Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage in vitro drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs.

/pdf/metallodrugs-are-unique-opportunities-and-challenges-of-370m076u4c.pdf

Metallodrugs are unique: opportunities and challenges of discovery and development

Transition metals can assemble to form multinuclear complexes by engaging in direct metal-to-metal interactions. Metal–metal covalent bonds provide a large perturbation in electronic structure, relative to mononuclear metal ions, and the unique properties of these dinuclear fragments can be harnessed in a broad range of applications—for example, as chromophores in photochemical processes, redox centers in molecular electronics, or structural elements in metal–organic materials. There is a growing body of evidence that metal–metal bonds may also be formed under conditions relevant to catalysis and play a key role in transformations that were previously assumed to only involve mononuclear species. These findings have stimulated interest in characterizing multinuclear reaction pathways and developing well-defined multinuclear platforms as catalytic active sites. In this Perspective, we present case studies in this emerging area of catalysis research, emphasizing the impact of metal–metal bonding in either en...

Metal–Metal Bonds in Catalysis

There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.

/pdf/metal-complexes-as-a-promising-source-for-new-antibiotics-58i06qfkdj.pdf

Metal complexes as a promising source for new antibiotics.

In the pursuit of new pharmaceuticals and agrochemicals, chemists in the life science industry require access to mild and robust synthetic methodologies to systematically modify chemical structures, explore novel chemical space, and enable efficient synthesis. In this context, photocatalysis has emerged as a powerful technology for the synthesis of complex and often highly functionalized molecules. This Review aims to summarize the published contributions to the field from the life science industry, including research from industrial-academic partnerships. An overview of the synthetic methodologies developed and strategic applications in chemical synthesis, including peptide functionalization, isotope labeling, and both DNA-encoded and traditional library synthesis, is provided, along with a summary of the state-of-the-art in photoreactor technology and the effective upscaling of photocatalytic reactions.

Photocatalysis in the Life Science Industry.

With the widespread rise of antimicrobial resistance, most traditional sources for new drug compounds have been explored intensively for new classes of antibiotics. Meanwhile, metal complexes have long had only a niche presence in the medicinal chemistry landscape, despite some compounds, such as the anticancer drug cisplatin, having had a profound impact and still being used extensively in cancer treatments today. Indeed, metal complexes have been largely ignored for antibiotic development. This is surprising as metal compounds have access to unique modes of action and exist in a wider range of three-dimensional geometries than purely organic compounds. These properties make them interesting starting points for the development of new drugs. In this perspective article, , the encouraging work that has been done on antimicrobial metal complexes, mainly over the last decade, is highlighted. Promising metal complexes, their activity profiles, and possible modes of action are discussed and issues that remain to be addressed are emphasized.

https://www.mdpi.com/2079-6382/9/2/90/pdf

Metal Complexes, an Untapped Source of Antibiotic Potential?

Fragment-based drug discovery (FBDD) is a powerful strategy for the identification of new bioactive molecules. FBDD relies on fragment libraries, generally of modest size, but of high chemical diversity. Although good chemical diversity in FBDD libraries has been achieved in many respects, achieving shape diversity - particularly fragments with three-dimensional (3D) structures - has remained challenging. A recent analysis revealed that >75% of all conventional, organic fragments are predominantly 1D or 2D in shape. However, 3D fragments are desired because molecular shape is one of the most important factors in molecular recognition by a biomolecule. To address this challenge, the use of inert metal complexes, so-called 'metallofragments' (mFs), to construct a 3D fragment library is introduced. A modest library of 71 compounds has been prepared with rich shape diversity as gauged by normalized principle moment of inertia (PMI) analysis. PMI analysis shows that these metallofragments occupy an area of fragment space that is unique and highly underrepresented when compared to conventional organic fragment libraries that are comprised of orders of magnitude more molecules. The potential value of this metallofragment library is demonstrated by screening against several different types of proteins, including an antiviral, an antibacterial, and an anticancer target. The suitability of the metallofragments for future hit-to-lead development was validated through the determination of IC50 and thermal shift values for select fragments against several proteins. These findings demonstrate the utility of metallofragment libraries as a means of accessing underutilized 3D fragment space for FBDD against a variety of protein targets.

/pdf/expanding-medicinal-chemistry-into-3d-space-metallofragments-2jbf34tdn5.pdf

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

Metal complexes have been widely used for applications in the chemical and physical sciences due to their unique electronic and stereochemical properties. For decades the use of metal complexes for medicinal applications has been postulated and demonstrated. The distinct characteristics of metal complexes, including their molecular geometries (that are not readily accessed by organic molecules) as well as their ligand exchange, redox, catalytic, and photophysical reactions, give these compounds the potential to interact and react with biomolecules in unique ways and by distinct mechanisms of action. Herein, the potential of metal complexes to act as components of bioactive therapeutic compounds is discussed.

Metal complexes for therapeutic applications

Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure–activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PAN endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PAN endonuclease, a class of highly active and selective fragments was developed that displays IC50 values <50 nM. This SAR led to structurally distinct molecules that also displayed IC50 values of ∼10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors.

Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.

Significant efforts have been reported on the development of influenza antivirals including inhibitors of the RNA-dependent RNA polymerase PA N-terminal (PAN) endonuclease. Based on recently identified, highly active metal-binding pharmacophores (MBPs) for PAN endonuclease inhibition, a fragment-based drug development campaign was pursued. Guided by coordination chemistry and structure-based drug design, MBP scaffolds were elaborated to improve activity and selectivity. Structure-activity relationships were established and used to generate inhibitors of influenza endonuclease with tight-binding affinities. The activity of these inhibitors was analyzed using a fluorescence-quenching-based nuclease activity assay, and binding was validated using differential scanning fluorometry. Lead compounds were found to be highly selective for PAN endonuclease against several related dinuclear and mononuclear metalloenzymes. Combining principles of bioinorganic and medicinal chemistry in this study has resulted in some of the most active in vitro influenza PAN endonuclease inhibitors with high ligand efficiencies.

Ryjul W. Stokes

Papers

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

Metal complexes for therapeutic applications

Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.

SAR Exploration of Tight-Binding Inhibitors of Influenza Virus PA Endonuclease.

Allylic aminations with hindered secondary amine nucleophiles catalyzed by heterobimetallic Pd-Ti complexes.