Synthesis of the RNA polymerase inhibitor tagetitoxin

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.

The initial impact of this research is likely to be in an advancement of knowledge; through synthesis of a selective inhibitor of RNA polymerases, we will enable detailed studies of transcription and an unravelling of the precise interplay between different RNAP subtypes in transcription events. By preparing relatively large quantities of tagetitoxin, as well as possibly providing analogues with greater potency or cell penetrating ability, we should enable in vivo studies of a type which were not previously possible.

A further impact will be in feeding the "people pipeline" - the PDRA who carries out the research will be intimately involved in the planning of synthetic strategies, and will develop their skills in carrying out a modern synthetic chemistry project, as well as broadening their knowledge of the chemical literature and of literature-searching techniques. He/she will also develop more generic skills in areas such as time management, project management, and oral and written communication. Through liaison with the project partner they will also gain experience in working in a larger project team, and in interdisciplinary areas. These skills will equip the individual for a successful career as a research leader in chemistry (e.g. pharmaceuticals, agrochemicals, biotech, academia) or in other related fields (e.g. patents, finance, consultancy).

A longer term potential impact of the research is in healthcare; specific inhibition of RNA polymerase III has been put forward as a potential novel therapeutic angle for treatment of cancer or cardiac hypertrophy. While such studies are beyond the scope of this project, synthesis of the ONLY known small-molecule inhibitor of RNA polymerase III is an important starting point to the development of more drug-like analogues which could allow the testing of this therapeutic hypothesis. A successful outcome to the current project will lead to further funding applications to explore these healthcare opportunities.