Table 2.
Major Classes of Chelators
Chelator | Properties | Mechanism of action | Clinical studies |
---|---|---|---|
DFO and analogs | |||
DFO | Hexadentate chelator hydrophilic, poor BBB penetration, short half-life (8–12 min) | Up-regulates HIF-1α by inhibiting PHDs (458), down-regulates APP via 5′-UTR (373, 441, 458), down-regulates α-synuclein via 5′-UTR (143) | DFO treatment may slow the rate of decline in AD patients by as much as twofold (300). |
DFP | Bidentate chelator, lipophilic, high BBB penetration, iron-DFP complex is hydrophilic | Reduces Aβ40, Aβ42, and BACE1 levels in the brain (356), decreases phosphorylation of tau but not ROS formation or brain iron levels (356). | Approved by FDA for treatment of secondary iron overload, phase II trials for treatment of PD undergoing (115, 156), open-label single-arm study for treatment of FA using combination therapy of idebenone and DFP (440).Treatment of FA adolescents with DFP reduced neuropathy and ataxic gait (48). |
DFX | Tridentate chelator, high bioavailability, long half-life (8–16 h) | Chelates iron in 2:1 DFX:iron ratio | Approved by FDA for treatment of secondary iron overload |
8-HQ analogs | |||
CQ | Lipophilic, high BBB penetration, may induce SMON (136) | 8HQ moiety forms 5-member chelate rings with Fe3+, forms complexes with copper and zinc: reduces plaque formation in AD (75, 453, 474), decreases levels of interstitial Aβ (4), down-regulates APP, BACE1, and presenilin 1 (453, 474) | Pilot phase II trial shows significant decrease in AD plasma Aβ42 after CQ treatment (371). |
PBT2 | Lipophilic, high BBB penetration | Inhibits redox activity via metal chelation (146), neutralizes Aβ toxicity by promoting clearance from existing deposits (99) | Phase IIa trial shows significant decrease in AD CSF Aβ42 following PBT2 treatment (141) |
VK28 | Contains 8HQ moiety | Protects against MPTP and 6-OHDA induced lesions in rat brains (14) | |
HLA-20 and M30 | Contains N-propargyl moiety, contains 8HQ moiety | Prevents ROS generation by inhibiting MAO (458), up-regulates HIF-1α (23), and attenuates tau phosphorylation (23, 247). | |
Prochelators | |||
SIH-B BSIH |
Parent molecule SIH, lipophilic, tridentate chelator | SIH-B is converted to SIH after exposure to hydrogen peroxide, which can then bind iron and copper (77, 282), BSIH is converted to SIH after removal of boron ester by hydrogen peroxide (76, 77, 282) | |
BHAPI | Isonicotynoyl backbone, binds trivalent and divalent metal ions | BHAPI is converted to HAPI after reaction with hydrogen peroxide or paraquat (228). | |
SWH | Lipophilic, contains metal chelating and amyloid binding moieties | SWH is converted to copper chelator CP after enzyme modification by β-secretase (155). Inhibits Aβ aggregation (155). | |
Aroylhydrazones | |||
PCIH | PIH analog, lipophilic, forms more stable complex with copper than iron (18, 268) | Induces iron mobilization and prevents iron uptake from Tf (268, 475), permeates mitochondrion to induce iron release (475) | |
PCTH | PCIH analog, high oral bioavailability | Faster membrane penetration than DFO or PCIH (268), able to penetrate inner and outer membrane of mitochondria, and prevents hydrogen peroxide-induced cytotoxicity (268) |
6-OHDA, 6 hydroxydopamine; 8HQ, 8-hydroxyquinolone; Aβ, amyloid β; AD, Alzheimer's disease; APP, amyloid precursor protein; BBB, blood brain barrier; CSF, cerebrospinal fluid; CQ, clioquinol; DFO, desferrioxamine; DFP, deferiprone; DFX, deferasirox; FA, Friedreich's ataxia; Fe3+, ferric iron; HIF-1α, hypoxia-inducible factor-1α; PCTH, 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone; PCIH, 2-pyridylcarboxaldehyde isonicotinoyl hydrazine; PD, Parkinson's disease; PHD, prolyl-4-hydroxylases; ROS, reactive oxygen species; SIH, salicylaldehyde isonicotynoyl hydrazine.