Beta-substituted beta-amino acids and analogs as chemotherapeutic agents

Abstract

β-Substituted β-amino acids, β-substituted β-amino acid derivatives, and β-substituted β-amino acid analogs and (bio)isosteres and their use as chemotherapeutic agents are disclosed. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and (bio)isosteres are selective LAT1/4F2hc substrates and exhibit rapid uptake and retention in tumors expressing the LAT1/4F2hc transporter. Methods of synthesizing the β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and methods of using the compounds for treating cancer are also disclosed. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs exhibit selective uptake in tumor cells expressing the LAT1/4F2hc transporter and accumulate in cancerous cells when administered to a subject in vivo. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and (bio)isosteres exhibit cytotoxicity toward several tumor types.

What is claimed is: 
     
         1 . A method of treating cancer in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula (1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from the group consisting of C 1-6  alkyl and C 1-6  alkoxy; 
         one of R 3  and R 4  is —N(—CH 2 —CH 2 —Cl) 2 ; 
         each of the other of R 2 , R 3 , R 4 , and R 5  is independently selected from the group consisting of hydrogen and deuterio; 
         R 6  is selected from the group consisting of —COOH and —CO(—OCH 3 ); 
         each R 7  is independently selected from the group consisting of hydrogen and deuterio; 
         R 8  is selected from the group consisting of hydrogen and deuterio; and 
         L is selected from the group consisting of a bond (“—”) and —CH 2 —. 
       
     
     
         2 . The method of  claim 1 , wherein,
 R 1  is selected from the group consisting of methyl and methoxy;   R 3  comprises a nitrogen mustard; and   each of R 2 , R 4 , and R 5  is hydrogen.   
     
     
         3 . The method of  claim 1 , wherein,
 R 1  is selected from the group consisting of methyl and methoxy;   R 4  comprises a nitrogen mustard; and   each of R 2 , R 3 , and R 5  is hydrogen.   
     
     
         4 . The method of  claim 1 , wherein L is a bond. 
     
     
         5 . The method of  claim 1 , wherein L is —CH 2 —. 
     
     
         6 . The method of  claim 1 , wherein, the compound of Formula (1) is selected from the group consisting of:
 3-amino-3-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]propanoic acid (1);   3-amino-3-[4-[bis(2-chloroethyl)amino]-2-methyl-phenyl]propanoic acid (2);   3-amino-4-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]butanoic acid (3);   3-amino-4-[4-[bis(2-chloroethyl)amino]-2-methyl-phenyl]butanoic acid (4);   (3S)-β-amino-4-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]butanoic acid (5);   (3R)-β-amino-4-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]butanoic acid (6); and   (3S)-β-amino-4-[5-[bis(2-chloroethyl)amino]-2-methoxy-phenyl]butanoic acid (7); and   or a pharmaceutically acceptable salt of any of the foregoing.   
     
     
         7 . The method of  claim 1 , wherein the compound of Formula (1) exhibits:
 a LAT1/4F2hc-dependent uptake of at least 10% that of gabapentin measured at an extracellular concentration of 1 mM (1 mmol/L); and   a system A-, system N-, a system ASC-, and a LAT2/4F2hc-dependent uptake of less than 50% that of L-leucine measured at an extracellular concentration of 1 mM (1 mmol/L).   
     
     
         8 . The method of  claim 1 , wherein administering comprises administering a pharmaceutical composition, wherein the pharmaceutical composition comprises:
 a therapeutically effective amount of the compound of Formula (1) or a pharmaceutically acceptable salt thereof; and   a pharmaceutically acceptable vehicle.   
     
     
         9 . The method of  claim 1 , wherein the cancer comprises cancerous tissue that over-expresses the LAT1/4F2hc compared to surrounding non-cancerous tissue. 
     
     
         10 . The method of  claim 1 , wherein the cancer is known to be treated by administering an alkylating agent. 
     
     
         11 . The method of  claim 1 , wherein the cancer is in the brain of the patient. 
     
     
         12 . The method of  claim 1 , wherein the cancer comprises brain cancer. 
     
     
         13 . The method of  claim 12 , wherein the brain cancer comprises glioblastoma. 
     
     
         14 . The method of  claim 1 , wherein the cancer comprises breast cancer. 
     
     
         15 . The method of  claim 14 , wherein the breast cancer comprises triple negative breast cancer. 
     
     
         16 . The method of  claim 1 , wherein the cancer comprises skin cancer. 
     
     
         17 . The method of  claim 16 , wherein the skin cancer comprises melanoma. 
     
     
         18 . The method of  claim 1 , wherein the cancer comprises prostate cancer. 
     
     
         19 . The method of  claim 1 , wherein the cancer comprises a tumor exhibiting a greater LAT1/4F2hc transport activity than a LAT1/4F2hc transport activity in surrounding non-cancerous tissue.