The fatty acid (FA), polyphenol content and evaluation of the antioxidant capacity of exhausted Myrtus communis berries (EMB) resulting from the production of myrtle liqueur were assessed. All parts of the exhausted berries exhibited high concentrations of carbohydrates, proteins, lipids and phenolic compounds. The lipid fraction contained a high amount of poly unsaturated fatty acids (PUFA), mainly represented by linoleic acid (>70%). Of the phenolic acids evaluated by liquid chromatography/mass spectrometry, ellagic acid was the most predominant (>50%), followed by gallic and quinic acids. Quercetin and quercetin3-O-rhamnoside were the most abundant flavonoids. The seed extracts showed a higher antioxidant potential than the pericarp extracts; the same trend was observed for total phenolic compounds evaluated by spectrophotometric assay. The overall high content of bioactive compounds and the high antioxidant potential of this byproduct sustain its suitability for a number of industrial applications, such as a food ingredient in novel foods, an additive in cosmetic formulations or a component of animal feed formulations.

The HIV-1 ribonuclease H (RNase H) function of the reverse transcriptase (RT) enzyme catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate, and represents a suitable target for drug development. A particularly attractive approach is constituted by the interference with the RNase H metal-dependent catalytic activity, which resides in the active site located at the C-terminus p66 subunit of RT. Herein, we report results of an in-house screening campaign that allowed us to identify 4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamides, prepared by the "click chemistry" approach, as novel potential HIV-1 RNase H inhibitors. Three compounds (9d, 10c, and 10d) demonstrated a selective inhibitory activity against the HIV-1 RNase H enzyme at micromolar concentrations. Drug-likeness, predicted by the calculation of a panel of physicochemical and ADME properties, putative binding modes for the active compounds, assessed by computational molecular docking, as well as a mechanistic hypothesis for this novel chemotype are reported.

Blotters are usually impregnated with hallucinogens such as lysergic acid diethylamide (LSD); only rarely other psychoactive substances are detected. In this work we identified 4-bromo-2,5-dimethoxyamphetamine (DOB) and 2,5-dimethoxyamphetamine (DMA) in illicit blotters seized in Italy. This report describes a rapid method for the simultaneous identification and quantitation of DOB and its precursor (DMA) by liquid chromatography tandem mass spectrometry (LC-MS-MS), using 2,3-dimethoxyphenethylamine-d3 as internal standard. Regression equations were linear over the tested concentration range with good correlation coefficients. The achieved levels of sensitivity may be suitable to confirm the possible presence of DOB and DMA also in low concentration or in traces in seized material for forensic analysis. The developed method showed good reproducibility and sensitivity, and could be used for similar routine analysis. To our knowledge, this is the first report describing the detection of DOB and DMA from blotters.

Background: Altered cellular bioenergetics and oxidative stress are emerging hallmarks of most cancers including pancreatic cancer. Elevated levels of intrinsic reactive oxygen species (ROS) in tumors make them more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm their adaptive antioxidant capacity and trigger ROS-mediated cell death. Recently, we have discovered a novel class of quinazolinediones that exert their cytotoxic effects by modulating ROS-mediated signaling.Methods: Cytotoxic potential was determined by colorimetric and colony formation assays. An XF24 Extracellular Flux Analyzer, and colorimetric and fluorescent techniques were used to assess the bioenergetics and oxidative stress effects, respectively. Mechanism was determined by Western blots.Results: Compound 3a (6-[(2-acetylphenyl)amino]quinazoline-5,8-dione) was identified through a medium throughput screen of similar to 1000 highly diverse in-house compounds and chemotherapeutic agents for their ability to alter cellular bioenergetics. Further structural optimizations led to the discovery of a more potent analog, 3b (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) that displayed anti-proliferative activities in low micromolar range in both drug-sensitive and drug-resistant cancer cells. Treatment with 3b causes Akt activation resulting in increased cellular oxygen consumption and oxidative stress in pancreatic cancer cells. Moreover, oxidative stress induced by 3b promoted activation of stress kinases (p38/JNK) resulting in cancer cell death. Treatment with antioxidants was able to reduce cell death confirming ROS-mediated cytotoxicity.Conclusion: In conclusion, our novel quinazolinediones are promising lead compounds that selectively induce ROS-mediated cell death in cancer cells and warrant further predinical studies.General significance: Since 3b (6-[(3-acetylphenyl)aminolquinazoline-5,8-dione) exerts Alct-dependent ROSmediated cell death, it might provide potential therapeutic options for chemoresistant and Alct-overexpressing cancers. (C) 2013 Elsevier B.V. All rights reserved.

