School of Pharmacy

Staff Profile

Dr Jon Sellars

Lecturer in Medicinal Chemistry

Background

Dr Jon Sellars is a Lecturer in Medicinal chemistry at the School of Pharmacy and the Institute of Cellular Medicine at Newcastle University. 

He gained a PhD with Prof. Patrick Steel at Durham University investigating the utility of silacyclohex-4-enes in organic synthesis. Subsequent employment at Sanofi-Aventis in Alwnick working on radio labelling active pharmaceutical ingredients was followed by a return to Durham University, to undertake a post doctoral position with Prof. Patrick Steel and Prof Robert Edwards investigating multiple herbicide resistance in black grass (supported by Syngenta).

In 2010, Jon was awarded an EPSRC Life Sciences Interface Fellowship to develop novel proteomic probes to study cytochrome P450's. After completion, Jon undertook a teaching fellowship at Durham University where in 2015 was appointed to a lectureship in medicinal chemistry at the School of Pharmacy. In August 2017 the School was transferred to Newcastle University resulting in the creation of the School of Pharmacy.

Areas of expertise

  • Organic Synthesis
  • Proteomics
  • Chemical Biology

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Research

Our group has a range of research interests that lie on the chemical biology interface, from developing novel chemical small molecule probes, inhibitors and delivery vehicles to the discovery and application of new synthetic methodology for their construction. All this provides us with the tools to challenge and answer important biological and chemical questions.


Antimicrobial agents

Antibiotics are the leading treatment for bacterial infections, with their discovery heralding the ability to cure previously untreatable infections. However, our reliance and miss-use over a 75-year period have brought about the prevalence of multidrug-resistant bacteria which is driving a global resistance problem. As a result, we are engaged in a number of projects focussing on the discovery of new antibacterials targeting mycolata bacteria, specifically Mycobacterium tuberculosis.


Project - Novel Benzoxa-[2,1,3]-diazole Substituted Amino Acid Hydrazides as Potential Anti-Tubercular Agents[1]

In this project we have developed a series of novel benzoxa-[2,1,3]-diazole substituted amino acid hydrazides as selective drugs for the treatment of TB, highlighting the importance of the benzo-[2,1,3]-diazole, amino acid (AA) and the substituted aryl hydrazine (R1), towards Mtb selectivity, potency, efficacy, and avoidance of toxicity against mammalian cells.


Cancer

Head and neck cancers are among the leading causes of mortality worldwide, and the incidence and mortality rates are increasing rapidly. For example, death rates from lip and oral cavity cancers increased by 35.6% between 2007-2017 and mortality from oral cancer is projected to continue increasing faster than any other cancer up to 2035. Consequently, there is a need to understand this, why it is happening and begin to design and develop

potential treatments.


Project - The role of the microbiome in oral cancer

Changes in the oral microbiome have been associated with different cancers including pancreatic cancer, colorectal carcinoma and oesophageal cancer. In the case of oral squamous cell carcinoma (OSCC), comparison of the microbiota present at cancerous lesions with anatomically matched non-cancerous sites identified a cancer-associated microbiome enriched in taxa that are correlated with periodontitis, including the genus Fusobacterium. This project aims to provide a preliminary characterisation of the role of Fusobacterium spp. and other bacteria in OSCC. The key objectives are (i) to develop techniques for detecting Fusobacterium spp. and for analysing the microbiome in formalin-fixed paraffin-embedded (FFPE) samples of oral precancerous lesions, (ii) to establish laboratory models for studying interactions between Fusobacterium spp. and epithelial cells, (iii) to develop an ethical approval for a future prospective study on the microbiome associated with OSCC.


Drug delivery vehicles

Metal-Organic-FrameworkS (MOFs) are polymeric, three dimensional, structures comprising metal nodes (e.g. Ag, Au, Fe) with interconnecting organic strands (e.g. bi-arylbenzoic acids). The hybridisation of the organic strands contributes significantly to the framework architecture often leading to accessible internal cavernous space that has recently drawn significant attention in current research directives. Sequestration of compounds into these cavities, such as CO2 and small molecule drugs has opened up the possibility for new applications in carbon capture and drug delivery systems.


Project – Development of new MOF’s as drug delivery platforms

To this end, it is our intention to address the issues (e.g. leaky cavities, biocompatibility) surrounding drug delivery applications through the synthesis of novel MOFs incorporating high-pressure cross-linking subunits to prevent leaking and the development of new metal nodes and clusters to combat biocompatibility.


Cytochrome P450’s

Cytochrome P450s (CYP450s) constitute a large family of haem-centred enzymes, with fundamental roles in the biotransformation of endogenous (steroid hormones, fatty acids, prostaglandins) and exogenous molecules (drugs, environmental chemicals, agrochemicals). As a direct result of their importance, particularly in xenobiotic and drug metabolism, a great deal of research has been conducted into the roles, identification of their sequences and their catalytic mechanism. Whilst a number of CYP450s, particularly human liver CYP450s and extra-hepatic CYP450s (i.e. CYP1A1, CYP1B1 and CYP2W1) have been the subject of intense investigation, much is still to be learnt from these mixed-function oxidases.


Project - Rational Development of Novel Activity Probes for the analysis of Human CYP450’s

New approaches to identify, evaluate and quantify functionally active CYP450s are of the utmost importance. Our group has shown that adaptation of a benzofuran with biotin to produce 1 is able to demonstrate selectivity against an array of bactosome-expressing CYP450s using streptavidin blotting. Probe 1 formed clear NADPH–dependent complexes with CYP1B1, CYP2B6 and CYP3A4, and to a lesser extent CYP2C9. The promiscuity of CYP450s is not unexpected, as they have been implicated in the metabolism of a variety of xenobiotic compounds in human liver. The level of selectivity displayed by 1 in binding to CYP450s in an NADPH-dependant manner with little to no binding observed in its absence is exemplary.[2]

Figure 5: Streptavidin blot of probe 1 incubated with bactosomes expressing a specific CYP450 isoform in the presence or absence of NADPH.


Spin crossover complexes

The phenomenon known as Spin Crossover (SCO) is the process of electronic spin transitions in octahedral d4-7 metal complexes, where the metal ions can exist in either the High (H.S.) or Low Spin (L.S.) states. This event can be induced by various stimuli such as temperature, pressure and photoirradiation only if the energy provided by the external source is sufficient to allow crossing between the two states.

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Project – Development of new Spin Crossover Complexes and their in-situ transition measurement

Spin crossover systems currently have their magnetic susceptibility measured and their spin state determined from Mössbauer spectrometery/SQUID with the crystal structure of the system then determined using X-ray diffraction. Our project focuses on the development of a system which allows for thermal and light-induced transitions to be measured using an X-ray diffractometer in-situ. By measuring the bond lengths, for example of Fe-N bonds which in L.S. are ~ 1.9 and in H.S. ~2.1 you can determine the complexes spin state. If this occurs thermally it is simple to measure with the use of any diffractometer with a cryostat system. To understand the LIESST, on the other hand, requires the addition of devices which can change the environment using light. This is generally achieved by lasers, but this project aims to use high powered LEDs which can have a large variety of wavelengths to promote spin-state switching in samples.


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References


[1] A. K. Brown, A. K. Aljohani, J. H. Gill, P. G. Steel, J. D. Sellars, Molecules 2019, 24, 811.

[2] J. D. Sellars, M. Skipsey, Sadr‐ul‐Shaheed, S. Gravell, H. Abumansour, G. Kashtl, J. Irfan, M. Khot, K. Pors, L. H. Patterson, et al., Chemmedchem 2016, 11, 1122–1128.

Publications