Development of the aza-Prins reaction; synthesis and biological evaluation of JBIR-102

Project Information

MESO-JBIR-102

Grant agreement ID: 706581

DOI

10.3030/706581

Project closed

EC signature date 19 April 2016

Start date 1 July 2016

End date 16 October 2018

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 195 454,80

EU contribution

€ 195 454,80

Coordinated by

UNIVERSITY OF GREENWICH
United Kingdom

Periodic Reporting for period 1 - MESO-JBIR-102 (Development of the aza-Prins reaction; synthesis and biological evaluation of JBIR-102)

Reporting period: 2016-07-01 to 2018-06-30

Summary of the context and overall objectives of the project

Human malignant pleural mesothelioma is an aggressive (fatal) lung cancer which is always associated with previous asbestos exposure. Typically symptoms do not appear until 35-40 years after the original exposure, with life expectancy then 12-18 months. There is no known cure for mesothelioma: traditional chemotherapeutic cancer treatments have had little impact on the disease and radiotherapy or partial pleurectomy have only very limited impact on life expectancy. However, very little in the way of mesothelioma research is taking place, as it is frequently not considered to be a ‘big enough market’ (<1% of all cancers in the U.K. approximately 2300 deaths per annum). Consequently there are currently no novel drugs in development for this disease. A second reason is that there have been no reported good lead compounds as a starting point for the drug discovery process. Hence any projects - such as this one - looking to address our fundamental knowledge of mesothelioma will be of significant societal impact.

This project aimed to study a novel, newly isolated natural product, named JBIR-102, and its associated anti-mesothelioma activity. This was addressed in two ways: first by the development of the aza-Prins reaction - a novel piece of synthetic chemistry to prepare nitrogen-containing heterocyclic structures and second to apply this developed method to the synthesis of JBIR-102. Within this, the first aim - developing the aza-Prins reaction - was achieved very successfully and the second half of the project was well advanced at the end of the contract.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

There were two overall aims for the project - developing and optimising the aza-Prins (and related) reactions for the preparation of nitrogen-containing heterocyclic structures, and second applying this to the total synthesis of JBIR-102.

During the project, the aza-Prins and aza-silyl-Prins reactions have been developed as a rapid method to prepare piperidines and related nitrogen-containing heterocycles. Specifically, the aza-Prins reaction has been:
a) optimised i.e. many different reaction conditions have been screened to find the best conditions. Variables studied included the choice of acid employed to catalyse the reaction (Bronsted or Lewis acids), solvents, temperature and reaction times.
b) the reaction was developed initially in a racemic form but crucially developed into an asymmetric version to give piperidines as a single enantiomer in very high yields. This involved the development of a novel chiral auxiliary.
c) an additional novel reaction - the aza-silyl-Prins reaction - related to the aza-Prins reaction, has also been developed and optimised.
d) adapted and modified to produce fused aza-bicycles (the core structural architecture found in JBIR-102).

Concerning the total synthesis and biological evaluation of JBIR-102, a large number of fused aza-bicyclic containing compounds have been prepared using the methodology prepared in the first part of the project. These are simplified versions of JBIR-102, containing some (but not all) of the structural features of the natural product. These are crucially undergoing biological evaluation to give an indication of the mode of action of JBIR-102. As a result of the action, additional funding has been secured (from the University Alliance DTA Co-FUND scheme) to continue the project and complete the synthesis of JBIR-102.

The work has been presented either by the Fellow or by the PI at several international conferences, including:
1. Royal Society of Chemisty Heterocyclic & Synthesis Group Grasmere International Heterocyclic Meeting (May 2017)
2. International Society of Heterocyclic Chemistry (ISHC), Regensburg Germany, September 2017
3. Anglo-Indian RSC-NOST Meeting, Leeds, September 2017
4. SCI-RSC Celebration of Organic Chemistry (UCB, Belgium, Sept 2018)
5. Action Mesothelioma Days (Leeds, UK) in July 2017 and July 2018

The first paper was accepted for publication in Organic Letters in November 2018, and at least 3 more are being drafted for submission.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The progress beyond the state of the art is the development of a completely new and novel method for the asymmetric synthesis of important nitrogen-containing heterocyclic rings - a revolutionary approach giving piperidines as a single enantiomer. This has fundamental applications in the synthesis of natural products and pharmaceutically active compounds, where it is crucial that compounds are obtained as a single enantiomer.
Second, the now proven ability to apply this method to the synthesis of complex natural products means that this methodology with be of great use to researchers world wide.
Third, the library of novel compounds prepared - in the region of 45-50 compounds - are being screened and tested against mesothelioma cell lines and will, when the results are obtained, provide crucial informal about this cancer and avenues for the development of novel therapies.

Fellow presenting at Anglo-Indian RSC-NOST Meeting, Leeds, September 2017