The US Food and Drug Administration has approved the use of chelating agents for conditions of heavy metal overload that are clearly pathogenic and clinically verified. Whether the species to be removed is a native metal like iron or copper, or a contaminant that arrived by nefarious or accidental means, like arsenic, mercury or plutonium, the goal of chelation therapy as defined by its approved medical uses is to inhibit the action of transgressing metals by sequestering them in high-affinity complexes that are excreted through the liver or kidneys. But not all chelating agents are the same. Their chemistry is not the same, and their biological response will certainly not be the same. If a metal ion has a biological role, either beneficial or pathological, there is a common misconception that selectively chelating it will inhibit that biological activity. There are two problems with that misconception. The first is about selectivity, since it is very difficult to have exquisite selectivity for one metal ion over all others, especially in a complex biological environment. The second is about the fate of the resulting metal complex, which may itself have a biological effect. Pharmacological interventions that alter the concentration, distribution, and reactivity of endogenous metals can have profound biological repercussions for good or bad. The following vignettes showcase the range and scope of chelating agents that may have clinical utility beyond the traditional notion of metal removal. The chosen examples are by no means exhaustive, but represent recent advances in four general categories of the way chelating agents can influence the biological activity of metal species (Figure 1).
From a clinical viewpoint, chelation therapy refers to the administration of a chemical agent to remove heavy metals from the body. It originated in the mid 20th century when compounds were developed to mitigate arsenic toxicity associated with chemical warfare agents like dichlorovinylarsine, known as Lewisite, as well as arsenic-containing syphilis treatments [1, 2]. British Anti-Lewisite (BAL), along with the more hydrophilic and less toxic DMSA (Figure 2), is still used to treat cases of
With easy access to information on the Internet, patients who suffer from incurable diseases, who are not responding to established medical practices, or who are wary of the medical establishment, can readily find marketers of ‘chelation therapy’ who promise cure-alls for all kinds of diseases, including cardiovascular disease, cancer, autism, and dementia. The premise for chelation therapy in these cases is similar to that of its approved uses: remove heavy metals from the body. However, this
The word ‘chelator’ derives from the Greek ‘chele’ for ‘claw’, which provides a good visual cue to the function of these molecules to clamp down on a metal ion the way a lobster claw grasps its prey. A chelator, or chelating agent, refers to a ligand that coordinates to a metal center by more than one point of attachment, thereby forming a ring with the metal atom [12]. The resulting metal complex is referred to as a chelate. The term chelator itself does not distinguish the number of points of
The last two decades have seen a growing interest in the hypothesis that chelating agents (chemically defined) may have potential to treat neurodegenerative diseases [14]. Several recent reviews cover the creative attempts of chemists to design molecules for such challenging applications [2, 15, 16, 17]. One of the drivers behind this surge is the moderate success of clioquinol (Figure 3), a bidentate chelating agent with a history of use as an antimicrobial [18]. The story of clioquinol in the
Metalloproteins comprise at least one-third of the human proteome, and many critical catalytic processes are carried out by metal centers within enzyme active sites. While high-affinity, non-selective chelating agents that strip metals from these sites are unlikely drug candidates, well-designed inhibitors that use chelating motifs to fill open coordination sites on the metal can block substrate access or otherwise disrupt catalytic function. Metal-binding pharmacophores are not often included
Continuing on the message that not all chelators are the same, this vignette showcases just how significant the chemical properties of a chelated complex are on the biological activity of a chelator. Because rapidly proliferating cancer cells need iron, iron chelation may be an effective anticancer strategy [24]. While iron sequestration from cancer cells would seem like a plausible strategy, iron chelators with potent anticancer activity have a more complex biological effect that is not
On the flip side of using chelators to generate cytotoxic metal complexes is to use them to passivate redox activity for cytoprotection. Finding the balance between high-affinity metal chelators that passivate the harmful reactions of metals without disturbing normal metal status is the impetus for designing agents that alter their metal-binding capacity in response to a disease-related trigger (Figure 4a). Recognizing that oxidative stress is associated with many diseases, and that
In conclusion, I reiterate a now recognizable theme: not all chelators are the same. The concept that metal–ligand binding produces complexes with unique chemical properties has been a foundational principle of coordination chemistry since Alfred Werner. Yet the subtleties of these interactions continue to amaze, especially in the context of how these complexes and their individual components interface with complex biological environments. We still have much to learn and explore. It is clear
Papers of particular interest, published within the period of review, have been highlighted as:
I would like to thank my current and former group members for their numerous contributions. Our work in this area has been funded by the National Institutes of Health (GM084176), the Sloan Foundation, the Camille and Henry Dreyfus Foundation, and the National Science Foundation (CHE-1152054).
2016, Colloids and Surfaces B Biointerfaces However, the accumulation of metals such as iron, copper, and zinc within the senile plaques can reach levels of up to 400, 950, and 1100 mm, respectively, which is 3–5 times higher in concentration as compared to healthy brain [16–19]. To reduce the harmful effects of excess metal deposition, newer therapies that focus on metal ion chelation for AD are being developed [20]. To date, NPs have attracted substantial attention in the therapeutics of AD due to their unique structural superiority, high stability, ease of surface functionalization and modification, and ready ability to cross the blood-brain barrier (BBB) [21,22].
