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 method of making a targeted antioxidant compound, comprising:
a. reacting an aldehyde of structure R1—C(O)—H— with (R)-2-methylpropane-2-sulfinamide to foam an imine, in which R 1 is C 1 -C 6 straight or branched-chain alkyl, optionally including a phenyl (C 6 H 5 ) group, that optionally is methyl-, hydroxyl- or fluoro-substituted;
b. reacting a terminal alkyne-1-ol (HCC—R 2 —CH 2 —OH), in which R 2 is not present or is branched or straight-chained alkylene, with a t-butyldiphenylsilane- salt to produce an alkyne;
c. reacting the imine with the alkyne in the presence of an organozirconium catalyst to produce an alkene;
d. acylating the alkene to produce a carbamate;
e. removing the t-butyldiphenylsilyl group from the carbamate to produce an alcohol;
f. oxidizing the alcohol to produce a carboxylic acid; and
g. reacting carboxylic acid with a nitroxide-containing compound comprising one of a hydroxyl or amine in a condensation reaction to produce the antioxidant compound.
2. The method of claim 1 , further comprising cyclopropanating the alkene before step d of acylating the alkene to produce a carbamate.
3. The method of claim 1 , wherein the antioxidiant compound has a structure of:
4. The method of claim 1 , wherein the antioxidant compound has a structure of:
wherein R 1 an 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 5 is an —N—O·,—N—OH or N═O containing group: 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-substitued.