ESR Project 9
Ghent University, Organic and Biomimetic Chemistry Research group, Department of Organic and Macromolecular Chemistry, Ghent, Belgium
Furan and porphyrin containing crosslinking ligands for covalent stabilisation of G quadruplexes as cell-permeable anti-cancer aptamers
Prof. Edvard Smith, Clinical Research Centre at Karolinska University Hospital (Clinician)
Prof. Eugen Stulz, University of Southampton (Academic)
Jack Barr obtained his MChem in Chemistry with International Experience in 2019 from the University of Manchester, United Kingdom.
His Master’s thesis was under the supervision of Prof. Michael Greaney and concerned the trifluoromethylation of disulfides using photocatalysis. As well as a Master’s thesis, Jack was also awarded a three-month DAAD RISE scholarship at the University of Cologne researching nanoparticle catalysed hydrogenation and completed an exchange year at the University of Hong Kong.
After graduation, Jack was selected for the AstraZeneca R&D Graduate Program located at the AZ Gothenburg site, Sweden. There he completed three eight month-long rotations in the New Modalities Chemistry Team, Genome Engineering Team and PROTAC Medicinal Chemistry Team where he contributed to a variety of company projects and academic collaborations.
The aim of this ESR PhD project will be to evaluate ONs and compounds targeting non-B DNA structures in cellular DNA in order to study the behaviour of such structures. Specifically, we will target telomerase activity and gene expression that is regulated by GQs for cancer therapy. GQs are Guanine-rich DNA and RNA sequences of the type (GGGXn)4 and are known to form stable intramolecular quadruplex structures containing stacks of G-quartets, particularly in the presence of K+. These structures play an important role in genome maintenance (telomer) and the regulation of gene expression (promoter), and can adopt a variety of tertiary structures (parallel, antiparallel, hybrid). We will aim at the design and synthesis of furan- and porphyrin containing ligands for covalent binding to specific GQ forms and by Cross-linking attempt to stabilise specific GQ folding. The GQ structures will be probed with different furan- and porphyrin-modified forms of the G4-stabilizing ligands and the effect on cancer cell viability will be studied.
This project is carried out in strong collaboration with the following groups:
Prof. Eugen Stulz, University of Southampton, UK
Dr. Shalini Andersson, AstraZeneca, Cardiovascular, Renal and Metabolic Diseases (CVRM), Sweden
Project summary in 3 min
Research activities in the OBCR group of Prof. Dr. Madder are focused on
(1) Design and synthesis of conformationally defined cyclic peptides for therapeutic purposes;
(2) Development of chemically modified aptamers for improved sensor development;
(3) Development of new methods for crosslinking and labeling of biomacromolecules such as peptides, proteins and oligonucleotides.
In the current project our furan-oxidation based nucleic acid crosslinking expertise will be exploited to design specific ligands for GQs and in collaboration with the other partners of the network, biological activity will be studied.