Dendritic nano-antioxidants
Provided are dendritic nano-antioxidant compounds according to Formula I, which may further comprise active agents covalently or non-covalently attached. Further provided are compositions comprising the disclosed compounds. Also disclosed are cosmetic compositions and dietary supplements comprising the compounds according to Formula I. The invention additionally provides methods of reducing free radicals or oxidative stress in a cell, a method of treating a subject, and a method of treating a condition comprising administering the compounds according to Formula I.
1. A compound of General Formula I:
wherein X is a multi-valent center selected from the group consisting of
Y is selected from the group consisting of N and C;
n is 2, if Y is N; and n is 3, if Y is C;
m is 1 to 4;
R is:
wherein R 0 is selected from the group consisting of a direct bond, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, azidylene, —NR 32 — and heterogenous groups; and
R 32 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, halo, —R 4 , and —O—R 4 ,
wherein R 4 is selected from the group consisting of hydrogen, alkylamino, heteroalkyl, hydroxyalkyl, alkylazide, and —R 6 —N(R 7 )(R 8 );
at least one of R 1 , R 2 , and R 3 is —OH;
R 6 is selected from the group consisting of alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, azidylene, and heterogenous groups; and
R 7 and R 8 are independently selected from the group consisting of hydrogen and —A,
wherein A is
wherein R 9 is selected from the group consisting of a direct bond, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, azidylene, —NR 32 — and heterogenous groups;
R 32 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; and
R 10 , R 11 , and R 12 are independently selected from the group consisting of hydrogen, halo, —R 13 , and —O—R 13 ,
wherein R 13 is selected from the group consisting of hydrogen, alkyl, alkylamino, heteroalkyl, hydroxyalkyl, alkylazide, alkenyl, and —R 14 —N(R 15 )(R 16 ); and
at least one of R 10 , R 11 , and R 12 is —OH;
R 14 is selected from the group consisting of alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, azidylene and heterogenous groups; and
R 15 and R 16 are independently selected from the group consisting of hydrogen and —B,
wherein B is
wherein R 17 is selected from the group consisting of a direct bond, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, azidylene, —NR 32 —, and heterogenous groups;
R 32 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and
R 18 , R 19 , and R 20 are independently selected from the group consisting of hydrogen, halo, —R 21 , and —O—R 21 ,
wherein R 21 is selected from the group consisting of hydrogen, alkyl, alkylamino, heteroalkyl, hydroxyalkyl, alkylazide, and alkenyl; and
at least one of R 18 , R 19 , and R 20 is —OH.
2. The compound of claim 1 , wherein at least one of R 1 , R 2 , and R 3 is —R 6 —N(R 7 )(R 8 ) or —O—R 6 —N(R 7 )(R 8 ).
3. The compound of claim 1 , wherein at least one of R 10 , R 11 , and R 12 is —R 14 —N(R 15 )(R 16 ) or —O—R 14 —N(R 15 )(R 16 ).
4. The compound of claim 1 , wherein at least one of R 1 , R 2 , or R 3 is —O—R 4 wherein R 4 is alkylamino, alkyl, or hydrogen.
5. The compound of claim 1 , wherein at least one of R 10 , R 11 , or R 12 is —O—R 13 wherein R 13 is alkylamino.
6. The compound of claim 1 , wherein at least one of R 18 , R 19 , and R 20 is —O—R 21 wherein R 21 is alkylamino.
7. The compound of claim 1 , wherein X is
and R 0 is methylene.
8. The compound of claim 1 , wherein X is
9. The compound of claim 1 , wherein Y is N.
10. The compound of claim 1 , wherein R is
and R 0 is alkylene.
11. The compound of claim 1 , wherein R is
and at least one of R 1 , R 2 , and R 3 is —O—R 4 wherein R 4 is hydrogen or alkyl.
12. The compound of claim 1 , wherein X is
Y is N, R 0 is alkylene, and at least one of R 1 , R 2 , and R 3 is —O—R 4 wherein R 4 is hydrogen or alkyl.
13. The compound of claim 1 , wherein the compound is selected from the group consisting of:
14. A composition comprising at least one active agent covalently attached to the compound according to claim 1 .
15. The composition of claim 14 , wherein the active agent is attached through a linker.
16. The composition of claim 15 , wherein the linker is selected from the group consisting of alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, —NR 32 —, —C(O)NR 32 —, —C(O)O—, azidylene, and —C(O)— groups; wherein R 32 is independently selected from hydrogen, alkyl, alkenyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl.
17. The composition of claim 14 , wherein the active agent is covalently attached to R 4 , R 13 , or R 21 .
18. The composition of claim 14 , wherein the active agent is selected from the group consisting of antibiotics, analgesics, anti-inflammatory agents, chemotherapeutic agents, asthma therapeutics, hormones, or cardiovascular drugs.
19. The composition of claim 18 , wherein the active agent is a chemotherapeutic selected from the group consisting of docetaxel or bicalutamide.
20. The composition of claim 14 , wherein the active agent is a steroid selected from the group consisting of prednisolone.
21. The composition of claim 18 , wherein the active agent is a cardiovascular drug selected from the group consisting of statins and niacin.
22. The composition of claim 14 , wherein the active agent is a cell-targeting agent or an imaging agent.
23. A cosmetic composition comprising the compound of claim 1 and a cosmetically acceptable excipient.
24. A method of reducing free radicals or oxidative stress in a cell comprising contacting the cell with an effective amount of the compound of claim 1 .
25. A method of treatment comprising administering to a subject in need thereof an effective amount of the compound of claim 1 or the composition of claim 14 .
26. A method of evaluating a subject comprising administering to the subject the composition of claim 14 , wherein the active agent is an imaging agent, and detecting the imaging agent in the subject.
27. A method of delivering an active agent comprising administering the composition of claim 14 .
28. A method of treating a condition in a subject comprising administering to the subject an effective amount of the compound claim 1 or the composition of claim 14 .
29. The method of claim 28 , wherein the condition is inflammation, cancer, asthma, a neurological disorder, a cardiovascular disease, or diabetes.
30. A dietary supplement comprising the compound of claim 1 .