Intracellular Catalysis with Selected Metal Complexes and Metallic Nanoparticles: Advances toward the Development of Catalytic Metallodrugs

Abstract

Platinum-containing drugs (e.g., cisplatin) are among the most frequently used chemotherapeutic agents. Their tremendous success has spurred research and development of other metal-based drugs, with notable achievements. Generally, the vast majority of metal-based drug candidates in clinical and developmental stages are stoichiometric agents, i.e., each metal complex reacts only once with their biological target. Additionally, many of these metal complexes are involved in side reactions, which not only reduce the effective amount of the drug but may also cause toxicity. On a separate note, transition metal complexes and nanoparticles have a well-established history of being potent catalysts for selective molecular transformations, with examples such as the Mo- and Ru-based catalysts for metathesis reactions (Nobel Prize in 2005) or palladium catalysts for C–C bond forming reactions such as Heck, Negishi, or Suzuki reactions (Nobel Prize in 2010). Also, notably, no direct biological equivalent of these transformations exists in a biological environment such as bacteria or mammalian cells. It is, therefore, only logical that recent interest has focused on developing transition-metal based catalytic systems that are capable of performing transformations inside cells, with the aim of inducing medicinally relevant cellular changes. Because unlike in stoichiometric reactions, a catalytically active compound may turn over many substrate molecules, only very small amounts of such a catalytic metallodrug are required to achieve a desired pharmacologic effect, and therefore, toxicity and side reactions are reduced. Furthermore, performing catalytic reactions in biological systems also opens the door for new methodologies to study the behavior of biomolecules in their natural state, e.g., via in situ labeling or by increasing/depleting their concentration at will. There is, of course, an art to the choice of catalysts and reactions which have to be compatible with biological conditions, namely an aqueous, oxygen-containing environment. In this review, we aim to describe new developments that bring together the far-distant worlds of transition-metal based catalysis and metal-based drugs, in what is termed “catalytic metallodrugs”. Here we will focus on transformations that have been performed on small biomolecules (such as shifting equilibria like in the NAD+/NADH or GSH/GSSG couples), on non-natural molecules such as dyes for imaging purposes, or on biomacromolecules such as proteins. Neither reactions involving release (e.g., CO) or transformation of small molecules (e.g., 1O2 production), degradation of biomolecules such as proteins, RNA or DNA nor light-induced medicinal chemistry (e.g., photodynamic therapy) are covered, even if metal complexes are centrally involved in those. In each section, we describe the (inorganic) chemistry involved, as well as selected examples of biological applications in the hope that this snapshot of a new but quickly developing field will indeed inspire novel research and unprecedented inte...

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