A Drug Discovery Study: Inhibitor Design for HRV 3C Protease Based on the Scaffold of (-)-Thysanone

This thesis is concerned with the drug development study against the common cold based on the ( )-thysanone scaffold. The common cold, majorly caused by the Human Rhinovirus, still remains one of the major causes of work-loss in industrialised countries and currently only symptomatic treatment is available to treat these viral infections. Thus, even though this illness is not life threatening, a direct anti-viral drug would be of significant benefit. ( )-Thysanone was isolated from the fungus Thysanophora penicilloides and was shown to inhibit the viral enzyme HRV 3C protease with an IC50 of 13 μg/mL (47 μM). HRV 3C protease is required for viral replication, thus inhibition of this enzyme will also inhibit the reproduction of the virus. O O O OH OH HO 7 9 (−)-thysanone This study is divided into three parts. The first part gives a brief introduction to the common cold, its major cause -the Human Rhinovirus- and attempts for drug development. The second part describes the determination of structure activity relationships (SAR) of a first generation library of inhibitors based on the ( )-thysanone scaffold and also pharmacodynamic aspects, such as the molecular mechanism of action of ( )-thysanone with HRV 3C protease, cross interactions with other important human proteases and cytotoxicity assays of our library of compounds against a human lung epithelia cell line. The third part then describes the syntheses of all analogues. Two literature known preparations of the natural product and the 7,9-dideoxy analogue were followed as well as the development of a new strategy for the synthesis of 2-carbathysanone using a Hauser-Kraus annulation as key-step and the development of a new synthetic approach for 7-deoxy analogues using an oxa-Pictet-Spengler reaction in the key step. This oxa-Pictet-Spengler approach was also used for development of a new synthetic strategy for thysanone also involving C-H activation chemistry.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2014

Author dc:creator

• Schünemann, Katrin

Advisors dc:contributor.advisor

• Brimble, M
• Fraser, J

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/22763

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/22763