Porphyrins with enhanced multi-photon absorption cross-sections for photodynamic therapy
View Patent ↗A method of increasing the multi-photon absorption cross-section of a porphyrin-based photosensitizer by attaching at least one TPA-chromophore at the meso- or beta-positions of a porphyrin structure of the porphyrin-based photosensitizer, and at least one intersystem crossing enhancing substituent to meso- or beta-positions of a porphyrin structure of the porphyrin-based photosensitizer, to thereby increase multi-photon absorption cross-section of the porphyrin-based photosensitizer to at least about 30 GM units at about its maximum wavelength for two-photon absorption. The TPA-chromophore is selected from a group of π-conjugated structures. The resulting porphyrin-based photosensitizer absorbs two photons of radiation in the range of about 700 nm to about 1300 nm.
1. A compound comprising the following porphyrin structure:
or any pharmaceutically acceptable salt thereof,
wherein:
R 1 is independently -TPA, -L-TPA, —H, —Ar, —(CH 2 ) n CH 3 , —CH═CH 2 , —(CH 2 O) n -G, -t-Butyl, or —C(O)OG;
R 2 is independently -TPA, -L-TPA, —H, —Ar, —(CH 2 ) n CH 3 , —CH═CH 2 , —(CH 2 O) n -G, -t-Butyl, or —C(O)OG;
R 3 is independently -TPA, -L-TPA, —H, —Ar, —(CH 2 ) n CH 3 , —CH═CH 2 , —(CH 2 O) n -G, -t-Butyl, or —C(O)OG;
or independently R 2 and R 3 are linked by —C 4 H 4 — to form a six-member ring;
M is either two hydrogen atoms or a metal ion;
each n is independently an integer ranging from 1 to 20;
each G is independently —H, or a C 1 to C 20 alkyl;
TPA is independently selected from the group consisting of the following structures TPA A through TPA H:
wherein in TPA A,
R is independently selected from the group consisting of H, alkyl, alkyloxy, and —(OCH 2 CH 2 ) m OG,
G is H or alkyl, and
m and n independently=1 to 5;
wherein in TPA B,
R is alkyl, and
n=1 to 5;
wherein in TPA C,
R is independently selected from the group consisting of H, CN, alkyl, and alkyloxy,
R′ is independently selected from the group consisting of alkyl, alkyloxyphenyl, phenyl, and phenyl-(OCH 2 CH 2 ) m OG,
G is H or alkyl, and
m and n independently=1 to 3;
wherein in TPA D,
R′ is independently selected from the group consisting of alkyl, alkyloxyphenyl, and phenyl-(OGH 2 CH 2 ) m OG,
G is H or alkyl, and
m and n independently=1 to 5;
wherein in TPA E,
R is independently selected from the group consisting of H, alkyl, and —OCH 2 CH 2 ) m OG,
R′ is alkyl,
G is H or alkyl, and
m and n independently=1 to 5;
wherein in TPA F,
R is independently selected from the group consisting of H, alkyl, and —(OCH 2 CH 2 ) m OG,
R′ is alkyl,
G is H or alkyl, and
m and n independently=1 to 3;
wherein in TPA G,
R is independently selected from the group consisting of H, CN, alkyl, alkyloxy, and —(OCH 2 CH 2 ) m OG,
R′ is independently selected from the group consisting of H, alkyl, alkyloxy, and —(OCH 2 CH 2 ) m OG,
G is H or alkyl, and
m=1 to 6; and
wherein in TPA H,
R is independently selected from the group consisting of alkyl, phenyl, alkyloxyphenyl, and phenyl-[(OCH 2 CH 2 ) m OG] x ,
G is H or alkyl,
m=1 to 4; and
x=1 to 4;
wherein in TPA A through TPA H, alkyl is C 1 to C 20 and the selected TPA is attached to the porphyrin structure at the point indicated by the wiggle line;
Ar is independently C 6 H 4 X, C 6 H 3 X 2 , C 6 H 2 X 3 , C 6 HX 4 , or C 6 X 5 , wherein X is independently F, Cl, Br, or I; and
L is a linking moiety between the porphyrin structure and the TPA and is independently selected from the group consisting of ethenyl, ethynyl, —(CH 2 ) n — where n is equal to 1 to 20, ortho-phenyl, meta-phenyl, para-phenyl, —C(═O)—O—, and 4-phenyl-2′-ethynyl;
wherein at least one of R 1 , R 2 or R 3 is a -TPA or -L-TPA moiety, and at least one of R 1 , R 2 or R 3 is not —H or a -TPA or -L-TPA moiety.
