Porphyrin-polyamine conjugates for cancer therapy

Abstract

Porphyrin-polyamine conjugate compounds are disclosed which have anticancer and antitumor effects. The porphyrin moiety selectively localizes in tumors, while the polyamine moiety serves as a cytotoxic agent. Methods of making and using the porphyrin-polyamine conjugate compounds are also disclosed.

1 . A composition comprising a compound according to the formula  
     
       
         
         
             
             
         
       
       wherein at least one of J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7  and J 8  is independently selected from the group consisting of  
         —(B-A-B) x -G-(B-A-B) m —(N(P)—B-A-B) n —K.  
       wherein each A is independently selected from the group consisting of: a nonentity, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 12  cycloalkyl, C 3 -C 8  cycloaryl, C 3 -C 12  cycloalkenyl, C 3 -C 12  cycloalkynyl, C 1 -C 12  alkanol, C 3 -C 12  cycloalkanol, and C 3 -C 8  hydroxyaryl;  
       each B is independently selected from the group consisting of: a nonentity, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 12  cycloalkyl, C 3 -C 8  cycloaryl, C 3 -C 12  cycloalkenyl, C 3 -C 12  cycloalkynyl, C 1 -C 12  alkanol, C 3 -C 12  cycloalkanol, and C 3 -C 8  hydroxyaryl;  
       and with the proviso that each —B-A-B— unit contain at least one carbon atom;  
       wherein G is independently selected from the group consisting of —N(P)—, —(C═O)—N(P)—, —N(P)—(C═O)—, and a nonentity;  
       x is independently 0 or 1;  
       m is independently 0 or 1;  
       n is independently an integer from 0 to 20;  
       each P is independently selected from the group consisting of H and C 1 -C 12  alkyl;  
       each K is independently selected from the group consisting of H, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 12  cycloalkyl, C 3 -C 8  cycloaryl, C 3 -C 12  cycloalkenyl, C 3 -C 12  cycloalkynyl, C 1 -C 12  alkanol, C 3 -C 12  cycloalkanol, and C 3 -C 8  hydroxyaryl, and Q;  
       where each Q is independently selected from the group consisting of  
       
         
           
           
               
               
           
         
       
        where each P is independently selected from the group consisting of H and C 1 -C 12  alkyl, each D is selected from the group consisting of H and C 1 -C 32  alkyl, y is an integer from 1 to 8, and z is an integer from 0 to 5, and where the Q moiety is attached to the remainder of the molecule at any C or N atom in the Q moiety (including C atoms in the D or P moieties) by removing a hydrogen atom, a P substituent, or a D substituent of the Q moiety to form an open valence for attachment to the remainder of the molecule;  
       and where the remaining members or member of J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7  and J 8  are each independently selected from the group consisting of H, —B-A-B, —COOH, —SO 3 H, —B-A-B—COOH, or —B-A-B—SO 3 H, where each A and each B are independently selected as defined above and with the proviso that each —B-A-B— unit has at least one carbon atom.  
     
   
   
       2 . A composition comprising a compound according to the formula  
     
       
         
         
             
             
         
