Synthesis and growth regulatory activity of a prototype member of a new family of aminothiol radioprotectors

Abstract

The synthesis, growth inhibition and radioprotective activity of the PrC-210 aminothiol, 3-(methyl-amino)-2-((methylamino)methyl)propane-l-thiol, and its polyamine and thiolated polyamine progenitors are reported. All of the molecules significantly inhibited growth of cultured normal human fibroblasts. The combination of an ROS-scavenging thiol group and a positively charged alkyl-amine backbone provided the most radioprotective aminothiol molecule.

1 . A method for protecting a subject from ionizing radiation, the method comprising:
 administering systemically to the subject a radioprotector compound comprising a free thiol and a positively-charged backbone, wherein the radioprotector compound comprises a structure according to:   
       
         
           
           
               
               
           
         
       
       wherein R and R′ are independently selected from H and CH 3 ,
 wherein systemic administration of the radioprotector compound to the subject protects the subject from ionizing radiation. 
 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The method of  claim 1  wherein administering systemically to the subject the radioprotector compound does not cause a side effect of nausea, vomiting, hypotension, or fainting in the subject. 
     
     
         5 . The method of  claim 1  further comprising blocking cell cycle progression at the G1/S cell cycle border. 
     
     
         6 . The method of  claim 1  wherein the radioprotector compound is sulfurous odor-free. 
     
     
         7 . The method of  claim 1  further comprising inhibiting the growth of a cell. 
     
     
         8 . The method of  claim 1  further comprising restoring cell cycle progression. 
     
     
         9 . The method of  claim 1  further comprising binding the positively-charged backbone to a DNA and displaying the free thiol away from the DNA. 
     
     
         10 . The method of  claim 1  further comprising scavenging reactive oxygen species. 
     
     
         11 . The method of  claim 1  wherein the subject is a mammal. 
     
     
         12 . The method of  claim 1  wherein the subject is a human. 
     
     
         13 . The method of  claim 1  wherein the subject is a human comprising a cell exposed to radiation for medical purposes. 
     
     
         14 . The method of  claim 1  wherein a cell or a tissue is protected from ionizing radiation. 
     
     
         15 . A method of providing protection to a subject's DNA against a reactive oxygen species, the method comprising:
 a) administering systemically to the subject a radioprotector compound comprising a free thiol and a positively-charged backbone, wherein the radioprotector compound comprises a structure according to:   
       
         
           
           
               
               
           
         
       
       wherein R and R′ are independently selected from H and CH 3 ;
 b) binding the positively-charged backbone of the radioprotector compound to a DNA of the subject; and 
 c) scavenging a reactive oxygen species with the free thiol, wherein the radioprotector compound provides protection to the subject's DNA against the reactive oxygen species. 
 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 15  further comprising inhibiting the growth of a cell. 
     
     
         18 . A method of providing radioprotection to a subject, the method comprising:
 a) providing a radioprotector compound that lacks the side effects of nausea/vomiting and hypotension/fainting, wherein the radioprotector compound comprises a structure according to:   
       
         
           
           
               
               
           
         
       
       wherein R and R′ are independently selected from H and CH 3 ;
 b) administering systemically the radioprotector compound to the subject, wherein the systemically administered radioprotector provides systemic radioprotection to the subject. 
 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 18  further comprising inhibiting the growth of a cell. 
     
     
         21 . The method of  claim 1 , wherein the radioprotector compound is in a form of an acid-addition salt. 
     
     
         22 . The method of  claim 15 , wherein the radioprotector compound is in a form of an acid-addition salt. 
     
     
         23 . The method of  claim 18 , wherein the radioprotector compound is in a form of an acid-addition salt.