Targeted nitroxide agents
View Patent ↗Provided herein are compositions and related methods useful for free radical scavenging, with particular selectivity for mitochondria. The compounds comprise a nitroxide-containing group attached to a mitochondria-targeting group. The compounds can be cross-linked into dimers without loss of activity. Also provided herein are methods, for preventing, mitigating and treating damage caused by radiation. The method comprises delivering a compound, as described herein, to a patient in an amount and dosage regimen effective to prevent, mitigate or treat damage caused by radiation.
1. A compound having the structure:
wherein X is one of
R 1 and R 2 are hydrogen, C 1 -C 6 straight or branched-chain alkyl, or a C 1 -C 6 straight or branched-chain alkyl further comprising a phenyl (C 6 H 5 ) group, that is unsubstituted or is methyl-, hydroxyl- or fluoro-substituted; R 4 is hydrogen, C 1 -C 6 straight or branched-chain alkyl, or a C 1 -C 6 straight or branched-chain alkyl further comprising a phenyl (C 6 H 5 ) group, that is unsubstituted or is methyl-, hydroxyl- or fluoro-substituted; R 3 is —NH—R 5 ; R is —C(O)—R 6 , —C(O)O—R 6 , or —P(O)—(R 6 ) 2 , wherein R 6 is C 1 -C 6 straight or branched-chain alkyl or C 1 -C 6 straight or branched-chain alkyl further comprising one or more phenyl (—C 6 H 5 ) groups that are independently unsubstituted, or methyl-, ethyl-, hydroxyl- or fluoro-substituted; R 5 has the structure
and wherein the compound is not XJB-5-208.
2. The compound of claim 1 , having the structure
3. The compound of claim 2 , having the structure
4. The compound of claim 3 , having the structure
5. The compound of claim 1 , in which R is Ac, Boc, Cbz, or —P(O)-Ph 2 .
6. The compound of claim 1 , in which R 1 , R 2 , R 4 and R 6 are independently chosen from hydrogen, methyl, ethyl, propyl, 2-propyl, butyl, t-butyl, pentyl, hexyl, benzyl, and hydroxybenzyl.
7. The compound of claim 1 , wherein when X is —CH═CR 4 —, R 4 is hydrogen, methyl or ethyl.
8. The compound of claim 1 , having the structure:
9. The compound of claim 1 , wherein X is
10. The compound of claim 9 , in which R is Ac, Boc, Cbz, or —P(O)-Ph 2 .
11. The compound of claim 9 in which R 1 , R 2 and R 4 independently are methyl, ethyl, propyl, 2-propyl, butyl, t-butyl, pentyl, hexyl, benzyl, and hydroxybenzyl.
12. The compound of claim 9 having a structure chosen from
wherein Ac is acetyl.
13. The compound of claim 1 wherein X is
14. The compound of claim 13 , in which R is Ac, Boc, Cbz, or —P(O)-Ph 2 .
15. The compound of claim 13 , in which R 1 , R 2 and R 4 independently are methyl, ethyl, propyl, 2-propyl, butyl, t-butyl, pentyl, hexyl, benzyl, and hydroxybenzyl.
16. The compound of claim 13 , having a structure chosen from:
wherein Ac is acetyl.
17. The compound of claim 1 , wherein R 5 has the structure:
18. The compound of claim 9 , wherein R 5 has the structure:
19. The compound of claim 10 , wherein R 5 has the structure:
20. The compound of claim 11 , wherein R 5 has the structure:
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 4 and a pharmaceutically acceptable carrier.