophenol, 5-fluorobenzothiazol-2-thiol, 5-fluorobenzoxazol-2-thiol, 5-phenylbenzoxazol-2-thiol, 5-methylbenzoxazol-2-thiol, 6-chlorobenzoxazol-2-thiol, 5-difluoromethoxybenzimidazol-2-thiol, 2-naphthalenethiol, 1H-imidazo[4,5-B]pyridin-2-thiol, 1-phenyltetrazol-5-thiol, 3-phenyl-1,3,4-thiadiazol-2(3H)thione potassium salt-5-thiol or 4-(4-pyridyl)thiazol-2-thiol.   
     
     
         3 . The method of  claim 2 , characterized in that the nucleophilic substitution reaction is performed under the following conditions: dissolving podophyllotoxin or 4′-demethylepipodophyllotoxin in an organic solvent, adding the reaction monomer followed by stirring, wherein the organic solvent may be a nucleophile which may be selected from trifluoroacetic acid, methanesulfonyl chloride or boron trifluoride diethyl ether. 
     
     
         4 . The method of  claim 3 , characterized in that the molar ratio of podophyllotoxin or 4′-demethylepipodophyllotoxin to the reaction monomer is 1:1-10, for example 1:1-8, for example 1:1. 
     
     
         5 . The method of  claim 3 , characterized in that the temperature in nucleophilic substitution reaction is −20-40° C., for example −20-20° C. 
     
     
         6 . The method of  claim 5 , characterized in that the temperature in nucleophilic substitution reaction is −10-10° C., for example 0-10° C. 
     
     
         7 . The method of  claim 3 , characterized by further comprising the steps of: pouring the reaction solution after the nucleophilic substitution reaction into deionized water, followed by separating out and filtering, and drying a filter cake to obtain 4-sulfur substituted podophyllotoxin derivatives crude products, wherein the volume of deionized water may be 20-50 times that of the reaction solution after the nucleophilic substitution. 
     
     
         8 . The method of  claim 7 , characterized by further comprising the steps of: sequentially separating the crude products by using silica gel column chromatography and gel column chromatography to obtain purified 4-sulfur substituted podophyllotoxin derivatives. 
     
     
         9 . Use of the compound or the salt thereof of  claim 1  in the preparation of an antitumor drug. 
     
     
         10 . An antitumor pharmaceutical composition, characterized by comprising an effective amount of the compound or the salt thereof of  claim 1  and a pharmaceutically acceptable carrier.