Restricted Diversity; Constrained Diversity-Oriented Synthesis
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
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.
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.
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.
Publications
Tan YS
(2012)
Using ligand-mapping simulations to design a ligand selectively targeting a cryptic surface pocket of polo-like kinase 1.
in Angewandte Chemie (International ed. in English)
O'Connell KM
(2012)
Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds.
in Beilstein journal of organic chemistry
Beckmann HS
(2013)
A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling.
in Nature chemistry
Tan YS
(2014)
The use of chlorobenzene as a probe molecule in molecular dynamics simulations.
in Journal of chemical information and modeling
Koutsoukas A
(2014)
How diverse are diversity assessment methods? A comparative analysis and benchmarking of molecular descriptor space.
in Journal of chemical information and modeling
Grossmann A
(2014)
Diversity-oriented synthesis of drug-like macrocyclic scaffolds using an orthogonal organo- and metal catalysis strategy.
in Angewandte Chemie (International ed. in English)
Laraia L
(2014)
High content screening of diverse compound libraries identifies potent modulators of tubulin dynamics.
in ACS medicinal chemistry letters
Alanine T
(2014)
Concise Synthesis of Substituted Quinolizin-4-ones by Ring-Closing Metathesis
in European Journal of Organic Chemistry
Ibbeson BM
(2014)
Diversity-oriented synthesis as a tool for identifying new modulators of mitosis.
in Nature communications
Lau YH
(2014)
Investigating peptide sequence variations for 'double-click' stapled p53 peptides.
in Organic & biomolecular chemistry
Zhang F
(2014)
Arene C-H functionalisation using a removable/modifiable or a traceless directing group strategy.
in Chemical Society reviews
Lau YH
(2014)
Linear aliphatic dialkynes as alternative linkers for double-click stapling of p53-derived peptides.
in Chembiochem : a European journal of chemical biology
Lau Y
(2014)
Functionalised staple linkages for modulating the cellular activity of stapled peptides
in Chem. Sci.
Alza E
(2015)
Synthesis of a novel polycyclic ring scaffold with antimitotic properties via a selective domino Heck-Suzuki reaction.
in Chemical science
Scanes R
(2015)
Enantioselective Synthesis of Chromanones via a Peptidic Phosphane Catalyzed Rauhut-Currier Reaction
in Organic Letters
Laraia L
(2015)
Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions.
in Chemistry & biology
Isidro-Llobet A
(2015)
A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds.
in Organic & biomolecular chemistry
Salvaggio F
(2015)
The Synthesis of Quinolone Natural Products from Pseudonocardia sp.
in European Journal of Organic Chemistry
Lau YH
(2015)
Double Strain-Promoted Macrocyclization for the Rapid Selection of Cell-Active Stapled Peptides.
in Angewandte Chemie (International ed. in English)
Tan YS
(2015)
The Application of Ligand-Mapping Molecular Dynamics Simulations to the Rational Design of Peptidic Modulators of Protein-Protein Interactions.
in Journal of chemical theory and computation
Lau YH
(2015)
Peptide stapling techniques based on different macrocyclisation chemistries.
in Chemical Society reviews
Lau Y
(2015)
A two-component 'double-click' approach to peptide stapling
in Nature Protocols
Frei MS
(2015)
Studies towards the synthesis of indolizin-5(3H)-one derivatives and related 6,5-azabicyclic scaffolds by ring-closing metathesis.
in Bioorganic & medicinal chemistry
Nie F
(2016)
A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles.
in Angewandte Chemie (International ed. in English)
Wiedmann MM
(2016)
Structural and calorimetric studies demonstrate that the hepatocyte nuclear factor 1ß (HNF1ß) transcription factor is imported into the nucleus via a monopartite NLS sequence.
in Journal of structural biology
Spring D
(2016)
Divergent Total Syntheses of Flavonoid Natural Products Isolated from Rosa rugosa and Citrus unshiu
in Synlett
O' Donovan D
(2016)
The reductive cleavage of picolinic amides
in Tetrahedron Letters
Geddis SM
(2016)
Divergent Synthesis of Quinolone Natural Products from Pseudonocardia sp. CL38489.
in European journal of organic chemistry
Spring D
(2016)
Diversity-Oriented Synthesis of Macrocycle Libraries for Drug Discovery and Chemical Biology
in Synthesis
Brear P
(2016)
Specific inhibition of CK2a from an anchor outside the active site.
in Chemical science
Glen RC
(2016)
Multiple-parameter Optimization in Drug Discovery: Example of the 5-HT1B GPCR.
in Molecular informatics
Twigg DG
(2016)
Partially Saturated Bicyclic Heteroaromatics as an sp(3) -Enriched Fragment Collection.
in Angewandte Chemie (International ed. in English)
Sum TH
(2016)
Combinatorial Synthesis of Structurally Diverse Triazole-Bridged Flavonoid Dimers and Trimers.
in Molecules (Basel, Switzerland)
Alanine TA
(2016)
Concise synthesis of rare pyrido[1,2-a]pyrimidin-2-ones and related nitrogen-rich bicyclic scaffolds with a ring-junction nitrogen.
in Organic & biomolecular chemistry
Bartlett S
(2016)
C-H activation: Complex peptides made simple.
in Nature chemistry
Janecek M
(2016)
Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2.
in Scientific reports
Ciardiello J
(2016)
An expedient strategy for the diversity-oriented synthesis of macrocyclic compounds with natural product-like characteristics
in Tetrahedron
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 |