Porphyrin-polyamine conjugates for cancer therapy
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 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;
wherein at least one K is Q, and 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.
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;
wherein at least one A substituent comprises a cyclopronyl group.
3. A composition comprising a of to 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)-G-(B-A-B)-(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;
wherein at least one B-A-B comprises a cycloalkyl moiety.
4. The composition of claim 3 , wherein at least one B-A-B unit comprises a cyclopropyl moiety.
5. The composition of claim 4 , where J 1 and J 2 are identical.
6. 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 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.
7. 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.
8. 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.
9. The composition of claim 6 , wherein —K is
10. The composition of claim 1 , wherein —K is
11. The composition of claim 1 , further comprising a pharmaceutically acceptable carrier.
12. The composition of claim 2 , further comprising a pharmaceutically acceptable carrier.
13. The composition according to claim 2 , wherein the compound is
and all salts thereof.
14. The composition according to claim 10 , wherein the compound is
and all salts thereof.
15. The composition of claim 13 , further comprising a pharmaceutically acceptable carrier.
16. The composition of claim 14 , further comprising a pharmaceutically acceptable carrier.