Abstract Pancreatic cancer is a complex disease. Late stage detection, poor prognosis, and resistance to available chemotherapeutics highlight the need to discover new and potent anticancer agents for its effective treatment. Altered cellular bioenergetics and oxidative stress are emerging hallmarks of most forms of cancer including pancreatic cancer. Cancer cells are more prone to reactive oxygen species (ROS)-mediated cell death due to their inherent elevated basal oxidative stress as compared to normal cells. Increased basal ROS levels could represent the Achilles’ heel of cancer cells. Even though cancer cells have adapted to survive in an oxidative stress environment, exogenous oxidative insults can overwhelm the adaptive antioxidant capacity of cancer cells and trigger ROS-mediated cell death We have identified a novel class of compounds that act as redox modulators and specifically induce cell death in cancer cells. Compound 3a was identified through a medium throughput screen of ∼1000 highly diverse in-house compounds and chemotherapeutic agents for their ability to alter cellular bioenergetics using XF 24 extracellular flux analyzer (Seahorse Bioscience, Billerica, MA). Further structural optimizations led to the discovery of a more potent analog, 3b that displayed anti-proliferative activities at low micromolar levels in both drug-sensitive and drug-resistant cancer cell lines. Treatment with compound 3b causes Akt activation resulting in increased cellular oxygen consumption, oxidative stress and depletion of cellular antioxidant pool in pancreatic cancer cells. Akt is a pro-survival kinase that is upregulated in several forms of human cancers. Hyperactive Akt inhibits apoptosis induced by numerous stimuli. However, Akt is unable to inhibit ROS-mediated cell death, and in fact, Akt aids in ROS-directed cell death by inducing cellular oxygen consumption, promoting ROS generation, and impairing ROS degeneration. Moreover, oxidative stress induced by 3b promoted activation of stress kinases (p38/JNK) and resulted in cancer cell apoptosis. Treatment with antioxidants was able to reduce cell death confirming ROS-mediated cytotoxicity. In conclusion, our novel class of compounds are promising leads that by exacerbating oxygen consumption, ROS production, and reducing the antioxidant capacity of cancer cells tip the balance towards activation of stress kinases that ultimately leads to cell death. Citation Format: Divya Pathania, Mario Sechi, Michele Palomba, Vanna Sanna, Francesco Berrettini, Angela Sias, Laleh Taheri, Nouri Neamati. Design and discovery of novel small molecule redox modulators as therapies for pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4555. doi:10.1158/1538-7445.AM2013-4555

Abstract Oxidative stress is an important hallmark of cancer. Elevated levels of intrinsic reactive oxygen species (ROS) make tumor cells more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm the adaptive antioxidant capacity of cancer cells and trigger ROS-mediated cell death. Increasing ROS production or decreasing ROS scavengers shows potential for selectively targeting tumor cells that are under persistent oxidative stress. Recently, we have discovered novel class of quinazolinediones that exert their anticancer effects by modulating ROS-mediated cell signaling.The sub-micromolar anti-proliferative properties of these compounds were demonstrated by MTT and colony formation assays in a panel of cancer cell lines of different origins. Treatment with these agents induced cell cycle arrest, and increased superoxide production in cancer cells. Furthermore, proteomics analysis of 600 target antibody array revealed that these molecules significantly affected several cell signaling pathways implicated in carcinogenesis, cancer progression, redox signaling, and cell death.In conclusion, quinazolinediones are promising lead compounds that selectively enhance ROS production and induce ROS-mediated cell death in cancer cells, and warrant further preclinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 682. doi:10.1158/1538-7445.AM2011-682

A number of quinolone derivatives have been reported to possess anti-mycobacterial activity. Generally. Mycobacterium tuberculosis isolates expressing resistance to both isoniazid and rifampin are susceptible to fluoroquinolones. Benzotriazole is a hetero-bicyclic aromatic ring endowed with interesting chemical and biological properties and pharmacological activities. In a preliminary study we have recently reported the activity of triazolo[4,5-h]quinolone-carboxylic acids, a new class of benzotriazole derivatives active against multi-drug resistant M. tuberculosis (MDR-Mtb). In this study we confirm that this novel class of quinolones is endowed with a selective anti-mycobacterial activity, coupled with absence of cytotoxicity. The SAR analysis of the new derivatives in comparison with the previous series shows that the methyl group is the most effective substituent in both N-3 and N-9 positions of the ring system.

