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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.

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Since the discovery in 1995 of α-galactosylceramide 1 (α-GalCer), also known as KRN7000,1 hundreds of compounds have been synthesized in order to activate invariant natural killer T (iNKT) cells. Such keen interest for this lymphocyte cell type is due to its ability to produce different cytokines that bias the immune response toward a Th1 or Th2 profile. Thus, an understanding of the immune polarization mechanism via iNKT activation may pave the way toward new therapeutics in various domains including cancer and infectious and autoimmune diseases. In this review, we propose an up-to-date analysis of iNKT activators associated with a structure-activity relationship (SAR) study aimed at complementing available reviews by highlighting molecular bases for a selective immune response.

CB2 receptor selective ligands are becoming increasingly attractive drugs due to the potential role of this receptor in several physiopathological processes. Thus, the development of our previously described series of 4-oxo-1,4-dihydroquinoline-3-carboxamides was pursued with the aim to further characterize the structure-affinity and structure-functionality relationships of these derivatives. The influence of the side chain was investigated by synthesizing compounds bearing various carboxamido and keto substituents. On the other hand, the role of the quinoline central scaffold was studied by synthesizing several 6-, 7-, or 8-chloro-4-oxo-1,4-dihydroquinolines, as well as 4-oxo-1,4-dihydronaphthyridine and 4-oxo-1,4-dihydrocinnoline derivatives. The effect of these modifications on the affinity and functionality at the CB2 receptor was studied and allowed for the characterization of new selective CB2 receptor ligands.

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor-bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a strategy that may be active against NSCLC.

Growing evidence shows that CB(2) receptor is an attractive therapeutic target. Starting from a series of 4-oxo-1,4-dihydroquinoline-3-carboxamide as selective CB(2) agonists, we describe here the medicinal chemistry approach leading to the development of CB(2) receptor inverse agonists with a 4-oxo-1,4-dihydropyridine scaffold. The compounds reported here show high affinity and potency at the CB(2) receptor while showing only modest affinity for the centrally expressed CB(1) cannabinoid receptor. Further, we found that the functionality of this series is controlled by its C-6 substituent because agonists bear a methyl or a tert-butyl group and inverse agonists, a phenyl or 4-chlorophenyl group, respectively. Finally, in silico studies suggest that the C-6 substituent could modulate the conformation of W6.48 known to be critical in GPCR activation.

The human selenoprotein thioredoxin reductase is involved in antioxidant defense and DNA synthesis. As increased thioredoxin reductase levels are associated with drug sensitivity to cisplatin and drug resistance in tumor cells, this enzyme represents a promising target for the development of cytostatic agents. To optimize the potential of the widely used cisplatin to inhibit the human thioredoxin reductase and therefore to overcome cisplatin resistance, we developed and synthesized four cis-diamminedichloroplatinum complexes of the lead 5-nitro-2-furancarbohydrazide 8 selected from high-throughput screening. Detailed kinetics revealed that the isolated fragments, 5-nitro-2-furancarbohydrazide and cisplatin itself, bind with micromolar affinities at two different subsites of the human enzyme. By tethering both fragments four nitrofuran-based cis-diamminedichloroplatinum complexes 13a-c and 20 were synthesized and identified as bi-ligand irreversible inhibitors of the human enzyme with nanomolar affinities. Studies with mutant enzymes clearly demonstrate the penultimate selenocysteine residue as the prime target of the synthesized cis-diamminedichloroplatinum complexes.