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G-quadruplex DNAs (G4 DNAs) are emerging as promising anticancer drug targets due to their presence in the promoter regions of different oncogenes. Utilizing different spectroscopic techniques like UV–Vis absorption titration, thermal denaturation, spectrofluorimetric titration, fluorescence displacement assay, Job plot analysis, circular dichroism spectroscopy and also, molecular docking studies, the interaction of a synthetic nitro-flavone, 2-(4-Nitrophenyl)-4H-chromen-4-one (4NCO), with various G4 DNA structures (c-KIT1, c-KIT2, c-MYC, h-TELO and VEGF) was elucidated. We also investigated the effect of 4NCO on different cancer cell lines. Effect on cell morphology, DNA damage, cell cycle arrest, viability and mode of cell death were evaluated in A375 melanoma cells. Our findings indicated that 4NCO showed preferential binding towards c-MYC promoter G4 to stabilize it with a binding constant (Kb) value of the order of ~105 M−1 and binding stoichiometry of ~1:1. It also showed a unique dual binding mode when bound to c-MYC with a lower binding free energy having multiple strong interactions when compared to the other G4s. In cells, it induced DNA damage resulting in cell cycle arrest at G1/S phase until 24 h, after which, cells strictly underwent apoptosis. It also showed a preferential cytotoxicity towards the A375 melanoma cells. The ability of 4NCO to stabilize the c-MYC G4 to possibly suppress the over-expression of MYC was responsible for inhibition of proliferation of these cells. Hence, these results present a novel finding on the effectiveness of the nitro-flavone derivative 4NCO as a potent ligand for c-MYC G4 DNA thereby, providing possibilities of its use in cancer therapy for regulating the oncogene expression in cancer cells.

In the title molecule, C15H12O3, the C atoms bearing the hydroxy group and the phenyl ring are disordered over two sets of sites with refined occupancies of 0.573 (7) and 0.427 (7). There is also disorder of the phenyl ring but the hydroxy group was refined as ordered. The dihedral angles between the benzene ring of the chromane ring system and the phenyl ring are 89.7 (2)° for the major component of disorder and 72.1 (3)° for the minor component. Both disorder components of the the dihydropyran ring are in a half-chair conformation. In the crystal, molecules are linked by pairs of O—H...O hydrogen bonds, forming inversion dimers with anR22(10) graph-set motif. Weak C—H...π interactions link these dimers into ladders along [001].

In the title compound, C20H16O3, the hydropyran ring adopts a distorted half-chair conformation with the methine C atom and the ring O atom displaced by −0.554 (2) and 0.158 (1) Å, respectively, from the plane of the other four atoms (r.m.s. deviation = 0.020 Å). Its mean plane (all atoms) is inclined to the naphthalene ring system at a dihedral angle of 11.67 (1)°. The dihedral angle between the napthalene ring system and the phenyl ring is 71.84 (1)°. In the crystal, no diectional interactions beyond van der Waals contacts could be identified.

The objective of this study was to investigate the structural requirements necessary for inhibition of glutathione S-transferase P1-1 (GSTP1-1) and GS-X pump (MRP1 and MRP2) activity by structurally related flavonoids, in GSTP1-1 transfected MCF7 cells (pMTG5). The results reveal that GSTP1-1 activity in MCF7 pMTG5 cells can be inhibited by some flavonoids. Especially galangin was able to inhibit almost all cellular GSTP1-1 activity upon exposure of the cells to a concentration of 25 muM. Other flavonoids like kaempferol, eriodictyol and quercetin showed a moderate GSTP1-1 inhibitory potential. For GSTP1-1 inhibition, no specific structural requirements necessary for potent inhibition could be defined. Most flavonoids appeared to be potent GS-X transport inhibitors with IC50 values ranging between 0.8 and 8 muM. Luteolin and quercetin were the strongest inhibitors with IC50 values of 0.8 and 1.3 muM, respectively. Flavonoids without a C2-C3 double bond like eriodictyol, taxifolin and catechin did not inhibit GS-X pump activity. The results of this study demonstrate that the structural features necessary for high potency GS-X pump inhibition by flavonoids are (1) the presence of hydroxyl groups, especially two of them generating the 3',4-catechol moiety; and (2) a planar molecule due to the presence of a C2-C3 double bond. Other factors, like lipophilicity and the total number of hydroxyl groups do not seem to be dominating the flavonoid-mediated GS-X pump inhibition. To identify the GS-X pump responsible for the DNP-SG efflux in MCF7 cells, the effects of three characteristic flavonoids quercetin, flavone and taxifolin on MRP1 and MRP2 activity were studied using transfected MDCKII cells. All three flavonoids as well as the typical MRP inhibitor (MK571) affected MRP1-mediated transport activity in a similar way as observed in the MCF7 cells. In addition, the most potent GS-X pump inhibitor in the MCF7 cells, quercetin, did not affect MRP2-mediated transport activity. These observations clearly indicate that the GS-X pump activity in the MCF7 cells is likely to be the result of flavonoid-mediated inhibition of MRP1 and not MRP2. Altogether, the present study reveals that a major site for flavonoid interaction with GSH-dependent toxicokinetics is the GS-X pump MRP1 rather than the conjugating GSTP1-1 activity itself. Of the flavonoids shown to be most active especially quercetin is frequently marketed in functional food supplements. Given the physiological levels expected to be reached upon supplement intake, the IC50 values of the present study point at possible flavonoid-drug and/or flavonoid-xenobiotic interactions especially regarding transport processes involved in toxicokinetics. (C) 2004 Elsevier Inc. All rights reserved.

Selected flavonoids were tested for their ability to inhibit the catalytic activity of DNA topoisomerase (topo) I and II. Myricetin, quercetin, fisetin, and morin were found to inhibit both enzymes, while phloretin, kaempferol, and 4',6,7-trihydroxyisoflavone inhibited topo II without inhibiting topo I. Flavonoids demonstrating potent topo I and II inhibition required hydroxyl group substitution at the C-3, C-7, C-3', and C-4' positions and also required a keto group at C-4. Additional B-ring hydroxylation enhanced flavonoid topo I inhibitory action. A C-2,C-3 double bond was also required, but when the A ring is opened, the requirement for the double bond was eliminated. Genistein has been previously reported to stabilize the covalent topo II-DNA cleavage complex and thus function as a topo II poison. All flavonoids were tested for their ability to stabilize the cleavage complex between topo I or topo II and DNA. None of the agents stabilized the topo I-DNA cleavage complex, but prunetin, quercetin, kaempferol, and apigenin stabilized the topo II DNA-complex. Competition experiments have shown that genistein-induced topo II-mediated DNA cleavage can be inhibited by myricetin, suggesting that both types of inhibitors (antagonists and poisons) interact with the same functional domain of their target enzyme. These results are of use for the selection of flavonoids that can inhibit specific topoisomerases at specific stages of the topoisomerization reaction. © 1995, American Chemical Society. All rights reserved. 58 217 225 Tradenames: vm 26, bristol myers squibb, United States vp 16, bristol myers squibb, United States Manufacturers: aldrich, United States bristol myers squibb, United States gibco, United States sigma, United States Cited By :222