Expand Flow · Accessing new chemical space via a combined flash- and photochemical flow chemistry approach for the functionalisation and ring expansion of heterocycles

Expand Flow – Accessing new chemical space via a combined flash- and photochemical flow chemistry approach for the functionalisation and ring expansion of heterocycles

The need for development of cost-effective and efficient methodologies for the exploration of new chemical space is imperative to streamline the access to new effective drugs. This demands progress in several areas of synthetic organic chemistry, and some of those are addressed with ExpandFlow. First, with the medicinal chemists' move away from molecular flatland towards sp3-rich chemical space with high conformational restriction, the need for the discovery and synthesis of novel strained saturated heterocycles is imperative. The importance of such novel motifs is manifold as they allow development of drug candidates outside of the already crowded intellectual property space, and may impart improved physicochemical properties, incl. lower off-target biding promiscuity, improved solubility and an increased probability of lead compounds advancing in clinical trials. ExpandFlow addresses this need in two ways. First, by developing new and improved synthetic methodologies for the introduction of already proven strained heterocycles (e.g., oxetanes, azetidines, aziridines) into functionalised molecules. This would allow the expansion of hitherto accessible chemical space and potentially path the way for the synthesis of new lead compounds. Second, ExpandFlow will develop completely new strained saturated heterocycles and investigate their potential as bioisosteres of common heterocycles found in drugs and drug candidates. The successful development of novel biologically useful heterocycles would expand the toolbox of the medicinal chemists in drug candidate development and relief some burden associated with the crowded patent space. In a second, overarching motif, ExpandFlow's will work to address the environmental targets set by the European Commission MSCA Green Charter and the Horizon Europe missions to become climate resilient by 2030. In addition, the project addresses several environmental needs described in the 2030 Agenda for Sustainable Development: 7) Affordable and clean energy; 9) Industry, innovation and infrastructure; 12) Responsible consumption and production; and 13) Climate Action. Currently, the pharmaceutical industry contributes an estimated 4-5% of global carbon emissions, so that meeting the EU's ambitious targets requires the prioritization of sustainable production technologies. ExpandFlow will address this need from a technology standpoint. Historically, pharmaceutical production has relied on batch processes which, although simple(r) and cheap, have inherent constraints in resource use and process control. An alternative approach is continuous processing (flow chemistry),which involves continuously pumping reagents into a plug flow reactor (PFR) or continuous-stirred tank reactor (CSTR), from which product is continuously discharged. Conducting reactions in continuous flow confers additional advantages. From a safety perspective, the limited reactor volume and fewer start-up and shutdown cycles reduce exposure to hazardous or toxic reagents. In addition, superior mixing and heat transfer mitigate the risk of thermal runaway. Furthermore, greater control over key reaction parameters (temperature, pressure, and residence time) enables milder reaction conditions, making it possible to tame intermediates that are otherwise inaccessible in batch reactors. ExpandFlow will further develop this technology, also in combination with photocatalysis, and showcase its utility in the development of novel synthetic methodology. Expand Flow thus presents a multidisciplinary project that lies in the intersection of flow chemistry (incl. photocatalysis), medicinal chemistry and computational chemistry, for the development of a selective, sustainable and applicable methodology for the functionalisation of (novel) strained heterocycles. Ultimately, its applicability to the pharmaceutical industry will be proven by the development of novel bioisosteres and their in silico and in vitro validation. Overall, this project will add a valuable tool to the synthetic chemist’s repertoire for the rapid, environmentally-friendly and cost-effective development of new drug candidates, by the versatile functionalisation of various heterocycles using flow technology. This innovative approach will have a high scientific, technological and societal impact, reinforcing the European competitiveness in the development of life-saving drugs.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз