DISULFIDE-MASKED PRO-CHELATOR COMPOSITIONS AND METHODS OF USE
Pro-chelator compositions featuring disulfide masks that upon activation yield active chelators. The pro-chelator compositions may be activated intracellularly, for example within cells featuring metal ion dysregulation, cells that proliferate abnormally, etc. The pro-chelators of the present invention include thiosemicarbazones, semicarbazones, and aroyl hydrazones. The pro-chelator compositions of the present invention may be used for a variety of purposes including inhibiting cell proliferation, or treating conditions associated with metal ion dysregulation or abnormal cell proliferation.
1 . A pro-chelator comprising at least one pro-ligand and a disulfide bond, wherein the disulfide bond is connected to the pro-ligand, and wherein each pro-ligand comprises at least two donor atoms.
2 . The pro-chelator of claim 1 , wherein the pro-chelator comprises two pro-ligands, connected by the disulfide bond.
3 . The pro-chelator of claim 1 , wherein the pro-chelator comprises one pro-ligand and a solubilizing or biologically active moiety, connected by the disulfide bond.
4 . The pro-chelator of claim 1 , wherein the pro-chelator is activated to transform each pro-ligand to an active bidentate, tridentate, or polydentate chelator.
5 . The pro-chelator of claim 4 , wherein the pro-chelator is activated by reduction of the disulfide bond.
6 . The pro-chelator of claim 4 , wherein each active chelator comprises a semicarbazone, a thiosemicarbazone, a hydrazone, or a thiohydrazone moiety.
7 . The pro-chelator of claim 4 , wherein each active chelator comprises an iminic position, and comprises an electron-withdrawing group at the iminic position.
8 . The pro-chelator of claim 4 , wherein each active chelator is configured to coordinate Fe to form a metal complex.
9 . The pro-chelator of claim 8 , wherein the metal complex has a Fe III /Fe II potential of about −200 to 200 mV compared to a Normal Hydrogen Electrode (NHE).
10 . The pro-chelator of claim 1 , wherein the pro-chelator comprises a structure according to Formula II, Formula III, Formula IV, or Formula V;
wherein R is H, alkyl, trifluoromethyl, aryl, or a derivative thereof;
wherein R is H, alkyl, aryl or a derivative thereof;
wherein:
if X 1 =O
then R 1 =Ph, pyridyl, p-CF 3 -Ph, p-NO 2 -Ph CCl 3 or CF 3 ;
X 2 =H, alkyl, alkoxy, halo, CF 3 or NO 2 ;
R 2 =H, alkyl, aryl, or substituted aryl; and
R 3 =H, alkyl, aryl, or substituted aryl;
or if X 1 =S
then R 1 =Ph, pyridyl, p-CF 3 -Ph, p-NO 2 -Ph CCl 3 or CF 3 ;
X 2 =H, alkyl, alkoxy, halo, CF 3 or NO 2 ;
R 2 =alkyl, aryl, or substituted aryl; and
R 3 =alkyl, aryl, or substituted aryl;
wherein: X 1 =O, or S;
R 1 =Ph, pyridyl, p-CF 3 -Ph, p-NO 2 -Ph CCl 3 or CF3 .
X 2 =H, alkyl, alkoxy, halo, CF 3 or NO 2 ; and
X 3 =H, alkyl, alkoxy, halo, CF 3 or NO 2 .
11 . A method of preventing iron-deficiency anemia while treating a subject having malignant cells characterized by a reprogrammed iron metabolism, the method comprising:
a. providing a pro-chelator to a bloodstream of the subject, the pro-chelator comprising at least one pro-ligand and a disulfide bond, wherein the disulfide bond is connected to the pro-ligands, and wherein each pro-ligand comprises at least two donor atoms; and
b. transporting the pro-chelator to an intracellular space of a malignant cell of the subject;
wherein an active chelator is selectively released from the pro-chelator by reduction of the disulfide bond within the intracellular space,
wherein the active chelator coordinates Fe selectively within the intracellular space to form a metal complex, and does not coordinate Fe in the bloodstream of the subject, and
whereby the selective coordination of Fe is effective for treating the malignant cells without causing iron-deficiency anemia.
12 . The method of claim 11 , wherein the pro-chelator comprises two pro-ligands, connected by the disulfide bond.
13 . The method of claim 11 , wherein the pro-chelator comprises one pro-ligand and a solubilizing or biologically active moiety, connected by the disulfide bond.
14 . The method of claim 11 , wherein the active chelator comprises a semicarbazone, a thiosemicarbazone, a hydrazone, or a thiohydrazone moiety.
15 . The method of claim 11 , wherein the metal complex has a Fe III /Fe II potential of about −200 to 200 mV compared to a Normal Hydrogen Electrode (NHE).
16 . The method of claim 11 , wherein the active chelator comprises an iminic position, and comprises an electron-withdrawing group at the iminic position.
17 . The method of claim 11 , wherein the active chelator is bidentate, tridentate, or polydentate.
18 . The method of claim 11 , wherein the pro-chelator comprises a structure according to Formula II, Formula III, Formula IV, or Formula V;
wherein R is H, alkyl, trifluoromethyl, aryl, or a derivative thereof;
wherein R is H, alkyl, aryl or a derivative thereof;
wherein:
if X 1 =O
then R 1 =Ph, pyridyl, p-CF 3 -Ph, p-NO 2 -Ph CCl 3 or CF 3 ;
X 2 =H, alkyl, alkoxy, halo, CF 3 or NO 2 ;.
R 2 =H, alkyl, aryl, or substituted aryl; and
R 3 =H, alkyl, aryl, or substituted aryl;
or if X 1 =S
then R 1 =Ph, pyridyl, p-CF 3 -Ph, p-NO 2 -Ph CCl 3 , or CF 3 ;
X 2 =H, alkyl, alkoxy, halo, CF 3 or NO 2 ;.
R 2 =alkyl, aryl, or substituted aryl; and
R 3 =alkyl, aryl, or substituted aryl;
wherein: X 1 =O, or S;
R 1 =Ph, pyridyl, p-CF 3 -Ph, p-NO 2 -Ph CCl 3 or CF3;
X 2 =H, alkyl, alkoxy, halo, CF 3 or NO 2 ; and
X 3 =H, alkyl, alkoxy, halo, CF 3 or NO 2 .
19 - 22 . (canceled)
23 . A pro-chelator according to Formula III, wherein R is H, alkyl, aryl or a derivative thereof.
24 . The pro-chelator of claim 23 , wherein the pro-chelator is redox-activated.
25 - 34 . (canceled)