BCPPlus · New directions in bicyclopentane research
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-07-16 → 2020-07-15
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
New directions in bicyclopentane research
The pharmaceutical industry is increasingly seeking new tactics for the structural modification of drug candidates that avoid problems with metabolic susceptibility, or to improve pharmacokinetic properties. Analogues called 'bioisosteres', which mimic the dimensions and substituent vectors of problematic structural motifs, but which are not themselves subject to the same pharmacological limitations, offer one solution. These are often based on scaffolds that are not found in ‘typical’ drug candidates. Within this growing field, rigid polycycles such as bicyclo[1.1.1]pentane (BCP) are receiving significant attention as arene bioisosteres, as they exhibit similar size and shape. Current methods for BCP synthesis require harsh conditions; this limits product scope and therefore the development of medicinally-relevant compounds. The invention of new methodology to access this motif will revolutionize use of BCPs in the pharmaceutical sector. The knowledge generated from this project will advance our understanding of caged hydrocarbons, transition metal catalysis and photoredox catalysis and will facilitate and accelerate the production of high-value pharmaceutical chemicals bearing BCP motifs. Translation of this research to drug discovery programs will create opportunities for commercialisation, adding substantial value to the biotechnology and pharmaceutical sectors. In addition, this proposal will lead to strong and rewarding national and international collaborations with global pharmaceutical and academic leaders. Objectives: The central objective of the project is to create methodology which will allow for the widespread use of the BCP motif in medicinal and agrochemical industries. Specifically we sought to: Explore general and mild ATRA-based syntheses of BCP derivatives with a particular focus on exploiting photoredox catalysis; Functionalize the bicyclo[1.1.1]pentane ring system, focussing on transition metal and photoredox catalysed transformations; Synthesise novel bicyclo[1.1.1]pentanes analogues of peptidic and non-peptidic drugs and natural product analogues. Conclusions: The methods which we have developed in this project enable easy synthesis to BCP compounds, significantly increasing the accessibility of these compounds in medicinal chemistry. These methodologies are already being utilised in the drug discovery programmes of our industrial collaborators and we anticipate that this research will soon result in new drugs which feature the BCP motif.
Data: CORDIS, © European Union
Project objective
The pharmaceutical industry is increasingly seeking new tactics for the structural modification of drug candidates to avoid metabolic susceptibility, or to improve pharmacokinetic properties. Analogues called 'bioisosteres', which mimic the dimensions and substituent directionality of problematic structural motifs, but which are not themselves subject to the same pharmacological issues, offer one solution. Often based on scaffolds not found in ‘typical’ drug candidates, bioisosteres can additionally occupy new areas of intellectual property space. Within this growing field, rigid polycycles such as bicyclo[1.1.1]pentane (BCP) are receiving significant attention as arene bioisosteres, as they exhibit similar ring diameters and substituent positioning, and also improve many pharmacokinetic properties relative to the parent arene. Despite the attractive nature of these motifs and current interest, the lack of general routes to complex BCP ring systems means this template is not yet fully accessible to industry. The invention of mild methods for [1.1.1.0]tricyclopentane (TCP) ring opening and functionalization could revolutionize use of BCPs in the pharmaceutical sector. One method not explored to date is an atom transfer radical addition reaction (ATRA) strategy. Using aryl or alkyl halides, ATRA could deliver an abundance of previously inaccessible polysubstituted BCPs from generalized TCP, which would revolutionize this immature, cutting-edge area of organic and medicinal chemistry. This research proposal seeks to: i) explore general and mild ATRA-based syntheses of BCP derivatives, including ring-expanded (hetero)bioisosteres; ii) functionalize BCP products using a range of contemporary processes, including C–H or C–X activation; and iii) apply these methodologies to synthesize BCP drugs / natural product analogues, and to test their biological activity via an industrial collaboration.
Original text from CORDIS.
Participants
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union