Nanoprobe-metal chelator complexes
Provided herein are compounds that are able to bind metal ions (e.g., free metal ions or metal ions bound to low affinity ligands) in a sample or subject. Also provided herein are methods of using the compounds for chelating metal ions and for the treatment of diseases associated with abnormal levels of metal ions. Methods of preparing the compounds and pharmaceutical compositions are also provided.
1. A compound of Formula I:
A-B I
or a pharmaceutically acceptable salt thereof, wherein:
A selected from the group consisting of formulas A-1 and A-2:
wherein:
indicates the bond between A and B;
X is selected from the group consisting of a bond, C, CH 2 , NH, O and S;
each R A is an independently selected anionic group selected from the group consisting of oxide, carbonate, carboxylate, phosphate, sulfide, sulfinate, and sulfonate;
each R C is an independently selected cationic group selected from the group consisting of ammonium, C 1-6 alkylammonium, di(C 1-6 alkyl)ammonium, and tri(C 1-6 alkyl)ammonium; and
L 1 , L 2 , and L 3 are each an independently selected C 1-6 alkylene group;
B is a biocompatible polymer substituted by one or more C groups and one or more -D-E groups;
each C is independently selected from the group consisting of H and an anionic group;
each D is an independently selected linking group; and
each E is an independently selected metal chelating group.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of polylysine, polylactic acid, poly(lactic-co-glycolic acid), polyaspartic acid, polyglutamic acid, and polyglutamic acid-poly(ethylene glycol) copolymer, each of which is substituted by one or more C groups and one or more -D-E groups.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each C is independently selected from the group consisting of hydrogen and an anionic group comprising one or more alkylene groups, one or more carbonyl groups, or one or more carboxyl groups, or any combination thereof.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein D is a linking group comprising one or more alkylene groups, one or more carbonyl groups, or one or more carboxyl groups, or any combination thereof.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E is selected from the group consisting of an iron chelating group, a lead chelating group, a copper chelating group, an arsenic chelating group, a mercury chelating group, and a manganese chelating group.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
B is selected from the group consisting of a biocompatible polypeptide and a biocompatible polyester, each of which is substituted by one or more C groups and one or more -D-E groups;
C is an anionic group of the following formula:
wherein:
indicates the bond between C and B;
p is an integer from 1 to 10;
D is a linking group of the following formula:
wherein:
indicates the bond between D and B;
indicates the bond between D and E; and
q is an integer from 1 to 10; and
E is a metal chelating group.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein E is selected from the group consisting of an iron chelating group, a lead chelating group, and a copper chelating group.
9. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E is an iron chelating group.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E is selected from the group consisting of dimercaptosuccinic acid, dimercaprol, ethylenediaminetetraacetic acid, p-aminosalicyclic acid, D-penicillamine, deferoxamine, deferiprone, and deferasirox.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E is deferoxamine.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is a bond or CH 2 .
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R C is an independently selected tri(C 1-6 alkyl)ammonium group.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R A is sulfonate.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is polylysine substituted by one or more C groups and one or more -D-E groups.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is:
wherein:
indicates the bond between B and A; and
n is an integer from 5 to 30; and
m is an integer from 1 to 10.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein C is an anionic group of the following formula:
wherein:
indicates the bond between C and B; and
p is an integer from 1 to 10.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
D is a linking group of the following formula:
wherein:
indicates the bond between D and B;
indicates the bond between D and E; and
q is an integer from 1 to 10.
20. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein E is selected from the group consisting of dimercaptosuccinic acid, dimercaprol, ethylenediaminetetraacetic acid, p-aminosalicyclic acid, D-penicillamine, deferoxamine, deferiprone, and deferasirox.