Stimulus-Responsive Prochelators for Manipulating Cellular Metals

Abstract

CONSPECTUS Metal ions are essential for a wide range of physiological processes, but they can also be toxic if not appropriately regulated by a complex network of metal trafficking proteins. Intervention in cellular metal distribution with small molecule or peptide chelating agents has promising therapeutic potential to harness metals to fight disease. Molecular outcomes associated with forming metal-chelate interactions in situ include altering concentration and subcellular metal distribution, inhibiting metalloenzymes, enhancing the reactivity of a metal species to elicit a favorable biological response, or passivating the reactivity of a metal species to prevent deleterious reactivity. The systemic administration of metal chelating agents, however, raises safety concerns due to the potential risks of indiscriminate extraction of metals from critical metalloproteins and inhibition of metalloenzymes. One can estimate that chelators capable of complexing metal ions with dissociation constants in the sub-micromolar range are thermodynamically capable of extracting metal ions from some metalloproteins and disrupting regular function. Such dissociation constants are easily attainable for multidentate chelators interacting with first-row d-block metal cations in relevant +1, +2, and +3 oxidation states. To overcome this challenge of indiscriminate metal chelation, we have pursued a prodrug strategy for chelating agents in which the resulting “prochelator” has negligible metal binding affinity until a specific stimulus generates a favorable metal binding site. The prochelator strategy enables conditional metal chelation to occur preferentially in spatial or temporal location initiated by disease- or therapy-associated stimuli, thereby minimizing off-target metal chelation. Our design of responsive prochelators encompasses three general approaches of activation: the “removal” approach operates by eliminating a masking group that blocks a potential metal chelation site to reveal the complete binding site under the desired conditions; the molecular “switch” approach involves a reversible conformational change between an inactive and active form of a chelator with differential metal binding affinity under specific conditions; while the “addition” approach adds a new ligand donor arm to the prochelator to constitute a complete metal chelation site. Adopting these approaches, we have created four categories of triggerable prochelators that respond to 1) reactive oxygen species, 2) light, 3) specific enzymes, and 4) biological regulatory events. This account highlights progress from our group on building prochelators that showcase these four categories of responsive metal chelating agents for manipulating cellular metals. The creation and chemical understanding of such stimulus-responsive prochelators enables exciting applications for understanding the cell biology of metals and for developing therapies based on metal-dependent processes in a variety of diseases.

Self-triggered click reaction in an Alzheimer's disease model:in situbifunctional drug synthesis catalyzed by neurotoxic copper accumulated in amyloid-β plaques

“…However, systemic administration of chelating agents may cause adverse side effects because of indiscriminate metal chelation. 3 It is a promising strategy to harness toxic Cu under pathological conditions for defense against disease rather than just to chelate Cu. [4][5][6] Due to its high efficiency, fast kinetics, and mild reaction conditions, the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has received special attention in many biochemical applications such as bioconjugation, [7][8][9][10][11] biosensing, [12][13][14] and drug synthesis.…”

Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals

“…As it stands, our best 8-HNT compounds maintain an ∼100-fold therapeutic window; clearly, work will be required to improve selectivity. In the search for strategies to treat metal overload diseases, there is growing interest in the development of “prochelators” ( 50 – 52 ), molecules that have little affinity for metal ions until they undergo activation in response to specific stimuli. Activation generally involves the removal of a protective moiety by stimuli such as enzyme activation, oxidative stress, or reducing environments.…”

Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress

“…10–12 For these cases, conditional chelation strategies that direct iron chelators preferentially to sites of localized need without adversely perturbing normal metal homeostasis are desirable. 11–14 Our lab has pursued a prodrug strategy for chelating agents in which the resulting “prochelator” has negligible metal binding affinity until a specific stimulus produces a chelation site. 14 Installation of a boronate masking group in place of a phenol of a multidentate chelating agent creates prochelators that are responsive to hydrogen peroxide, a reactive oxygen species that contributes to oxidative stress.…”

“…11–14 Our lab has pursued a prodrug strategy for chelating agents in which the resulting “prochelator” has negligible metal binding affinity until a specific stimulus produces a chelation site. 14 Installation of a boronate masking group in place of a phenol of a multidentate chelating agent creates prochelators that are responsive to hydrogen peroxide, a reactive oxygen species that contributes to oxidative stress. 15–21 The conditional removal of the boronate mask by hydrogen peroxide thus conscripts iron sequestration specifically under oxidative conditions in which silencing redox-active iron can minimize further cell damage.…”