Restricted Diversity; Constrained Diversity-Oriented Synthesis

Lead Research Organisation: University of Cambridge
Department Name: Chemistry


The UK is at the forefront of the worldwide pharmaceutical industry, which develops new medicines for many diseases, and benefits the British economy through income, employment, expertise and major investment. The UK pharmaceutical industry directly employs around 70,000 people and typically contributes £10 billion to the UK's GDP. Figures for 2007 show that the industry invested a total of £3.9 billion in UK research and development, and that exports of pharmaceutical products from the UK totalled £14.6 billion, creating a trade surplus in pharmaceutical products of £4.3 billion. This is an important industry to support with academic research. The industry is concerned with the creation of small molecules. Pharmaceutical drugs are small molecules. The discovery of small molecules that have specific properties or functions is clearly important for scientific progress that will impact on everyday life. Unfortunately, there is a serious problem in the development of new drugs. Drug discovery has been hampered by a high rate of attrition of clinical candidates. This has been ascribed to the clinical candidates not having the correct properties or binding profiles.

This proposal aims to exemplify new strategies to access efficiently and discover novel small molecules within a desired range of properties or binding profiles that are directly relevant to the pharmaceutical industry. This strategy has been termed constrained diversity-oriented synthesis. The project will involve the development of new chemistry, the synthesis of new small molecules, differential assessment of restricted diversity and the discovery of biologically active compounds and potential chemotherapeutic agents. The approach will lay the scientific and technological foundations for the development of protein-protein interaction modulation as a tool for chemical biology and molecular therapeutics. The proposed work has the potential to transform current approaches to drug discovery, and to radically extend the repertoire of tools available for chemical biology.

Small molecules are essential to everyday life. They have importance beyond the pharmaceutical industry, since plastics derive from small molecules, hydrocarbon fuels are small molecules, etc. Therefore, our research has the potential to impact widely on health and quality of life.

Planned Impact

The impact of this research programme arises from the development of new strategies and approaches to small molecule synthesis. In contrast to conventional target-oriented and combinatorial synthesis strategies, the research concepts of this proposal represent a major step-change from the chemist's current approaches to access small molecules with desired functionality. The research program has involved consultation with AstraZeneca who will ensure that the restricted diversity research is relevant to industrial applications. This research will have a broad impact across modern society because the molecules that make up everyday products such as medicines, plastics and chemical commodities are small molecules with appropriate physicochemical properties. Methods to discover improved products will be highly applicable. Therefore, the outputs from this research will provide better ways of discovering molecules, that lead to new medicines through accelerated drug discovery, advances in chemical biology and materials, and an enhanced knowledge base that will underpin the future of the UK 'Chemical Economy'.

Who might benefit from this research? How might they benefit from this research?

Academic community - the major beneficiaries of this research will be researchers in chemical synthesis, medicinal chemistry, chemical biology and life science research that will benefit from the new synthesis methods and chemical tools that we will invent. The research will develop new knowledge and skills that other researchers can use to access new small molecules that can be used to address problems in broader areas of science, and will therefore act as a focal point for chemistry driven multi-disciplinary ventures.

Industry - Constrained diversity-oriented synthesis will have impact across the chemical industry. In the pharmaceutical industry, medicinal chemists will benefit enormously from this research because it will provide a faster access to medicines by using new methods to identify and make molecules quickly.

General Public - Improvements to health and quality of life are potential impacts of the research in this proposal, and while these benefits may be seen through improved consumer products, we will make every effort to communicate the fundamental breakthroughs we make to the general public.

Education - We will influence the education of chemistry students. Diversity-oriented synthesis is being taught to undergraduates and will make its way into textbooks providing high value impact in education.

Economy - There are many potential benefits to the UK economy that stem from applications of this research. For example, it will provide a highly skilled and educated workforce, boosting the knowledge base and hence economic output of the chemical industry. I am at the stage in my career where many top quality researchers apply to work in my laboratory and many of them will secure fellowships from their home countries. Therefore the Fellowship will provide leverage to access further funding from other agencies, providing high value for money to EPSRC.


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Bartlett S (2016) C-H activation: Complex peptides made simple. in Nature chemistry

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Brear P (2018) Novel non-ATP competitive small molecules targeting the CK2 a/ß interface. in Bioorganic & medicinal chemistry

Description This project is complete, and results have been very promising. We have illustrated new strategies to make novel chemical entities that could have important biological function. We have discovered several new chemotypes with biological activity, as described in our publications. The approach has been extended to conformational constraint of peptides, and this is proving very important to generically inhibit protein-protein interactions.
Exploitation Route The work has inspired many other groups' research programmes.
Sectors Chemicals

Description At this stage the project is only just having impact from publications over the last few years. We have expanded our ideas into conformational constraints in peptides.
Sector Chemicals
Impact Types Economic

Description AstraZeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution We have been working with AstraZeneca on developing new drug discovery fragments, macrocycles and linker technologies.
Collaborator Contribution AstraZeneca have been contributing expertise, access to facilities and student funding.
Impact There will be publication outputs from this multi-disciplinary collaboration.
Start Year 2012