Moses - Design and syntheses of new functional molecular entities
With a background in Synthetic Organic Chemistry, the primary research interests of the Moses research group are in the design and syntheses of new functional molecular entities, and the development of new methodologies for challenging and useful chemical reactions/transformations.
A significant proportion of the Moses group’s research is multidisciplinary and conducted in collaboration with specialists, allowing us to explore beyond the boundaries of our own discipline and achieve greater outcomes.
Our research interests are diverse in application and scope, yet can be categorised into one of three main areas: i. Click Chemistry; ii. Natural Product Synthesis, and iii. Chemical Biology. These research themes naturally blend well together: “To search for function, and apply knowledge, skills and techniques to the study and chemical intervention of natural & biological systems.”
Click chemistry is a synthesis approach developed for the rapid construction of functional molecules, including new drugs, functional materials and important chemical tools for biology. By their very nature, click reactions are high yielding, wide in scope, create only inoffensive by-products, are specific, simple to perform and can be conducted in easily removable or benign solvents. They enable the unification of discrete units or ‘building blocks’ in a controlled fashion, thereby building-up complexity with exquisite control.
Sulfur-Fluoride Exchange (SuFEx) is a new branch of click chemistry and focuses around the exchange of the sulfur-fluorine bond for an incoming nucleophile, often an aryl silyl ether or amine.
In the Moses group, we focus on the development and application of new functional click chemistry, with particular emphasis on anticancer drug discovery, new antibiotics and chemical biology.
For example, we have employed this new technology for the rapid generation of new heterocycles and compounds containing pendant sulfonyl fluorides through the latest sulfur hub, 1-bromoethene-1-sulfonyl fluoride (BESF).
We have also developed an efficient amide coupling reagent ‘SuFExAmide’ mediated through sulfur-fluoride exchange chemistry for the synthesis of challenging amides. We have demonstrated its application in the difficult amide coupling to synthesise GNF6702 a promising candidate for the treatment of Chagas disease, leishmaniasis and sleeping sickness.
Antibiotic drug discovery
Anti-microbial resistance (AMR) is an emerging threat to human health, and one of the greatest challenges facing the world currently.
According to the WHO: “A post-antibiotic era—in which common infections and minor injuries can kill—far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century”.
Unfortunately, the problem is not improving, and no new antibiotic class has been developed in decades. The historical low cost and relatively short life-span of antibiotics have resulted in many companies moving away from antibiotic research due to poor economic return relative to investment.
Traditionally, natural products have been the feedstock of new and diverse antibiotics (e.g. penicillins). However, the success of antibiotics is dependent upon their availability. Typically isolated in minute quantities from nature, the foundation of a sustainable supply is vital. This challenge is further compounded by the fact that many natural antibiotics are incredibly complex and sophisticated molecules, rendering them impractical for large scale synthesis (see Chem Eur J 2016).
Rather than pinning all hopes on discovering new antibiotics; a process that is likely to take decades before they reach the clinic, a realistic short-to-medium-term solution is to re-engineer existing, readily available drugs such that they are not susceptible to existing resistance mechanisms. This approach will facilitate a “shortcut to the clinic” by fast-tracking toxicological and clinical trials given prior knowledge of the particular antibiotic class.
In the Moses group, we are developing a novel approach to help fight anti-microbial resistance by employing click chemistry as a tool to reengineer antibiotics to overcome currently known resistance mechanisms.
Biomimetic synthesis of complex natural products
Biomimetic chemistry is a synthetic approach towards the synthesis of natural products. It draws inspiration from the elegant higher order complexity-generating processes that 'Mother Nature' employs in her biosynthetic schemes — allowing rapid and efficient entry to complex core structures that may otherwise require lengthy and difficult schemes.
The Moses group are pioneers in the field, and particularly in the development of concerted and pre-disposed tandem reaction sequences. For example, we have a long-standing interest in the study and synthesis of polyketide derived metabolites (the tridachiahydropyrones) isolated from marine molluscs. We have proposed and demonstrated, through experimentation, a complex biosynthetic scheme to explain the origins of these interesting compounds. Using our biomimetic photochemical approach, we have been able to synthesise and investigate the biological activities of these precious molecules. Employing complex biophysical techniques we have provided convincing evidence that these metabolites function as membrane bound sunscreens with anti-lipid peroxidation activity (see Phys Chem Chem Phys., 2012).
Chemical biology demonstrates how chemistry can be applied to solve biological problems, and with expertise in both Click and Biomimetic chemistry, we are ideally placed to exploit our skills in chemical biology applications.
In collaboration with Professor Neil Oldham, we have developed a new protein foot-printing approach for application in the study of protein-protein, and protein-drug interactions. A photo-chemically activated molecular click probe, that when irradiated, inserts into given regions of the target proteins. Mass spectroscopy techniques are then used to pinpoint patches of ligand-protein surface binding.
What makes our approach unique is the flexibility of the probe design, which allows us to tune them to focus on certain areas of the protein. We have demonstrated the feasibility of our method for in a proof of principle study in several systems, and are currently developing the method for wider application. We are particularly keen to develop collaborations where we can utilise our molecular based methodology as a supporting technology for biology (see Nat Comm., 2016).