C-type lectin receptors are calcium dependent proteins able to selectively recognize and bind to polyglycosylated surfaces exposed by invading pathogens and damaged cells, thus acting as first-line host defense. However, C-lectins activity can be also responsible for the pathogenesis of infection and inflammatory diseases, thus representing a class of promising therapeutic targets.1
In recent years, our group showed that pseudo-tetramannosylated dendrons 1a,b based on a polyester scaffold are effective antagonists of both DC-SIGN mediated pathogen invasion2 and MBL triggered reperfusion damage,3 with kd values in the low micromolar range. Unfortunately, these constructs proved to be rather chemically unstable: hydrolysis of the polyester scaffold precludes chromatographic purification (both direct and reverse phase) and occurs even in water solution at physiologic pH (27% hydrolysis in 6 h).
Here we present the synthesis of two tetravalent analogs 2a,b characterised by an optimised scaffold, that allowed remarkable chemical stability, while retaining water solubility and biological activity. The versatility of this new scaffold was further exploited for the synthesis of the 16-valent glycodendrimer 3a