Synthesis of oxygen containing heterocycles as potential IDO inhibitors

Carvalho, Catarina (2013) Synthesis of oxygen containing heterocycles as potential IDO inhibitors. PhD thesis, University of Nottingham.

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Abstract

One potentially attractive approach to cancer therapy is to recruit the body’s own immune system to reject solid tumours. The enzyme indoleamine 2,3-dioxygenase (IDO) has been shown to play a major role in supressing immune response, and there is now growing evidence to support the hypothesis that inhibition of IDO produces significant anticancer effects. The development of chemotherapeutic agents for cancer based on the inhibition of indoleamine 2,3-dioxygenase is the purpose of this present work.

Chapter I contains an overview of indoleamine 2,3-dioxygenase, describing its structure, activation cycle, catalytic mechanism and inhibitors.

Chapter II is divided in two parts. Initially the efforts towards the synthesis of a simple analogue, containing the isobenzofuranquinone moiety of annulins A and C are described. The aim was to verify which part of the molecule was important for IDO inhibiton. Four main approaches to the analogue are described. Next, investigations into the total synthesis of annulins A and C are discussed. These led to the synthesis of the naphthoquinone core of both natural products by performing a Diels Alder reaction. Attempts to introduce the furan ring proved challenging, and different approaches to this problem are described in this Chapter.

In Chapter III, the synthetic approaches towards annulin B are discussed. The possibility to access this natural product via Diels Alder reaction, prompted us to investigate the synthesis of the required dienophile – a chroman-3-one substrate. We succeeded in constructing this highly advanced intermediate using two different strategies, namely a Dieckmann condensation and an intramolecular O-H insertion reaction.

Finally, the synthesis and biological evaluation of a narrow range of benzofuranquinones with varying substituents are presented in Chapter IV. Their synthesis was based on the structure of the benzofuran ACH488, previously identified as a good IDO inhibitor.

The experimental details of the above work are described in Chapter V.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Moody, C.J.
Lygo, B.
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 13093
Depositing User: EP, Services
Date Deposited: 11 Aug 2016 09:41
Last Modified: 14 Sep 2016 07:25
URI: http://eprints.nottingham.ac.uk/id/eprint/13093

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