Guanidinium delivery carriers

Abstract

Disclosed herein are transmembrane transporter compounds containing guanidinium groups. Also disclosed herein are methods for transporting a biologically active moiety across a biological membrane using the transmembrane transporter compounds. Particularly, this invention provides a method for the delivery of a biologically active moiety across the biological membranes of such membranes as endothelial tissues.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein each T is a terminal group independently selected from the group consisting of hydrogen, an alkylcarbonyl, a N-terminal peptide, a group that forms an N-terminal peptide bond, a C-terminal peptide, a group that forms a C-terminal peptide bond, a reporting moiety, a imaging agent moiety, and a therapeutic moiety; 
         wherein Z has the structure: 
       
       
         
           
           
               
               
           
         
         wherein s is 0 or 1; 
         wherein when s is 1, Y has the structure: 
       
       
         
           
           
               
               
           
         
         wherein when s is 0, Y has the structure: 
       
       
         
           
           
               
               
           
         
         wherein m is an integer from 1 to 6; 
         wherein n is an integer from 0 to 10; 
         wherein p is an integer from 0 to 5; 
         wherein the sum of m and p is an integer from 6 to 11; 
         wherein each G is separately selected from a group having the formula: 
       
       
         
           
           
               
               
           
         
         wherein:
 each R 1 , R 2 , R 3 , and R 4  are separately selected from the group consisting of hydrogen, an optionally substituted C 1 -C 12  alkyl, an optionally substituted C 2 -C 12  alkenyl, an optionally substituted C 2 -C 12  alkynyl, and pentamethylchroman-6-sulfonyl; and 
 
         wherein each L is independently a linker moiety comprising a group selected from the group consisting of mono-substituted, poly-substituted or unsubstituted variants of the following residues: C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 1 -C 24  heteroalkyl, C 2 -C 24  heteroalkenyl, C 2 -C 24  heteroalkynyl, an amide group, an ester group, and a disulfide group, or L is absent. 
       
     
     
         2 . The compound of  claim 1 , wherein at least one T is a reporting moiety, an imaging agent moiety, a therapeutic moiety, 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein at least one T comprises a peptide nucleic acid, a polypeptide, a protein antigen, a tumor antigen, a metal ion, an antimicrobial agent, an epitope tag, or an anti-cancer agent. 
     
     
         4 . The compound of  claim 1 , wherein each L is independently selected from the group consisting of mono-substituted, poly-substituted or unsubstituted variants of the following residues: C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 1 -C 12  heteroalkyl, C 2 -C 12  heteroalkenyl, C 2 -C 12  heteroalkynyl, an amide group, an ester group, and a disulfide group. 
     
     
         5 . The compound of  claim 1 , wherein each L is independently selected from the group consisting of: C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 1 -C 12  heteroalkyl, C 2 -C 12  heteroalkenyl and C 2 -C 12  heteroalkynyl, each substituted with one or more substituents selected from the group consisting of halogen, acyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxy carbonyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, cycloalkylacyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, and halogenated alkyl. 
     
     
         6 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein each T is a terminal group independently selected from the group consisting of hydrogen, an alkylcarbonyl, a N-terminal peptide or group that forms an N-terminal peptide bond, a C-terminal peptide or group that forms a C-terminal peptide bond, a reporting moiety, an imaging agent moiety, and a therapeutic moiety; 
         wherein Z has the structure: 
       
       
         
           
           
               
               
           
         
         wherein s is 0 or 1; 
         wherein when s is 1, Y has the structure: 
       
       
         
           
           
               
               
           
         
         wherein when s is 0, Y has the structure: 
       
       
         
           
           
               
               
           
         
         wherein p is an integer from 0 to 10; 
         wherein q is an integer from 0 to 5; 
         wherein r is an integer from 0 to 5; 
         wherein m is an integer from 1 to 6; 
         wherein n is an integer from 0 to 10; 
         wherein the sum of m, q, and r is an integer from 6 to 21; 
         wherein each G is separately selected to be a group having the formula: 
       
       
         
           
           
               
               
           
         
         wherein:
 each R 1 , R 2 , R 3 , and R 4  are separately selected from the group consisting of hydrogen, optionally substituted C 1 -C 12  alkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, and pentamethylchroman-6-sulfonyl; and 
 
         wherein each L is independently a linker moiety comprising a group selected from the group consisting of mono-substituted, poly-substituted or unsubstituted variants of the following residues: C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 1 -C 24  heteroalkyl, C 2 -C 24  heteroalkenyl, C 2 -C 24  heteroalkynyl, an amide group, an ester group, and a disulfide group, or L is absent. 
       
     
     
         9 . The compound of  claim 8 , wherein at least one T is a reporting moiety, an imaging agent moiety, a therapeutic moiety, 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 8 , wherein at least one T comprises a peptide nucleic acid, a polypeptide, a protein antigen, a tumor antigen, a metal ion, an antimicrobial agent, an epitope tag, or an anti-cancer agent. 
     
     
         11 . The compound of  claim 8 , wherein each L is independently selected from the group consisting of mono-substituted, poly-substituted or unsubstituted variants of the following residues: C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 1 -C 12  heteroalkyl, C 2 -C 12  heteroalkenyl, C 2 -C 12  heteroalkynyl, an amide group, an ester group, and a disulfide group. 
     
     
         12 . The compound of  claim 8 , wherein each L is independently selected from the group consisting of: C 1 -C 12  alkyl, C 2 -C 24  alkenyl, C 2 -C 12  alkynyl, C 1 -C 12  heteroalkyl, C 2 -C 12  heteroalkenyl and C 2 -C 12  heteroalkynyl, each substituted with one or more substituents selected from the group consisting of halogen, acyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxy carbonyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, cycloalkylacyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, and halogenated alkyl. 
     
     
         13 . The compound of  claim 8 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A method for transporting a biologically active moiety across a biological membrane, comprising contacting a biological membrane with a compound having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable salt and pro-drug ester thereof. 
     
     
         15 . The method of  claim 14 , wherein the biological membrane is a cell membrane selected from the group consisting of a mammalian cell membrane, a cancer cell membrane, an insect cell membrane, a plant cell membrane, and a yeast cell membrane. 
     
     
         16 . The method of  claim 14 , wherein the biological membrane is a prokaryotic cell membrane. 
     
     
         17 . A method of treating cancer comprising contacting a cancer cell in a mammal with a compound having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 17 , wherein the cancer cell is a prostate cancer cell or melanoma cancer cell. 
     
     
         19 . The method of  claim 17 , wherein the mammal is a rodent or human.