C-Geranylated flavanone diplacone enhances in vitro antiproliferative and anti-inflammatory effects in its copper(II) complexes.

Two copper(II) complexes containing diplacone (H4dipl), a naturally occurring C-geranylated flavanone derivative, in combination with bathophenanthroline (bphen) or 1,10-phenanthroline (phen) with the composition [Cu3(bphen)3(Hdipl)2]⋅2H2O (1) and {[Cu(phen)(H2dipl)2]⋅1.25H2O}n (2) were prepared and characterized. As compared to diplacone, the complexes enhanced in vitro cytotoxicity against A2780 and A2780R human ovarian cancer cells (IC50 ≈ 0.4-1.2 µM), human lung carcinoma (A549, with IC50 ≈ 2 µM) and osteosarcoma (HOS, with IC50 ≈ 3 µM). Cellular effects of the complexes in A2780 cells were studied using flow cytometry, covering studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/superoxide production. These results uncovered a possible mechanism of action characterized by the G2/M cell cycle arrest. The studies on human endothelial cells revealed that complexes 1 and 2, as well as their parental compound diplacone, do possess anti-inflammatory activity in terms of NF-κB inhibition. As for the effects on PPARα and/or PPARγ, complex 2 reduced the expression of leukocyte adhesion molecules VCAM-1 and E-selectin suggesting its dual anti-inflammatory capacity. A wide variety of Cu-containing coordination species and free diplacone ligand were proved by mass spectrometry studies in water-containing media, which might be responsible for multimodal effect of the complexes.

Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance.

Multidrug resistance (MDR) is a common problem when fighting cancer with chemotherapy. P-glycoprotein (P-gp, or MDR1) is an active pump responsible for the efflux of xenobiotics out of the cell, including anti-cancer drugs. It is a validated target against MDR. No crystal structure of the human P-gp is available to date, and only recently several cryo-EM structures have been solved. In this paper, we present a comprehensive computational approach that includes constructing the full-length three-dimensional structure of the human P-gp and its refinement using molecular dynamics. We assessed its flexibility and conformational diversity, compiling a dynamical ensemble that was used to dock a set of lignan compounds, previously reported as active P-gp inhibitors, and disclose their binding modes. Based on the statistical analysis of the docking results, we selected a system for performing the structure-based virtual screening of new potential P-gp inhibitors. We tested the method on a library of 87 natural flavonoids described in the literature, and 10 of those were experimentally assayed. The results reproduced the theoretical predictions only partially due to various possible factors. However, at least two of the predicted natural flavonoids were demonstrated to be effective P-gp inhibitors. They were able to increase the accumulation of doxorubicin inside the human promyelocytic leukemia HL60/MDR cells overexpressing P-gp and potentiate the antiproliferative activity of this anti-cancer drug.

Antiproliferative and cytotoxic activities of C-Geranylated flavonoids from Paulownia tomentosa Steud. Fruit.

Prenylated or geranylated flavonoids have been studied for their promising antiproliferative and cytotoxic activities. Twelve natural geranylated flavonoids (1-12) were isolated from the fruit of Paulownia tomentosa Steud. Their structures were elucidated using UV and IR spectroscopy, mass spectrometry, and 1D and 2D NMR spectroscopy. The absolute configurations were determined using NMR and circular dichroism. Seven of the compounds were characterized as new geranylated derivatives isolated from a natural source for the first time, namely 3'-O-methyl-5'-hydroxyisodiplacone (3), paulodiplacone A (5), tomentone II (6), tomentone B (7), tomentodiplacone P (8), paulodiplacone B (9), and tomentoflavone A (12). After 24 h of incubation at concentrations in the range 1-30 µM, the isolated compounds were tested for their antiproliferative and cytotoxic potentials against the human monocytic leukaemia cell line THP-1, using WST-1 and LDH assays, respectively. Almost all of the test compounds induced a concentration-dependent reduction in the metabolic activity of THP-1 cells and a concentration-dependent reduction in the cell viability. Diplacone (1) was the most potent antiproliferative and cytotoxic agent (IC50 9.31 ± 0.72 µM, LC50 18.01 ± 1.19 µM). 3'-O-Methyl-5'-hydroxydiplacone (2) showed relatively strong antiproliferative effect (IC50 12.61 ± 0.90 µM) and weaker cytotoxic activity (LC50 > 30 µM), indicating that it may serve as a potential lead compound for further testing. The structure-activity relationship for the 12 isolated compounds is discussed.