3,4,5-Trihydroxypiperidines belong to the family of 1,5-dideoxy-1,5-iminosugar natural products and are structural analogues of pentose monosaccharides in the pyranose form. The biological activities of these apparently structurally simple molecules and their N- and O-alkylated and -arylated derivatives are no less remarkable than their C-6 hydroxymethyl counterparts of the hexoses (such as 1-deoxynojirimycin, DNJ). Their biological profiles indicate that the hydroxymethyl branch is crucial to neither potency nor selectivity, with O-alkylation demonstrated to produce exquisite selectivity extending beyond glycosidase inhibition, to immunosuppressant and antibacterial activities.

Endocytosis is a process essential to the health and well-being of cell. It is required for the internalisation and sorting of “cargo”—the macromolecules, proteins, receptors and lipids of cell signalling. Clathrin mediated endocytosis (CME) is one of the key processes required for cellular well-being and signalling pathway activation. CME is key role to the recycling of synaptic vesicles [synaptic vesicle recycling (SVR)] in the brain, it is pivotal to signalling across synapses enabling intracellular communication in the sensory and nervous systems. In this review we provide an overview of the general process of CME with a particular focus on two key proteins: clathrin and dynamin that have a central role to play in ensuing successful completion of CME. We examine these two proteins as they are the two endocytotic proteins for which small molecule inhibitors, often of known mechanism of action, have been identified. Inhibition of CME offers the potential to develop therapeutic interventions into conditions involving defects in CME. This review will discuss the roles and the current scope of inhibitors of clathrin and dynamin, providing an insight into how further developments could affect neurological disease treatments.

3,4,5‐Trihydroxypiperidines represent a family of biologically active natural products, found to modulate principally the glycosidase enzymes. This is ascribed to their structural and electronic resemblance to the pyranose monosaccharides, their natural counterparts. Expedient syntheses are crucial to access these valuable high Fsp3 index drug leads. In this review we present the literature strategies to this class of iminosugars to spur further research into drug leads targeting the glycobiological machinery of living systems.

Stereoselective and biocatalysed synthetic routes to 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatisations are reviewed. These iminosugars effectively modulate glycosidase enzymes and display biological activities in immunosuppression, as anti‐inflammatory agents and as anti‐viral agents. Syntheses to these building blocks and their N‐ and O‐derivatives are predicted to produce drug leads of high Fsp3 index. This is also crucial in the collection of structure‐activity relationship data, particularly for diseases dependant on glycosidase modulation.

The effect of different leaving groups on the substitution versus elimination outcomes with C-5 d-glucose derivatives was investigated.