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-1-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 via intraperitoneal injection intravenous injection, or enterally by mouth in an amount effective to protect the subject from ionizing radiation. 
     
     
         2 . The method of  claim 1  wherein the positively-charged backbone of the radioprotector compound comprises an amine. 
     
     
         3 . The method of  claim 1  wherein the radioprotector compound comprises a structure according to: 
       
         
           
           
               
               
           
         
       
       wherein R and R′ are independently selected from H, CH 3 , alkyl, and heteroalkyl. 
     
     
         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  wherein the amount administered is effective to block 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  wherein the amount administered is effective to inhibit the growth of a cell. 
     
     
         8 . The method of  claim 1  wherein the amount administered is effective to permit restoration of cell cycle progression. 
     
     
         9 . The method of  claim 1  wherein the administering is effective to bind the positively-charged backbone to a DNA while displaying the free thiol away from the DNA. 
     
     
         10 . The method of  claim 1  wherein the administering is effective to scavenge 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 an effective amount of the radioprotector compound is administered systemically at an effective time before or after radiation exposure. 
     
     
         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 via intraperitoneal injection, intravenous injection, or enterally by mouth in an amount effective to protect the subject's DNA from reactive oxygen species;   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 . The method of  claim 15  wherein the radioprotector compound comprises a structure according to: 
       
         
           
           
               
               
           
         
       
       wherein R and R′ are independently selected H and CH 3 . 
     
     
         17 . The method of  claim 16  further comprising inhibiting the growth of a cell. 
     
     
         18 . A method of providing radioprotection to a subject, the method comprising:
 a) providing a radioprotector that lacks the side effects of nausea/vomiting and hypotension/fainting; and   b) administering systemically the radioprotector to the subject via intraperitoneal injection, intravenous injection, or enterally by mouth in an amount effective to provide systemic radioprotection to the subject.   
     
     
         19 . The method of  claim 18  wherein the radioprotector compound comprises a structure according to: 
       
         
           
           
               
               
           
         
       
       wherein R and R′ are independently selected from H and CH 3 . 
     
     
         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 systemically administered enterally by mouth in a manner effective to provide a systemic radioprotective effect against the ionizing radiation. 
     
     
         22 . The method of  claim 1  wherein the radioprotector compound is systemically administered enterally by mouth in a manner effective to provide a systemic radioprotective effect against the ionizing radiation that is equivalent to 20-100% of a systemic radioprotective effect against the ionizing radiation provided by intraperitoneal injection of an amount of the radioprotector compound that is 0.5 times a maximum tolerated dose administered by intraperitoneal injection. 
     
     
         23 . The method of  claim 1  wherein the radioprotector compound is systemically administered enterally by mouth in a manner effective to provide a systemic radioprotective effect against the ionizing radiation that is equivalent to a systemic radioprotective effect against the ionizing radiation provided by intraperitoneal injection of an amount of the radioprotector compound that is 0.5 times a maximum tolerated dose administered by intraperitoneal injection. 
     
     
         24 . The method of  claim 1  wherein the amount systemically administered enterally by mouth is an amount of from about 25% to about 61% of a maximum tolerated dose systemically administered enterally by mouth.