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...