Project description
Photoactivation for enhanced Sml2 catalytic efficiency
Bioisosteric replacement of aromatic pharmacophores is a strategy in drug development to reduce the formation of toxic metabolites. Substituting aromatic cores with rigid, carbon-rich scaffolds can improve both metabolic stability and potency. However, many analogues remain unexplored due to the lack of efficient synthetic methods. Recent work has made significant progress in this area using SmI2 in radical relay catalysis to enable the synthesis of bioisosteric scaffolds. With support from the Marie Skłodowska-Curie Actions programme, the Sam-4-Bio project will build on this progress by integrating a novel approach with recent discoveries on enhancing SmI2 catalytic efficiency. The project aims to develop a versatile platform for generating bioisosteres of ortho-arenes, such as 1,2-BCHeps.
Objective
The concept of bioisosteric replacement of arene pharmacophores in drug candidates has garnered increasing attention as a powerful tool to circumvent the production of toxic metabolites through detrimental metabolic modifications of the arene backbone. Replacement of the arene core in drug candidates with rigid, C(sp3)-rich bioisosteric scaffold improves their metabolic stability, potency, lipophilicity, and solubility. Crucially, cage-like structures with defined exit vectors renders them bioisosteres with superior ability to dock in the chiral binding pocket of the target receptor. Therefore, the demand for C(sp3)-rich bioisosteric replacements is skyrocketing and recent endeavors have provided a variety of decorated saturated systems mimicking substituted arenes. While initial studies were mostly directed towards bioisosteres of mono- and para-substituted arenes, recent efforts have focussed more on bioisosteres for ortho- and meta-substituted aromatic rings. Despite the significant development of synthetic strategies for preparing already proven bioisosteres, the lack of synthetic methods to access many unexplored analogues, such as bicyclo[2.2.1]heptanes (BCHeps), renders their potential undetermined to date. Consequently, developing general, catalytic, sustainable methods for rapidly accessing 1,2-BCHeps is an urgent necessity. Recent breakthroughs from the Procter group have set a new benchmark by applying radical relay catalysis using SmI2 for accessing bioisosteric scaffolds. Sam-4-Bio will integrate this novel concept with the group’s recent finding of enhancing catalytic efficiency of SmI2 by photoactivation, to develop a catalytic platform for accessing unexplored bioisosteres of ortho-arenes like 1,2-BCHeps. Challenging insertion of alkene into the bridgehead bond of strained housane ketones under SmI2-catalysis will deliver key intermediates for downstream manipulation en route to new saturated analogues of validated drugs with superior bioactivity.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences chemical sciences organic chemistry hydrocarbons
- natural sciences chemical sciences catalysis
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2024-PF-01
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M13 9PL Manchester
United Kingdom
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