Divergent synthesis and chemoinformatic studies of natural product-derived small molecules for biomedical applications

This Ph.D. thesis deals with the drug discovery field and its aim is to apply a toolbox of approaches, strategies, and technologies through which small molecules have been designed and synthesized to find out new leads of interest. In the first part of this thesis, there are reported two different works (work 1 and work 2) in which there have been employed Pd-catalyzed directing group-promoted C(sp3)-H bond activation reactions: - in work 1, we combined the use of the Castagnoli-Cushman Reaction (CCR) with the 8-AQ-directed C(sp3)-H bond activation reaction that let us to identify two inhibitors BACE-1 (an Alzheimer's disease related enzyme) with a sub-micromolar inhibitory activity. This research let us to publish a paper on Organic and Biomolecular Chemistry in 2024 (https://doi.org/10.1039/D3OB02117C ) - in work 2, we set up a synthetic route to access enantiopure (1S,2S)-aminocyclopentancarboxylic acid (ACPC) and then we applied two different C(sp3)-H activation strategies (a β- and a γ-CH activation), that let us to obtain two different functionalized ACPC derivatives to be used for the synthesis of foldamers. In the second part of this thesis, there are reported two different applications (work 3 and work 4) of the Diversity-Oriented Synthesis (DOS): - in work 3, we synthesized a little library of tyrosine-derived peptidomimetics which let us to identify a compound with multitarget inhibitory activity within MMP2-αVβ3 integrin, two macromolecules both involved in tumor angiogenesis and metastasis. Thanks to this work, we published a paper on Molecules in 2022 (https://doi.org/10.3390/molecules27041249 ). - in work 4, we applied two different fashions of the Ugi-MCR to expand the organic reaction toolbox for DNA-encoded library (DEL) synthesis, that let us to generate DNA-conjugated polisubstituted compounds, including lactams. This work let us to publish a paper on ACS Omega in 2024 (https://doi.org/10.1021/acsomega.3c07136), and we published a review on the matching of DOS and DEL in 2021 on Bioorganic and Medicinal Chemistry (https://doi.org/10.1016/j.bmc.2021.116218)