Recent data indicated that the CB(2) cannabinoid receptor constitutes an attractive drug target due to its potential functional role in several physiological and pathological processes. A set of 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives, characterized by the presence of some important structural requirements exhibited by other classes of cannabinoid ligands, such as an aliphatic or aromatic carboxamide group in position 3, and an alkyl or benzyl group in position 1, was synthesized and assayed to measure their respective affinity for both human CB(1) and CB(2) cannabinoid receptors. The results indicate that these 3-carboxamido-quinolones derivatives exhibited a CB(2) receptor selectivity, particularly derivatives 28-30, and 32R. Moreover, in the [(35)S]-GTPgammaS binding assay, all the compounds behaved as CB(2) receptor agonists. Molecular modeling studies showed that compound 30 interacts with the CB(2) receptor through a combination of hydrogen bond and aromatic/hydrophobic interactions. In conclusion, 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives constitute a new class of potent and selective CB(2) cannabinoid receptors agonists.

In this study, the dynamically folded conformation of squalene (SQ) is taken advantage of to link this natural compound to the anticancer nucleoside analogue gemcitabine (gem) in order to achieve the spontaneous formation of nanoassemblies (SQgem) in water. Cryogenic transmission electron microscopy examination reveals particles (104 nm) with a hexagonal or multifaceted shape that display an internal structure made of reticular planes, each particle being surrounded by an external shell. X-ray diffraction evidences the hexagonal molecular packing of SQgem, resulting from the stacking of direct or inverse cylinders. The respective volumes of the gem and SQ molecules as well as molecular modeling of SQgem suggest the stacking of inverse hexagonal phases, in which the central aqueous core, consisting of water and gem molecules, is surrounded by SQ moieties. These SQgem nanoassemblies also exhibit impressively greater anticancer activity than gem against a solid subcutaneously grafted tumor, following intravenous administration. To our knowledge, this is the first demonstration of hexagonal phase organization with a SQ derivative.

We describe here new nanoparticles based on the bioconjugation of penicillin G to squalene in order to overcome severe intracellular infections by pathogen bacteria whose mechanism of resistance arises from the poor intracellular diffusion of several antibiotics. Two different squalene–penicillin G conjugates were synthesized (pH-sensitive and pH-insensitive), and their self-assembly as nanoparticles was investigated through morphology and stability studies. These nanoparticles had a size of 140 ± 10 nm (polydispersity index of 0.1) and a negative charge, and they did not display any supramolecular organization. Furthermore, they were found stable in water and in different culture medium. The cellular uptake and localization of these fluorescently labeled nanoparticles were explored on the macrophage cell line J774 by flow cytometry and confocal microscopy analysis. The squalenoylated nanoparticles were found to be cell internalized through clathrin-dependent and -independent endocytic pathways. Moreover, they induced an improved intracellular antibacterial activity on the facultative intracellular pathogen S. aureus, compared with free penicillin G, despite the absence of co-localization between the bacteria and the nanoparticles in the cells. This study suggests that the bioconjugation of an antibiotic to a squalene template could be a valuable approach for overcoming the antibiotic resistance due to intracellular bacterial infections.