Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.

Whereas the all-cis tetrahydrofuran framework of the cytotoxic anhydrophytosphingosine jaspine B is considered as a relevant pharmacophore, little is known about the influence of the aliphatic chain of this amphiphilic molecule on its activity. We developed a synthetic strategy allowing flexible introduction of various lipophilic fragments in the jaspine's skeleton. The route was validated with two distinct approaches to jaspine B. Five chain-modified analogues were also prepared. Biological evaluation of these derivatives demonstrated a good correlation between their cytotoxicity and their capacity to inhibit conversion of ceramide into sphingomyelin in melanoma cells. A series of potent and selective inhibitors of sphingomyelin production was thus identified. Furthermore, the good overall potency of an ω-aminated analogue allowed us to dissociate of the pharmacological action of jaspine B from its amphiphilic nature.

Sphingolipids (SLs) are ubiquitous membrane constituents that have emerged as essential lipid mediators involved in signal transduction and cancer development. Due to the implication of SLs in the alteration of cell proliferation, adhesion or migration, their metabolism has been targeted in search for novel anti-cancer therapeutic approaches. In this context, much attention has been directed towards SLs analogues interfering with these complex signalization pathways as well as the immune system. A general structural modulation of the basic sphingosine backbone of SLs concerns its cyclisation into various types of conformationally constrained derivatives. Different series of both natural and synthetic compounds can be considered according to this common structural feature. The present review article lists these naturally occuring sphingolipids cyclic derivatives including anhydrophytosphingosine-type marine products pachastrissamine (jaspine B), penaresidine/penazetidine, broussonetine, prosopine/prosopinine/prosophylline derivatives, as well as conceptually related synthetic products. A brief statement of their biological activity is presented. Detailed informations concerning the organic synthetic aspects are given with emphasize on the natural azetidine, pyrrolidine and all the synthetic analogues that had never been reviewed before.