Professor Karl J. Hale

Research

Whilst the vast majority of research within the Hale group is focused upon the development of new organic reactions and complex molecule total synthesis, many of our programmes in chemical genomics, chemical proteomics and small molecule drug discovery entail us collaborating with teams from other research disciplines such as molecular biology, molecular medicine, molecular modelling, biological NMR spectroscopy and pharmacology. As a consequence, members of our group are not only trained in high level organic synthesis, they are also exposed to cutting-edge research technologies from a range of other important science areas.

There are four major research themes pursued by the group.

Total Synthesis of Complex Biologically-Active Natural Products and Their Analogues, and The Use of Such Molecules in Chemical Genomics, Chemical Proteomics, and Small Molecule Drug Discovery

Our efforts in complex molecule total synthesis are usually driven by the need to access various highly rare, biologically active, natural products for chemical genomics and chemical proteomics studies. Virtually all of the molecules that we select for synthesis have some form of powerful in vivo anticancer, antimicrobial, antiviral, anti-obesity or anti-inflammatory effect that is generally allied to a novel molecular architecture and a unique mechanism of biological action. Whilst, in the vast majority of cases, the natural products that we synthesise are not themselves exploitable as disease-modifying drugs, they still often play a very important role in the overall drug discovery process, by enabling many novel proteins and genes to be properly validated as therapeutic targets in appropriate animal models of human disease.

A significant number of the analogues and probe structures that come from our programmes also provide powerful new insights into the functioning of important genes and signalling pathways within cells. In some instances, appropriately modified natural product probes also allow the isolation and structural characterisation of previously unknown proteins or genes by affinity chromatography techniques or by hybridised synthetic organic chemistry-molecular biology approaches. It will thus be appreciated that complex natural product total synthesis is an important research endeavour which not only advances the field of synthetic organic chemistry, it also leads to significant breakthroughs in modern-day biology, medicinal chemistry and molecular medicine. For all these reasons, we continue to make this exciting line of work our primary research focus here at Queen’s.

Examples of complex antitumour natural products that our team has successfully synthesised over the past decade include the molecules (+)-A83586C, (+)-kettapeptin, (+)-azinothricin, (-)-agelastatin A, bryostatin 7, (+)-eremantholide A, and (+)-pumiliotoxin B, all of which are now driving important chemical genomics and proteomics programmes within these laboratories.

 

 

New target molecules that we are currently, or are soon to begin, synthesising include the powerful antibacterial agent the antifungal geranylgeranyltransferase inhibitor massadine, the anticancer macrolide (+)-acutiphycin, and the analgesic alkaloid
(-)-Incarvilline, the structures of which are shown below:

 

New Organic Reaction Development

Underpinning many of the total synthesis programmes of our group are important methodological programmes aimed at identifying new types of organic reaction. Past successes, in this regard, include the tandem asymmetric hydrazination-nucleophilic cyclisation protocol that was introduced for building up homochiral piperazic acids. Not only did the latter methodology underpin our asymmetric total synthesis of A83586C, it also helped secure our route to the (3R,5R)-5-hydroxypiperazic acid component of (-)-himastatin which, like A83586C, is a powerful antitumour cyclodepsipeptide of microbial origin. We also used this technology to perform the first asymmetric synthesis of optically pure 5-chloro-piperazic acids.

 

Another important reaction that has been developed by our group is the Ph₃SnH and cat. Et₃B mediated O-directed free radical hydrostannation reaction of propargylically-oxygenated disubstituted alkynes, which has now emerged as a highly useful method for stereodefined trisubstituted olefin synthesis. It is presently being applied in a number of important total synthesis projects in our laboratory and recently led to a considerably abridged and fully stereocontrolled formal total synthesis of (+)-pumiliotoxin B that intersected with Overman’s previous 1996 route to this naturally-occurring frog toxin; for more details see our Selected Publications list.

 

Anticancer Drug Design and Chemical Biology

Current collaborators in the chemical oncology field include Dr Mohamed El-Tanani QUB Centre for Cancer Research and Cell Biology (CCRCB). Together, our groups are studying the pathways, genes and proteins that regulate Wnt/b-catenin signalling within cancer cells using novel small molecule probes based on the antitumour alkaloid (-)-agelastatin A, (+)-kettapeptin and (+)-A83586C. Whilst the ultimate long-term aim of these studies is to identify new drugs that will cooperatively act to prevent tumour cell growth and metastasis, we are currently employing our small molecule inhibitors of Wnt and b-catenin signalling to help us isolate and identify new biological targets of clinical relevance to the prevention of metastatic malignant cancer. Our group is also actively involved in E2F and osteopontin inhibitor design in collaboration with the group of Dr Mohamed El-Tanani of the QUB CCRCB

Biogenetically Modelled Natural Product Total Synthesis

Yet another highly challenging research sphere in which we routinely operate is in the area of biogenetically modelled natural product total synthesis. Here we are generally trying to chemically imitate a plausible biosynthetic pathway or a key enzymatically-driven step for the chemical construction of a highly challenging natural product target molecule in an in vitro laboratory setting. Often such synthetic work is fraught with difficulties, and is invariably reliant upon the careful orchestration of many key molecular recognition and self-assembly processes to arrive at the final end-point. Despite the risks involved in such research, this type of work can often pay handsome dividends when successful, as exemplified by the endgame that we developed for total synthesis of A83586C, which brought together two highly elaborate coupling partners to give an ornate glycal that readily underwent hydration to produce the natural product.

 

In biomimetic natural product total synthesis, the great challenge is usually to carefully design appropriately functionalised molecular precursors that will readily self-assemble with minimal external assistance. Although we have several synthetic programmes ongoing in this area, probably the most chemically advanced project of this type that we are presently involved in is our biogenetically-modelled asymmetric total synthesis of the complex antitumour agent halichomycin (see below).