Eight-membered cyclic amines as novel scaffolds for drug discovery

The research conducted in this PhD thesis is one of the six projects of iDESIGN, an EU-funded European Industrial Doctorate Innovative Training Network (EU-EID-ITN). iDESIGN’s principal research objective was to design and synthesise novel compound libraries of structurally and functionally diverse, three-dimensional molecules with attractive physicochemical properties for early-stage drug discovery. Due to their conformational flexibility and presence in various bioactive natural products, eight-membered cyclic amine derivatives were considered valuable starting points for drug discovery as they represent an underexplored – and therefore underexploited – region of chemical space. Literature compound N-Boc-(Z)-5-oxo-3,4,5,8-tetrahydroazocine was synthesed in five steps, including an optimised ring-closing metathesis reaction as the key step, which was scaled up to gramme scale. By selectively manipulating the embedded enone functionality in this N-Boc-azacyclooctenone parent scaffold, three structurally distinct core scaffolds, comprising an azacyclooctylamine, a family of 8-5/8-6 fused aromatic heterocycles and an 8-5 fused pyrrolidine, were synthesised, each with multiple appendable handles. From these scaffolds, three diverse compound libraries were designed in silico and then prepared via parallel synthesis. Using KNIME and DataWarrior, the compound libraries were designed to display maximum diversity in drug-like physicochemical, structural and molecular shape space, which was validated using principal component analysis and Tanimoto similarity calculations. From the 200 synthesised library compounds, a representative selection was screened for hERG activity, whilst a broad range of measured ElogD values reflected the effort in maximising calculated physicochemical values (e.g., clogP) during in silico library design. All of the library compounds have been submitted to the Haworth Chemically Enabled Compound Collection (HC$^3$), a collaborative screening collection which is maintained by the Birmingham Drug Discovery Hub. Biological screening of these compounds against Mycobacteria and representative ESKAPE pathogens is planned for the near future

Synthesis of N-Acyl Sulfamates from Fluorosulfates and Amides

A novel synthetic strategy toward  N-acyl sulfamates was developed. Interestingly, fluorosulfates, a new emerging class of electrophiles, were used to construct the sulfamate core. This precludes handling of chlorosulfonyl isocyanate and sulfamoyl chloride. In combination with amides, a wide and diverse set of N-acyl sulfamates was synthesized, including functionalized bioactive compounds. Furthermore, initial results showed that this method is also amenable to access N-thioacyl sulfamates.status: publishe

Design, synthesis and biological evaluation of pyrazolo[3,4-d] pyrimidine-based protein kinase D inhibitors

The multiple roles of protein kinase D (PKD) in various cancer hallmarks have been repeatedly reported. Therefore, the search for novel PKD inhibitors and their evaluation as antitumor agents has gained considerable attention. In this work, novel pyrazolo[3,4-d]pyrimidine based pan-PKD inhibitors with structural variety at position 1 were synthesized and evaluated for biological activity. Starting from 3-IN-PP1, a known PKD inhibitor with IC50 values in the range of 94-108 nM, compound 17m was identified with an improved biochemical inhibitory activity against PKD (IC50 = 17-35 nM). Subsequent cellular assays demonstrated that 3-IN-PP1 and 17m inhibited PKD-dependent cortactin phosphorylation. Furthermore, 3-IN-PP1 displayed potent anti-proliferative activity against PANC-1 cells. Finally, a screening against different cancer cell lines demonstrated that 3-IN-PP1 is a potent and versatile antitumoral agent.status: publishe