       
       wherein at least one of J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7  and J 8  is independently M, where each M is independently selected from the group consisting of  
         —(B-A-B) x -G-(B-A-B) m —(N(P)—B-A-B) n —K  
       wherein each A is independently selected from the group consisting of: a nonentity, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 12  cycloalkyl, C 3 -C 8  cycloaryl, C 3 -C 12  cycloalkenyl, C 3 -C 12  cycloalkynyl, C 1 -C 12  alkanol, C 3 -C 12  cycloalkanol, and C 3 -C 8  hydroxyaryl;  
       each B is independently selected from the group consisting of: a nonentity, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 12  cycloalkyl, C 3 -C 8  cycloaryl, C 3 -C 12  cycloalkenyl, C 3 -C 12  cycloalkynyl, C 1 -C 12  alkanol, C 3 -C 12  cycloalkanol, and C 3 -C 8  hydroxyaryl;  
       and with the proviso that each —B-A-B— unit contain at least one carbon atom;  
       wherein G is independently selected from the group consisting of —N(P)—, —(C═O)—N(P)—, —N(P)—(C═O)—, and a nonentity;  
       x is independently 0 or 1;  
       m is independently 0 or 1;  
       n is independently an integer from 0 to 20;  
       each P is independently selected from the group consisting of H and C 1 -C 12  alkyl;  
       each K is independently selected from the group consisting of H, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 12  cycloalkyl, C 3 -C 8  cycloaryl, C 3 -C 12  cycloalkenyl, C 3 -C 12  cycloalkynyl, C 1 -C 12  alkanol, C 3 -C 12  cycloalkanol, and C 3 -C 8  hydroxyaryl, and Q;  
       where each Q is independently selected from the group consisting of  
       
         
           
           
               
               
           
         
       
        where each P is independently selected from the group consisting of H and C 1 -C 12  alkyl, each D is selected from the group consisting of H and C 1 -C 32  alkyl, y is an integer from 1 to 8, and z is an integer from 0 to 5, and where the Q moiety is attached to the remainder of the molecule at any C or N atom in the Q moiety (including C atoms in the D or P moieties) by removing a hydrogen atom, a P substituent, or a D substituent of the Q moiety to form an open valence for attachment to the remainder of the molecule;  
       and where the remaining members or member of J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7  and J 8  are each independently selected from the group consisting of H, —B-A-B, —COOH, —SO 3 H, —B-A-B—COOH, or —B-A-B—SO 3 H, where each A and each B are independently selected as defined above and with the proviso that each —B-A-B— unit has at least one carbon atom;  
       with the proviso that M excludes moieties of the form  
         —K 1 -G 5 -L 5 -(N(P 5 )-A 5 ) n -K 2    
       where K 1  is independently selected from the group consisting of C 1 -C 8  alkyl and where the valence to the left of K 1  attaches to the porphyrin ring;  
       G 5  is —O—, —(C═O)—, —C(═O)—O—, —O—(C═O)—, —O—(C═O)—O—, —O—(C═O)—N—, —N—(C═O)—O—, or a nonentity;  
       L 5  is C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloaryl, C 1 -C 8  alkoxy, C 1 -C 8  alkyl-C 3 -C 8  cycloalkyl, C 1 -C 8  alkyl-C 3 -C 8  cycloaryl, C 1 -C 8  alkoxy-C 3 -C 8  cycloaryl, C 3 -C 8  cycloalkyl-C 3 -C 8  cycloaryl, C 3 -C 8  cycloalkyl-C 1 -C 8  alkyl, C 3 -C 8  cycloaryl-C 1 -C 8  alkyl, C 3 -C 8  cycloaryl-C 1 -C 8  alkoxy, C 3 -C 8  cycloaryl-C 3 -C 8  cycloalkyl, or a nonentity;  
       each A 5  is independently selected from the group consisting of C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloaryl, C 3 -C 8  cycloalkenyl, and C 3 -C 8  cycloalkynyl;  
       P 5  is selected from the group consisting of H and C 1 -C 8  alkyl;  
       n is an integer from 2 to 8;  
       and K 2  is independently selected from the group consisting of H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloaryl, C 3 -C 8  cycloalkenyl, C 3 -C 8  cycloalkynyl, C 1 -C 8  alkanol, C 3 -C 8  cycloalkanol, and C 3 -C 8  hydroxyaryl.  
     
   
   
       3 . The composition of  claim 2 , where G is independently selected from —(C═O)—N(P)— and —N(P)—(C═O)—.  
   
   
       4 . The composition of  claim 2 , where the Q moiety is attached to the remainder of the molecule at any N atom in the Q moiety by removing a P substituent of the Q moiety to form an open valence for attachment to the remainder of the molecule.  
   
