Quercetin-POC conjugates: Differential stability and bioactivity profiles between breast cancer (MCF-7) and colorectal carcinoma (HCT116) cell lines.

In the course of our ongoing efforts to develop novel quercetin conjugates with enhanced stability profiles, we introduced an isopropyloxycarbonylmethoxy (POC) group to 7-OH and/or 3-OH of quercetin and prepared three novel quercetin conjugates. The quercetin-POC conjugates were stable up to 96 h in PBS but slowly hydrolyzed with half-lives of 1-54 h in cell-free culture medium, which is reminiscent of the stability profiles of the previously reported quercetin-POM (pivaloxymethyl) conjugates. However, the quercetin-POC conjugates were more susceptible to passive transport, intracellular hydrolysis, and metabolism in breast cancer (MCF-7) cell line compared with their POM congeners to result in low concentration of quercetin in this cell line and thereby low antiproliferative effect. In contrast, upon incubation with colorectal carcinoma HCT116 cells, the quercetin-POC conjugates were shown to undergo slow hydrolysis and metabolism to maintain concentrations of the active quercetin species high enough to exert enhanced cytotoxicity. Taken together, the quercetin-POC conjugates synthesized in this study exhibited cell type-specific stability as well as bioactivity profiles, which warrants further investigation into the underlying mechanisms and therapeutic potential.

4-Aminoethylpiperazinyl aryl ketones with 5-HT1A/5-HT7 selectivity.

The well-known 5-HT(1A)/5-HT(7) selectivity issue was tackled by a new series of 4-aminoethylpiperazinyl aryl ketones (1a-1l) specifically designed to distinguish the two hydrophobic sites centered at the anchoring salt bridge. The 4-aminoethylpiperazinyl aryl ketones showed a wide spectrum of activity and selectivity for the 5-HT receptors depending on the type of the hydrophobic groups attached at the aryl piperazinyl ketone scaffold. Docking study of the most active compounds against 5-HT(7)R and 5-HT(1A)R revealed that both receptors have two hydrophobic pockets around the anchoring salt bridge. These two binding sites are perpendicular to each other in 5-HT(7)R but parallel in 5-HT(1A)R, and this observation is well matched with the previous report which claimed that 5-HT(7)R affinity arises from bent conformation of the bound ligand whereas an extended one is best suited for 5-HT(1A)R selectivity. Also, as these pockets have different size and shape, inhibitory activity as well as selectivity of the 4-aminoethylpiperazinyl aryl ketones against 5-HT(7)R and 5-HT(1A)R seemed to be determined by combination of two hydrophobic substituents attached at both ends of the title compounds.

Separation of quercetin's biological activity from its oxidative property through bioisosteric replacement of the catecholic hydroxyl groups with fluorine atoms.

An oxidative property has endowed quercetin with numerous biological benefits, and some of quercetin's biological activities may be related, at least partly, to its antioxidant activity. On the other hand, the oxidative property and associated susceptibility to oxidative decomposition has hampered in-depth investigation of the biological targets as well as underlying mechanisms for quercetin's biological activity. This study was undertaken to separate quercetin's biological activities from its antioxidant properties through bioisosteric replacement of the phenolic hydroxyl groups. The novel quercetin derivative 3',4'-difluoroquercetin (2), thus prepared, showed nonoxidizable property with no attenuation of biological activity. Rather, 2 showed a subtle but significant increase in biological activity compared with quercetin, which might be attributed to its lack of oxidative property. The nonoxidizable nature along with the potent biological activity of the quercetin mimic 2 suggests possible oxidation-independent mechanisms for the biological activities of the quercetin that do not require oxidative formation of the highly electrophilic metabolites.

2,6-Bis-arylmethyloxy-5-hydroxychromones with antiviral activity against both hepatitis C virus (HCV) and SARS-associated coronavirus (SCV).

In this study, as a bioisosteric alternative scaffold of the antiviral aryl diketoacids (ADKs), we used 5-hydroxychromone on which two arylmethyloxy substituents were installed. The 5-hydroxychromones (5b-5g) thus prepared showed anti-HCV activity and, depending on the aromatic substituents on the 2-arylmethyloxy moiety, some of the derivatives (5b-5f) were also active against SCV. In addition, unlike the ADKs which showed selective inhibition against the helicase activity of the SCV NTPase/helicase, the 5-hydroxychromones (5b-5f) were active against both NTPase and helicase activities of the target enzyme. Among those, 3-iodobenzyloxy-substituted derivative 5e showed the most potent activity against HCV (EC(50) = 4 µM) as well as SCV (IC(50) = 4 µM for ATPase activity, 11 µM for helicase activity) and this might be used as a platform structure for future development of the multi-target or broad-spectrum antivirals.