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Copper is an essential trace element involved in plenty of redox reactions in living systems, however, unbound copper ions cause damage to various biomolecules via excessive generation of reactive oxygen species. Flavonoids, ubiquitous plant secondary metabolites, possess complex effects on human health and chelation of transient metal ions is one of their proposed mechanisms of action. In this in vitro study, 26 flavonoids from various subclasses were screened for their interactions with both copper oxidation states at four (patho)physiologically relevant pH conditions (4.5, 5.5, 6.8 and 7.5) by two spectrophotometric approaches and compared with the clinically used copper chelator trientine. In a slightly competitive environment, the majority of flavonoids were able to chelate cupric ions, however, under more competitive conditions, only flavones and flavonols were able to chelate both cupric and cuprous ions. Apparently, the 2,3-double bond was essential for stable copper chelation. The most efficient copper chelation sites were the 3-hydroxy-4-keto group in flavonols and the 5,6,7-trihydroxyl group in flavones. On the other hand, the 3 0 ,4 0 -dihydroxyl group was associated only with a weak activity. 3-Hydroxyflavone, kaempferol and partly baicalein were even more potent than trientine in the acidic environment, however, none of the tested flavonoids was able to surpass it at physiological pH or slightly acidic conditions. In conclusion, flavonoids possessing appropriate structural characteristics were efficient copper chelators and some of them were even more potent than trientine under acidic conditions.

Natural polyphenol compounds are often good antioxidants, but they also cause damage to cells through more or less specific interactions with proteins. To distinguish antioxidant activity from cytotoxic effects we have tested four structurally related hydroxyflavones (baicalein, mosloflavone, negletein, and 5,6-dihydroxyflavone) at very low and physiologically relevant levels, using two different cell lines, L-6 myoblasts and THP-1 monocytes. Measurements using intracellular fluorescent probes and electron paramagnetic resonance spectroscopy in combination with cytotoxicity assays showed strong antioxidant activities for baicalein and 5,6-dihydroxyflavone at picomolar concentrations, while 10 nM partially protected monocytes against the strong oxidative stress induced by 200 µM cumene hydroperoxide. Wide range dose-dependence curves were introduced to characterize and distinguish the mechanism and targets of different flavone antioxidants, and identify cytotoxic effects which only became detectable at micromolar concentrations. Analysis of these dose-dependence curves made it possible to exclude a protein-mediated antioxidant response, as well as a mechanism based on the simple stoichiometric scavenging of radicals. The results demonstrate that these flavones do not act on the same radicals as the flavonol quercetin. Considering the normal concentrations of all the endogenous antioxidants in cells, the addition of picomolar or nanomolar levels of these flavones should not be expected to produce any detectable increase in the total cellular antioxidant capacity. The significant intracellular antioxidant activity observed with 1 pM baicalein means that it must be scavenging radicals that for some reason are not eliminated by the endogenous antioxidants. The strong antioxidant effects found suggest these flavones, as well as quercetin and similar polyphenolic antioxidants, at physiologically relevant concentrations act as redox mediators to enable endogenous antioxidants to reach and scavenge different pools of otherwise inaccessible radicals.

The most common solid tumors show intrinsic multidrug resistance (MDR) or inevitably acquire suchwhen treated with anticancer drugs. In this work, we describe the discovery of a peripherally restricted, potent, competitive NMDA receptor antagonist 1l by a structure-activity-study of the broad-acting ionotropic glutamate receptor antagonist 1a. Subsequently, we demonstrate that 1l augments the cytotoxic action of sorafenib in murine hepatocellular carcinoma (HCC) cells. The underlying biological mechanism was shown to be interference with the lipid signaling pathway, leading to reduced expression of MDR transporters and therebyan increased accumulation of sorafenib in the cancer cells. Interference with lipid signaling pathwaysby NMDA receptor inhibition is a novel and promising strategy for reversing transporter-mediated chemoresistance in cancer cells.

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Modern-day drug discovery is now blessed with a wide range of highthroughput hit identification (hit-ID) strategies that have been successfully validated in recent years, with particular success coming from high-throughput screening, fragmentbased lead discovery, and DNA-encoded library screening. As screening efficiency and throughput increases, this enables the viable exploration of increasingly complex threedimensional (3D) chemical structure space, with a realistic chance of identifying highly specific hit ligands with increased target specificity and reduced attrition rates in preclinical and clinical development. This minireview will explore the impact of an improved design of multifunctionalized, sp 3 -rich, stereodefined scaffolds on the (virtual) exploration of 3D chemical space and the specific requirements for different hit-ID technologies.

The base n -BuLi with sparteine allows a kinetic resolution of N -Boc-2-aryl-4-methylenepiperidines. The 2,2-disubstituted products and recovered starting materials were isolated with high enantiomeric ratios. From VT-NMR spectroscopy and DFT studies, the rate of rotation of the N -Boc group is fast. Lithiation and trapping of the enantioenriched starting materials gave 2,2-disubstituted piperidines with retention of stereochemistry. Functionalization of the 4-methylene group led to a variety of 2,4-disubstituted piperidines without loss of enantiopurity that could be useful building blocks for drug discovery.