Periodic Reporting for period 1 - MESO-JBIR-102 (Development of the aza-Prins reaction; synthesis and biological evaluation of JBIR-102)
Periodo di rendicontazione: 2016-07-01 al 2018-06-30
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.
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.
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.