Synthetic toolkit for fragment oriented synthesis

The discovery of small bioactive molecules is a central challenge in chemical biology and medicinal chemistry, and typically involves iterative cycles of design, synthesis and biological evaluation. A narrow toolkit of reliable synthetic methods drives such workflows, and focuses on heteroatom / sp2 carbon functionalization and protecting group manipulation. The dominance of the toolkit has tended to exacerbate the historically uneven exploration of chemical space, and to focus attention on flatter and more lipophilic compounds. Within fragment-based drug discovery, direct fragment growth is rare, essentially being limited to heteroatom functionalization. In practice, more elaborated fragments tend to be synthesised de novo when direct fragment elaboration would actually be desirable.

Direct fragment growth will not only contribute to improve productivity of early stages drug development by reducing the synthetic burden, but also will allow to navigate through unexplored chemical space. In particular, the exploitation of molecules with increased tridimensionality has been linked to the discovery of drug candidates with higher probabilities of reaching the market. Hence, the research proposed for the current action will contribute with know-how to the global efforts of targeting new diseases by providing new better drugs while increasing pipeline productivity.

The overall objective of the action is the development of a synthetic toolbox that facilitates the introduction of a range of medicinally-relevant functionalities into fragment molecules through their direct activation. The toolbox usefulness will be demonstrated by the discovery of new bioactive molecules able to interact with protein function.

The fellow populated the synthetic toolbox with three new transformations capable of directly growing fragment molecules featuring saturated N-heterocycles. The methods formally explore the activation of otherwise non-reactive saturated carbon-hydrogen bonds, to install small carbon segments featuring bioactive functionality. The discovery process included initial testing and development using model fragment molecules. This allow prioritizing the best methods for additional tier testing using real-life fragment examples and active principal ingredients. At the moment of closure of the fellowship the Host group had identified new fragment hits for Aurora-A kinase featuring the same classes of saturated N-heterocycles on which the fellow demonstrated the synthetic toolbox. This will allow to use the chemistry developed by the fellow to showcase the direct modification of fragment hits to modulate their binding capabilities towards Aurora-A kinase.
Two of the three new reactions will be submitted for publishing featuring only synthetic studies, whilst the third method is expected to be published in the following year in combination with the fragment hit elaboration for Aurora A kinase. At the moment of closure of the fellowship, to protect the know-how no public presentation on seminars/congress or other forms of dissemination had been delivered. Nevertheless, the project achieved important dissemination actions through informal closed meetings with fragments end users, companies that focus on fragment-based drug discovery to drive drug development pipelines, where the findings were reported through oral presentation.

The project has been successful in populating the synthetic toolbox with complementary methodologies that enable direct fragment growth. The state-of-art has been progressed through exploitation of inactive carbon-hydrogen bonds to grow fragment with medicinally relevant functionalities. As molecular complexity increases, the more difficult is to achieve further functionalization while sparing native existent one. This limitation is one of the root causes for the need of de novo synthesis. Hence, the ability of introduce novel functionality in highly complex molecules, including principal active ingredients, in a selective manner is an impactful discovery. Thus we anticipate that the knowledge generated by this research will attract the attention of drug discovery scientists, synthetic chemists and structural biologists.

Periodic Reporting for period 1 - SYNFOS (Synthetic toolkit for fragment oriented synthesis)

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