Key Thrust. The work centers on structure, function, and mechanism elucidation in bioinorganic and inorganic chemistry. Significant effort is devoted to fundamental studies aimed at delineating the physical, chemical, and biochemical behavior of novel complexes of metal ions.

Compounds. The compounds of interest include porphyrins, metalloporphyrins, pyrrole-based macrocycles, and other metal chelates often, but not always, of relevance in biology, medicine, and/or biochemistry (Figure 1). Computational (in silico) design methods are used to create novel metallodrug candidates and semi-synthetic metalloenzymes. Since structure normally underpins function, much of the group’s work is structure-based and employs appropriate methods such as X-ray crystallography and molecular/macromolecular simulations to gain a fundamental understanding of chemical structures and their conformational behavior at atomic resolution.

Student Training. Over the years, many MSc and PhD-level students (as well as academic and technical staff) have been trained in the art and science of organic and inorganic synthesis, spectroscopy, biochemistry, DFT simulations, and small molecule crystallography. Recent efforts have moved into the realm of protein crystallography. Specific studies now focus on macromolecular structures of metal-based anticancer agents (e.g. metallointercalators bound to DNA), artificial metalloenzymes, and molecular recognition/imaging of receptor proteins as the research program shifts closer to the interface between chemistry and biology.

Chemotherapeutic Agents. We design, synthesize, and test novel pre-clinical chemotherapeutic agents for cancer, drug-resistant bacterial infections, and pathogenic viruses. The chemotherapeutic agents make use of metal ions such as Au(III) to exert a cytotoxic effect and they fall into the broad category of metallodrugs such as auranofin, bleomycin, and cisplatin. The most important feature of our work is that we spend significant time delineating the mechanism of action of the novel compounds we make. In short, we go from design and discovery to mechanism elucidation, sometimes in a single 5-year focused study.

In contrast to drugs such as cisplatin, which were discovered through serendipity rather than design, our group uses modern computational tools (Gaussian 16 and Schrodinger 2020) to target a specific biomolecule such as DNA and the nuclear enzymes that regulate DNA (e.g., human topoisomerase I or II, Figure 2). We are also interested in targeting bacterial DNA gyrase and topoisomerase 1A.

Synthesis and Mechanism. After a novel series of compounds have been designed, MSc and PhD students as well as post-doctoral research fellows in the group set upon the synthesis and characterization of the new metal chelates. Because the laboratory is set up for both chemistry and biochemistry, we evaluate the efficacy of the metal chelates against macromolecular targets using biophysical methods, spectroscopy, and computational biology. In 2021, protein X-ray crystallography will be added as a core method with a newly acquired macromolecular diffractometer (which replaces an older Bruker Proteum instrument). Collectively, these studies are designed to establish whether the complexes function as intended against DNA or the enzyme of interest and to uncover their mechanism of action. This is ultimately a challenging task with metallodrugs.

Collaboration. In partnership with colleagues in Pharmacology and the School of Molecular and Cell Biology at WITS, as well as collaborators overseas (e.g. UCF Medical School and the DTP of the NCI), compounds are screened for their cytotoxicity or bactericidal efficacy.

Gold(III) Chelates. Since 2008, research focused on the design of pyrrole-based chelates and macrocycles of gold(III) as well as isoquinoline-amide chelates of this metal has been pursued. In 2018 we reported (in collaboration with Kyle Rohde's group at UCF Medical School) that a simple bis(pyrrolide-imine) Au(III) chelate has remarkable bactericidal activity against both Mycobacterium tuberculosis and Mycobacterium abscessus (https://doi.org/10.1128/AAC.01696-17) and that the hit compound inhibits bacterial topoisomerase 1A. This work followed on from our patented anticancer compounds which are novel catalytic inhibitors and poisons of human topoisomerases I and II (Top1 and Top2), pivotal nuclear enzymes that regulate DNA supercoiling and replication.

Regarding human topoisomerases I and II, these two enzymes are validated anticancer drug targets since they are present at higher levels in tumor cells (relative to normal cells) and their inhibition by cytotoxic compounds induces apoptosis (controlled cell death) and thus tumor regression.

Mechanisms. Our work has shown that gold(III) chelates and macrocycles with appropriate ligands bind either to the DNA nucleobase targets of Top1 and Top2 by intercalation (Top1 and Top2 inhibitors) or irreversibly to the ternary DNA-drug-enzyme catalytic intermediates (e.g. Top2 poisons). In the case of the gold(III) macrocycles, the metal ion is irremissible for activity and we have been able to show that the lead compound fails to bind to DNA unless the gold(III) ion is present to stabilize the intercalation adduct through electrostatic binding of the metal ion to a thymine carbonyl oxygen (https://doi.org/10.1021/ja412350f ).

In other studies with collaborators, we have delineated the mechanism of solvatochromism in a binuclear Cu(II) metallocycle and the probable catalytic mechanism of Fe(II) and Ni(II) pincer chelates in the transfer hydrogenation of aromatic ketones. In all cases we use molecular simulations in unison with experimental data to delineate the mechanism at the molecular level.

Work in the group is presently focused on novel complexes of the metals Au(III), Cu(II), Pd(II), and Ga(III). We are also exploring some organometallic Ru(II), Fe(II) and Au(III) complexes in collaboration with Prof. Burgert Blom (Maastricht University, Netherlands) and Prof. Daniela Bezuidenhout (University of Oulu, Finland).