2. A compound according to claim 1 , wherein the compound is 5-[4′″-(diphenylamino)-4″-stilbenyl]-15-[2′,6′-dichlorophenyl]-21H, 23H-porphyrin.
3. A compound according to claim 1 , wherein M is a metal atom.
4. A compound according to claim 1 , wherein M is two hydrogen atoms.
5. A photodynamic therapy agent comprising a compound according to any one of claims 1 or 2 - 4 .
6. A method of increasing the multi-photon absorption cross-section of a porphyrin-containing photosensitizer to at least about 30 GM units at about its maximum wavelength for two-photon absorption, comprising:
attaching at least one TPA-chromophore either directly or through a linking moiety to the meso or beta positions of a porphyrin of the porphyrin-containing photosensitizer, and
attaching at least one intersystem crossing enhancing substituent to the meso or beta positions of the porphyrin of the porphyrin-containing photosensitizer,
wherein
the linking moiety is independently selected from the group consisting of ethenyl, ethynyl, —(CH 2 ) n — where n is equal to 1 to 20, ortho-phenyl, meta-phenyl, para-phenyl, —C(═O)—O— and 4-phenyl-2′-ethenyl;
the intersystem crossing enhancing substituent is independently selected from the group consisting of C 6 H 4 X, C 6 H 3 X 2 , C 6 H 2 X 3 , C 6 HX 4 , and C 6 X 5 where X is independently F, Cl, Br or I; and
the TPA chromophore is independently selected from the group consisting of the following structures TPA A through TPA H:
wherein in TPA A,
R is independently selected from the group consisting of H, alkyl, alkyloxy, and —(OCH 2 CH 2 ) m OG,
G is H or alkyl, and
m and n independently=1 to 5;
wherein in TPA B,
R is alkyl, and
n=1 to 5;
wherein in TPA C,
R is independently selected from the group consisting of H, CN, alkyl, and alkyloxy,
R′ is independently selected from the group consisting of alkyl, alkyloxyphenyl, phenyl, and phenyl-(OCH 2 CH 2 ) m OG,
G is H or alkyl, and
m and n independently=1 to 3;
wherein in TPA D,
R′ is independently selected from the group consisting of alkyl, alkyloxyphenyl, and phenyl-(OCH 2 CH 2 ) m OG,
G is H or alkyl, and
m and n independently=1 to 5;
wherein in TPA E,
R is independently selected from the group consisting of H, alkyl, and —(OCH 2 CH 2 ) m OG,
R′ is alkyl,
G is H or alkyl, and
m and n independently=1 to 5;
wherein in TPA F,
R is independently selected from the group consisting of H, alkyl, and —(OCH 2 CH 2 ) m OG,
R′ is alkyl,
G is H or alkyl, and
m and n independently=1 to 3;
wherein in TPA G,
R is independently selected from the group consisting of H, CN, alkyl, alkyloxy, and —(OCH 2 CH 2 ) m OG,
R′ is independently selected from the group consisting of H, alkyl, alkyloxy, and —(OCH 2 CH 2 ) m OG;
G is H or alkyl, and
m=1 to 6; and
wherein in TPA H,
R is independently selected from the group consisting of alkyl, phenyl, alkyloxyphenyl, and phenyl[-(OCH 2 CH 2 ) m OG] x ,
G is H or alkyl,
m=1 to 4, and
x=1 to 4;
wherein in TPA A through H, alkyl is C 1 to C 20 and the selected TPA is attached to the porphyrin at the point indicated by the wiggle line.
7. The method according to claim 6 , wherein the increased multi-photon absorption cross-section of the porphyrin-containing photosensitizer is at least about 50 GM units at about its maximum wavelength for two-photon absorption.
8. The method according to claim 6 , wherein the increased multi-photon absorption cross-section of the porphyrin-containing photosensitizer is at least about 70 GM units at about its maximum wavelength for two-photon absorption.
9. The method according to claim 6 , wherein the porphyrin core of the porphyrin-containing photosensitizer is selected from the group consisting of porphyrin, chlorin, bacteriochlorin, and isobacteriochlorin.
10. The method according to claim 6 , wherein the porphyrin-containing photosensitizer absorbs two photons of radiation in the range of about 700 nm to about 1300 nm.
