Russo, Camilla (2024) The green soul of medicinal chemistry: innovative synthetic approaches towards new anticancer agents. [Tesi di dottorato]

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Abstract

In the past decades, an increasing awareness of environmental issues has set the stage for the widespread application of the Green Chemistry principles to all fields of Chemical Sciences, both in academia and industry. From a synthetic and pharmaceutical perspective, this has meant looking for novel and more sustainable synthetic approaches to drug-like scaffolds. Whitin this context, multicomponent reactions and visible light photoredox catalysis have both emerged as powerful tools to build up molecules with ease and elegance, while optimising synthetic efficiency, preventing waste generation, and minimising energy consumption. Capitalising on Prof. Mariateresa Giustiniano’s established interest in isocyanide chemistry, this Doctoral Thesis focuses on the development of innovative green synthetic strategies enabling access to a wide and sometimes unexplored chemical space by exploiting either well-known or unconventional reactivities of the chameleonic isocyano- functional group, most of the time under visible light irradiation. After a general introduction to the basic principles of Green Chemistry, isocyanide-based multicomponent reactions, and visible light photoredox catalysis (Chapter 1), Chapter 2 may be described as a methodological one, as it includes our studies aiming to provide innovative synthetic solutions of general utility to the scientific community. In Section 2.1, a novel visible light photocatalytic three-component reaction between N-alkyl-N-methylanilines, (N-isocyanoimino)triphenyl phosphorane, and carboxylic acids, affording pharmaceutically relevant 1,5-disubstituted-1,3,4-oxadiazole derivatives under very mild conditions, is presented. Section 2.2 deals with our commitment to contribute to the flourishing of in water photochemical transformations. It describes a photomicellar catalysed synthesis of amides from N-alkyl-N-methyl aromatic amines and isocyanides, with particular focus on the study of the localisation of the photocatalyst with respect to the micelles, in order to provide experimental data to drive the identification of the photocatalyst/surfactant pairing with optimal catalytic efficiency. In line with our interest in exploring isocyanides’ unconventional reactivities under visible light irradiation, Section 2.3, Section 2.4, and Section 2.5 report our recent findings about the ability of aromatic isocyanides to harvest the energy of photons, reach an electronically excited state, and promote the formation of radical species from suitable precursors, via single electron transfer oxidation events. After exploiting these observations to perform Ugi and Ugi-like self-catalysed multicomponent reactions (Section 2.3, and Section 2.4) and preliminary assessing the use of aromatic isocyanides as catalytic organic photoactive oxidants in a series of α-amino C(sp3)-H functionalisations (Section 2.3), our efforts to verify the ability of aromatic isocyanides to promote the generation of both alkyl and acyl radicals from more challenging radical precursors (i.e., Hantzsch esters, potassium alkyltrifluoroborates, and α-oxoacids) are described in Section 2.5. UV-visible absorption and fluorescence experiments, as well as electrochemical measurements of the ground-state redox potentials along with computational calculations of both the ground- and the excited-state redox potentials of a set of nine different aromatic isocyanides provided key insights to drive the rational design of a new generation of isocyanide-based organic photoredox catalysts. As for isocyanides’ unconventional reactivities not requiring visible light, in Section 6 a new domino isocyanide insertion/5-exo-dig cyclisation of readily available Strecker 3-component adducts, elicited by ligation to ytterbium triflate, is reported. Such an approach enabled a fast and easy access to 4-substituted-5-aminoimidazole derivatives, a class of pharmaceutically relevant heterocyclic scaffolds, whose current synthetic strategies are still poorly efficient. In Chapter 3, the potentialities and the opportunities of applying isocyanides’ multifaceted reactivities in the context of medicinal chemistry and drug discovery are further highlighted. Thanks to their high exploratory power, isocyanide-based multicomponent reactions represent a unique tool to rapidly provide diversity and complexity with unprecedent synthetic efficiency, which is particularly relevant for the construction of molecular libraries for biological evaluations and structure-activity relationship studies. We applied such an approach to the identification of novel small molecule inhibitors acting on emerging anticancer targets. In Section 3.1, based on the increasing evidence of a possible involvement of MICAL2 protein in neo-angiogenesis and metastasis formation in several human cancers, the design, synthesis, biological and computational evaluations of a small library of CCG-1423 analogues (the only MICAL2 small molecule inhibitor known do date) are reported. These studies provided new insights into the structure–activity relationships of CCG-1423, thus paving the way for the discovery of novel MICAL2 inhibitors. Section 3.2 focuses on the identification of a new class of NOD antagonists. NOD1 and NOD2 proteins are pattern recognition receptors whose overactivation has been found to play a role in several inflammatory diseases and human cancer types. We exploited a multicomponent synthetic approach to access a new chemotype, namely 2,3-diaminoindoles, and expand the chemical space of NOD inhibitors. This resulted in the identification of a novel low micromolar NOD1 antagonist, whose direct binding to NOD1, along with characterisation of its binding site, were proved by means of a combination of NMR spectroscopy and computational techniques. Finally, considering the growing relevance of organic electrosynthesis as a green activation method, Chapter 4 summarises my six-month stay as a visiting PhD student in the Laboratory of Medicinal and Molecular Electrochemistry of Prof. Kevin Lam, University of Greenwich. Besides experiencing first-hand the opportunities and the challenges of synthetic organic electrochemistry, this resulted in the development of a new, practical, mild, and high-yielding hydrogen-free electrochemical method for the reduction of alkene, alkyne, nitro- and azido- compounds. The strategy represents an interesting alternative to classic metal-based catalytic hydrogenations, thus confirming once more the importance of developing innovative and more sustainable synthetic approaches for both organic and medicinal chemistry applications.

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