A375 Melanoma Cells are Sensitized to Cisplatin-Induced Toxicity by a Synthetic Nitro-Flavone Derivative 2-(4-Nitrophenyl)-4H-Chromen-4-one Through Inhibition of PARP1

Background: Cisplatin has been extensively used in therapeutics for its broad-spectrum anticancer activity and frequently used for the treatment of solid tumors. However, it presents several side-effects and several cancers develop resistance. Combination therapy of cisplatin with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors has been effective in increasing its efficacy at lower doses. Methods and Results: In this work, we have shown that the nitro-flavone derivative, 2-(4-Nitrophenyl)-4H-chromen-4-one (4NCO), can improve the sensitivity of cancer cells to cisplatin through inhibition of PARP1. The effect of 4NCO on cisplatin toxicity was studied through combination therapy in both exponential and density inhibited A375 melanoma cells. Combination index (CI) was determined from isobologram analysis. The mechanism of cell killing was assessed by lactate dehydrogenase (LDH) assay. Temporal nicotinamide adenine dinucleotide (NAD+) assay was done to show the inhibition of PARP1. We also performed in silico molecular modeling studies to know the binding mode of 4NCO to a modeled PARP1-DNA complex containing cisplatin-crosslinked adduct. The results from both in silico and in cellulo studies confirmed that PARP1 inhibition by 4NCO was most effective in sensitizing A375 melanoma cells to cisplatin. Isobologram analysis revealed that 4NCO reduced cell viability both in exponential and density inhibited A375 cells synergistically. The combination led to cell death through apoptosis. Conclusion: The synthetic nitro-flavone derivative 4NCO effectively inhibited the important nuclear DNA repair enzyme PARP1 and therefore, could complement the DNA-damaging anticancer drug cisplatin in A375 cells and thus, could act as a potential adjuvant to cisplatin in melanoma therapy.

Pachypodostyflavone, a New 3-methoxy Flavone and Other Constituents with Antifilarial Activities from the Stem Bark of Duguetia staudtii

A new flavone derivative named pachypodostyflavone (1), along with 8 known compounds (2–9) and a mixture of β-sitosterol and stigmasterol were isolated from the stem bark of Duguetia staudtii (Annonaceae), based on a bioassay-guided fractionation. Their structures were determined using high-resolution mass spectrometry and NMR spectroscopic data, as well as by comparison with the literature values of their analogs. Selected isolated compounds were evaluated for their in vitro antifilaricidal activities on Onchocerca ochengi microfilariae and adult worms. Inhibition of motility was evaluated spectroscopically on microfilaria and adult male worms. Viability was determined on adult female worms by the MTT/ Formazan assay. Auranofin at 10 µM and 2% DMSO were used as positive and negative controls, respectively. Compounds 1 and 7 showed potent anti-onchocerca activities with 100% activity at 250 µg/mL on both O. ochengi adult male and female worms, while compound 5 displayed 100% activity at 30 µg/mL.

A Selective, Dual Emission β-Alanine Aminopeptidase Activated Fluorescent Probe for the Detection of Pseudomonas aeruginosa, Burkholderia cepacia, and Serratia marcescens

Selective detection of β-alanyl aminopeptidase (BAP)-producing Pseudomonas aeruginosa, Serratia marcescens, and Burkholderia cepacia was achieved by employing the blue-to-yellow fluorescent transition of a BAP-specific enzyme substrate, 3-hydroxy-2-(p-dimethylaminophenyl)flavone derivative, incorporating a self-immolative linker to β-alanine. Upon cellular uptake and accumulation of the substrate by viable bacterial colonies, blue fluorescence was generated, while hydrolysis of the N-terminal peptide bond by BAP resulted in the elimination of the self-immolative linker and the restoration of the original fluorescence of the flavone derivative.

SYNTHESIS AND ANTIOXIDANT EVALUATION OF 3-BROMO-FLAVONE

Objective: The objective of the study was to obtain a flavone derivative compound through N-bromosuccinimide (NBS) reducing the reaction. Theantioxidant activity of the synthetic compound was then assayed by the 2,2-diphenyl-1-picrylhydrazyl method.Methods: Chalcone (3 mmol) as intermediate precursor was suspended with dimethyl sulfoxide and reacted with NBS (3 mmol), stirred at roomtemperature for 25 min and diluted in cold water. The synthesis of flavone derivatives resulted in yellow crystalline powder, freely soluble in methanoland ethanol, renamed 60% with a melting point of 87.7°C. Detection by thin-layer chromatography using hexane:chloroform (2:1) showed single spotwith Rf = 0.38 which is different from the Rf value of the starting compound (chalcone, 0.66 and 0.78).Results: The results of the characterization of the synthesized compound using ultraviolet-visible and Fourier transform-infared showed the groupcharacteristic containing C=C (1604.77 and 1639.49 cm-1), C=O (1681.93 cm-1), C-O-C (1242.16 cm-1), Ar-H (3032.1 and 3062.96 cm-1), and C-Br(663.51 cm-1) at maximum absorption of wavelength 253 nm.Conclusion: The synthesis of flavone using NBS resulted in 3-bromo-flavone with a weak antioxidant activity.