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Details of Grant 

EPSRC Reference: EP/P000428/1
Title: Synthesis of the RNA polymerase inhibitor tagetitoxin
Principal Investigator: Porter, Dr MJ
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Newcastle University
Department: Chemistry
Organisation: UCL
Scheme: Standard Research
Starts: 01 October 2016 Ends: 28 February 2020 Value (£): 389,768
EPSRC Research Topic Classifications:
Chemical Biology Chemical Synthetic Methodology
EPSRC Industrial Sector Classifications:
Pharmaceuticals and Biotechnology
Related Grants:
Panel History:
Panel DatePanel NameOutcome
12 May 2016 EPSRC Physical Sciences Chemistry - May 2016 Announced
Summary on Grant Application Form
Chemical compounds obtained from natural sources frequently have interesting biological effects; between 1981 and 2010, over one-third of new drugs were either natural products or derivatives of them. The importance of such compounds can further be gauged by the award of the 2015 Nobel Prize for Medicine to scientists who discovered natural products which could treat malaria and river blindness.

The proposed research focuses around a natural product called tagetitoxin, which has unique biological effects: it is the only compound known to selectively inhibit an enzyme called RNA polymerase III. This enzyme is one of a family of enzymes responsible for translating the genetic code of DNA into RNA, a fundamental biological process known as transcription.

Inhibition of RNA polymerase III is of interest for biologists studying the detailed mechanism of transcription and a compound which is a selective inhibitor would be valuable in unravelling the complex interplay between the various enzymes involved. Furthermore, the activity of RNA polymerase III has been found to be suppressed in various cancers, and this has led to the suggestion that inhibition of the enzyme could prove a novel therapeutic pathway for the treatment of cancer and/or cardiac hypertrophy.

Tagetitoxin was isolated from bacteria over 30 years ago. A chemical structure was proposed in 1983, but this initial proposal was rejected in favour of a different structure in 1989. Recently, we have shown that the 1989 structure is also incorrect and have formulated a new structure.

In this research, we aim to use synthetic chemistry to assemble the tagetitoxin molecule from scratch. As well as confirming the structure of the compound, this will allow us to supply cell biologists with an invaluable tool in the study of transcription. By preparing the compound synthetically, we open the possibility of developing analogues of tagetitoxin which could have even greater potency or selectivity, and of synthesising compounds which could lead to the development of new drugs.
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