11. The method according to claim 10 , wherein the absorbed radiation is in a range of about 700 nm to about 1100 nm.
12. An improved method of conducting photodynamic therapy comprising administering a therapeutically effective amount of a photoactive compound to a subject and exposing an area to be treated within the subject to radiation with a wavelength ranging from between about 700 nm to about 1300,
wherein the improvement comprises administering a therapeutically effective amount of a photoactive compound of the following porphyrin structure:
or any pharmaceutically acceptable salt thereof,
wherein
R 1 is independently -TPA, -L-TPA, —H, —Ar, —(CH 2 ) n CH 3 , —CH═CH 2 , —(CH 2 O) n -G, -t-Butyl, or —C(O)OG;
R 2 is independently -TPA, -L-TPA, —H, —Ar, —(CH 2 ) n GH 3 , —CH═CH 2 , —(CH 2 O) n -G, -t-Butyl, or —C(O)OG;
R 3 is independently -TPA, -L-TPA, —H, —Ar, —(CH 2 ) n CH 3 , —CH═CH 2 , —(CH 2 O) n -G, -t-Butyl, or —C(O)OG;
or independently R 2 and R 3 are linked by —C 4 H 4 — to form a six-membered ring;
M is either two hydrogen atoms or a metal ion;
n is independently an integer ranging from 1 to 20;
G is independently —H, or a C 1 to C 20 alkyl;
TPA is independently selected from the group consisting of the following structures TPA A through TPA H:
wherein in TPA A,
R is independently selected from the group consisting of H, alkyl, alkyloxy, and —OCH 2 CH 2 ) m OG,
G is H or alkyl, and
m and n independently=1 to 5;
wherein in TPA B,
R is alkyl, and
n=1 to 5;
wherein in TPA C,
R is independently selected from the group consisting of H, CN, alkyl, and alkyloxy,
R′ is independently selected from the group consisting of alkyl, alkyloxyphenyl, phenyl, and phenyl-(OCH 2 CH 2 ) m OG,
G is H or alkyl, and
m and n independently=1 to 3;
wherein in TPA D,
R′ is independently selected from the group consisting of alkyl, alkyloxyphenyl, and phenyl-(OCH 2 CH 2 ) m OG,
G is H or alkyl, and
m and n independently=1 to 5;
wherein in TPA E,
R is independently selected from the group consisting of H, alkyl, and —(OCH 2 CH 2 ) m OG,
R′ is alkyl,
G is H or alkyl, and
m and n independently=1 to 5;
wherein in TPA F,
R is independently selected from the group consisting of H, alkyl, and —(OCH 2 CH 2 ) m OG,
R′ is alkyl,
G is H or alkyl, and
m and n independently=1 to 3;
wherein in TPA G,
R is independently selected from the group consisting of H, CN, alkyl, alkyloxy, and —(OCH 2 CH 2 ) m OG,
R′ is independently selected from the group consisting of H, alkyl, alkyloxy, and —(OCH 2 CH 2 ) m OG,
G is H or alkyl, and
m=1 to 6; and
wherein in TPA H,
R is independently selected from the group consisting of alkyl, phenyl, alkyloxyphenyl, and phenyl-[(OCH 2 CH 2 ) m OG] x ,
G is H or alkyl,
m=1 to 4, and
x=1 to 4;
wherein in TPA A through H, alkyl is C 1 to C 20 and the selected TPA is attached to the porphyrin structure at the point indicated by the wiggle line;
Ar is independently C 6 H 4 X, C 6 H 3 X 2 , C 6 H 2 X 3 , C 6 HX 4 , or C 6 X 5 , wherein X is independently F, Cl, Br, or I; and
L is a linking moiety between the porphyrin structure and the TPA and is independently selected from the group consisting of ethenyl, ethynyl, —(CH 2 ) n — where n is equal to 1 to 20, ortho-phenyl, meta-phenyl, para-phenyl, —C(═O)—O—, and 4-phenyl-2′-ethynyl;
wherein at least one of R 1 , R 2 or R 3 is a -TPA or -L-TPA moiety, and at least one of R 1 , R 2 or R 3 is not H or a -TPA or -L-TPA moiety.
13. The method according to claim 12 , wherein the compound is 5-[4′″-(diphenylamino)-4″-stilbenyl]-15-[2′,6′-dichlorophenyl]-21H, 23H-porphyrin.
14. The method according to claim 12 , wherein M is a metal atom.
15. The method according to claim 12 , wherein M is two hydrogen atoms.
16. The method according to claim 12 , wherein a therapeutically effective amount ranges from about 0.1 mg to about 10 mg per kg of body weight.