RESEARCH PROJECTS

Current Areas of Study

HYDROXYLAMINES

The investigation and implementation of underrepresented groups functional groups has had a profound impact on the medicinal chemistry and drug discovery space. One such underrepresented group, the trisubstituted hydroxylamine, has long been regarded as a structural alert in medicinal chemistry due to the presence of the weak N-O bond, as well as supposed genotoxicity and mutagenicity. Efforts from our lab implementing the trisubstituted hydroxylamine as a bioisostere have demonstrated these substrates to be stable, lack mutagenicity or genotoxicity, as well as revealing interesting properties such as increased penetrance of the blood brain barrier and increased solubility, amongst others. We have developed numerous synthetic methods which have improved access to these under investigated compounds, in the process providing lead compounds suitable for further development. We continue to investigate the trisubstituted hydroxylamine and its properties via new chemistry development as well as judicious implementation of hydroxylamines as bioisosteres.

AMINOGLYCOSIDE ANITBIOTICS

Aminoglycoside antibiotics (AGAs) are listed by the WHO as critically important antimicrobials for human therapy. Their high efficacy, broad-spectrum antibacterial activity in combination with unmatched rapid bactericidal potency, lack of drug-related allergy, little protein binding and minimal drug metabolism, absence of interaction with other pharmaceutical agents and with the host’s intestinal microbiome, are features that combine to make aminoglycosides a potent and powerful choice for treatment of serious infections by Gram-negative pathogens.
Work in our laboratory has and continues to focus on the design and development of next generation AGAs for the treatment of multidrug resistant Gram-negative infections with the emphasis on overcoming resistance by aminoglycoside modifying enzymes and ribosomal methyltransferases, with concomitant reduction of side effects due to oto- and nephrotoxicity.

MECHANISMS IN CARBOHYDRATES

Progress in the glycosciences has long been hindered by the inaccessibility of significant quantities of pure, homogeneous natural glycans and their conjugates and by the difficulties inherent in their chemical synthesis. We take the position that existing chemical approaches to improved glycosylation methods suffer from a lack of understanding of the basic reaction mechanisms. As such we apply a variety of physical organic methods to provide insight into the nature of the key intermediates and into how they react. Building on this insight we then develop and apply improved and more stereoselective methods and apply them to the synthesis of suitable targets.