   
       5 . The composition of  claim 2 , wherein each A and B substituent, if present, is selected from C 1 -C 12  alkyl.  
   
   
       6 . The composition of  claim 2 , wherein at least one A substituent comprises a cyclopropane group.  
   
   
       7 . The composition of  claim 2  comprising a compound of the formula  
     
       
         
         
             
             
         
       
     
     where J 1  and J 2  are independently M and each M is independently selected from the group consisting of —(B-A-B) x -G-(B-A-B) m —(N(P)—B-A-B) n —K; 
 J 3 , J 4 , J 6  and J 8  are independently selected from methyl and ethyl; and  
 J 5  and J 7  are independently selected from methyl, ethyl, and —SO 3 H.  
 
   
   
       8 . The composition of  claim 7 , where J 1  and J 2  are independently M and each M is independently selected from the group consisting of  
       —(B-A-B)-G-(B-A-B)—(N(P)—B-A-B) n —K.  
   
   
       9 . The composition of  claim 8 , wherein at least one B-A-B unit comprises a cycloalkyl moiety.  
   
   
       10 . The composition of  claim 9 , wherein at least one B-A-B unit comprises a cyclopropyl moiety.  
   
   
       11 . The composition of  claim 7 , where J 1  and J 2  are independently M and each M is independently selected from the group consisting of —C 1 -C 12  alkyl-G-C 1 -C 12  alkyl-(N(P)—B-A-B) n —K.  
   
   
       12 . The composition of  claim 7 , where J 1  and J 2  are independently M and each M is independently selected from the group consisting of —C 1 -C 12  alkyl-(C═O)—N(P)—C 1 -C 12  alkyl-(N(P)—B-A-B) n —K.  
   
   
       13 . The composition of  claim 7 , where J 1  and J 2  are independently M and each M is independently selected from the group consisting of —(CH 2 ) 2 C(═O)N(P 2 )—C 1 -C 4  alkyl-[NH(CH 2 CH 2 CH 2 CH 2 )] f C 1 -C 12  alkyl, where P 2  is H, methyl, or ethyl, and f is an integer from 1 to 10.  
   
   
       14 . The composition of  claim 10 , where J 1  and J 2  are identical.  
   
   
       15 . The composition of  claim 11 , where J 1  and J 2  are identical.  
   
   
       16 . The composition of  claim 1 , wherein each —K is independently Q; 
 where each Q is independently selected from the group consisting of                           wherein only one D moiety is selected from the group consisting of C 1 -C 32  alkyl and all remaining D moieties are H; wherein three P groups are selected from the group consisting of —H and —CH 3 ; wherein the fourth P group is absent and the Q moiety is attached to the remainder of the molecule at that valence; and wherein y is 2, 3, or 4 and z is 0, 1; or 2.    
   
   
       17 . The composition of  claim 2 , wherein each —K is independently Q; 
 where each Q is independently selected from the group consisting of                           wherein only one D moiety is selected from the group consisting of C 1 -C 32  alkyl and all remaining D moieties are H; wherein three P groups are selected from the group consisting of —H and —CH 3 ; wherein the fourth P group is absent and the Q moiety is attached to the remainder of the molecule at that valence; and wherein y is 2, 3, or 4 and z is 0, 1, or 2.    
   
   
       18 . The composition of  claim 6 , wherein each —K is independently Q; 
 where each Q is independently selected from the group consisting of                           wherein only one D moiety is selected from the group consisting of C 1 -C 32  alkyl and all remaining D moieties are H; wherein three P groups are selected from the group consisting of —H and —CH 3 ; wherein the fourth P group is absent and the Q moiety is attached to the remainder of the molecule at that valence; and wherein y is 2, 3, or 4 and z is 0, 1, or 2.    
   
   
       19 . The composition of  claim 1 , wherein —K is  
     
       
         
         
             
             
         
       
     
   
   
       20 . The composition of  claim 2 , wherein —K is