An experiment was carried out to investigate 1) the transfer of aflatoxin M1 (AFM1) into the milk of dairy ewes fed diets naturally contaminated with aflatoxin B1 (AFB1); 2) the effect of the addition of dried yeast culture in the diet on this transfer; and 3) the alteration of enzymatic activities in the liver of ewes fed diets contaminated with AFB1. Twenty-four Sarda dairy ewes were divided in 4 groups and fed a concentrate mix containing 4 amounts of wheat meal naturally contaminated with aflatoxins. The diet of the control group had no wheat meal, whereas that of treated groups had low, medium, or high amounts of contaminated wheat, which corresponded to 1.13, 2.30, and 5.03 microg of AFB1/kg of feed, respectively. The experiment lasted 14 d. On d 8 to 14 from the beginning of the trial, 12 g/d of a commercial dried yeast product (DYP) of Kluyveromyces lactis was added to the diet of each ewe. The AFM1 concentration in individual milk samples and the blood serum metabolites were measured periodically. The presence of AFM1 was first detected in milk on d 1 of administration, and then its concentration increased and approached a steady-state condition on d 3 simultaneously in all treated groups. The AFM1 in milk at the steady-state condition, which was linearly related to the AFB1 intake, was 39.72, 50.38, and 79.29 ng/L in the low-aflatoxin, medium-aflatoxin, and high-aflatoxin groups, respectively. The AFM1 concentration in milk of the high-aflatoxin group was approximately 1.5-fold greater than the European Commission maximum tolerance level (50 ng/kg). The addition of DYP to the diet did not affect the AFM1 concentration in milk. After the withdrawal of the contaminated concentrate mix, the AFM1 mean concentrations decreased quickly and were no longer detected after 3 d in all treated groups. Daily milk yield and composition did not differ because of aflatoxin treatment. Blood serum parameters (creatinine, glutamic oxalacetic transaminase, glutamic pyruvic transaminase, gamma glutamyl transferase, alkaline phosphatase, lactate dehydrogenase, cholesterol, protein, urea, calcium, and phosphorus) were not influenced by AFB1 intake. Therefore, the effect of DYP on certain blood parameters (gamma glutamyl transferase, urea, creatinine, and calcium) could not be attributed to amelioration of the aflatoxin-contaminated diet. In conclusion, diet contamination by AFB1 near the European Union tolerance level (0.005 mg/kg) in complete feed for dairy animals (e.g., high-aflatoxin group) can result in an AFM1 milk concentration higher than the European Commission maximum tolerance level. Transfer of aflatoxin from feed to milk was not affected by dietary addition of a commercial DYP.

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Angular N-tricyclic systems as triazolo[ 4,5-f]quinolines, triazolo[ 4,5-h] quinolines, imidazo[ 4,5-f]quinolines, imidazo[ 4,5-h]quinolines were in the past obtained by connection of either f or h sides of the quinoline ring and both the adjacent carbon atoms of five-membered rings containing nitrogen atoms. Several attempts at obtaining the corresponding linear N-tricycles were made in the last century, but only the angular derivatives were obtained. Since 2000 a new simple pathway, involving suitable quinoline derivatives, which afforded the linear azolo and pyrido quinolines (imidazo[4,5-g]quinolines, triazolo[ 4,5-g]quinolines and pyrido[2,3-g]quinoxalines) has been developed. Several linear N-tricyclic derivatives have shown some interesting pharmaceutical activity.

A number of novel quinolone derivatives have been recently reported to posses in vitro and in vivo anti mycobacterial and DNA gyrase inhibition activities. It is known that mycobacteria expressing resistance to both isoniazid and rifampin (multi-drug resistant, MDR) is sensible to fluoroquinolones. Ciprofloxacin, oxfloxacin, moxifloxacin and levofloxacin are increasingly used for the treatment of tuberculosis, because they inhibit the topoisomerases II (DNA gyrases) and IV, essential enzymes to maintain the supercoils in bacterial DNA. It has been demonstrated that complex mutations in DNA gyrase GyrA2GyrB2 associated with quinolone resistance or hypersusceptibility take place in several MDR clinical isolates of M. tuberculosis. In this article we report the anti mycobacterial properties, mode of action and structure activity relationship (SAR) studies of the known quinolone derivatives. Furthermore, we report the synthesis and activity of 3,9-disubstituted-6-oxo-6,9-dihydro-3H-[1,2,3]-triazolo[4,5-h]quinolone-carboxylic acids and their esters as a new class of potent anti mycobacterial agents. The triazoloquinolone derivatives are particularly interesting for their activity against MDR M. tuberculosis. Keywords: Quinolones, anti-tubercular activity, anti-mycobacterial activity, triazoloquinolones, MDR-TB, DNA gyrase inhibitors, SAR analysis

Alcuni acidi triazolo[4,5-h] e [4,5-f]chinoloncarbossilici angolari, sintetizzati in precedenza come antiinfettivi del tratto urinario, hanno mostrato interessanti valori di MIC 90 nei confronti di M. tuberculosis H37Rv. Allo scopo di approfondire le nostre conoscenze sui rapporti struttura-attivita di questa classe, abbiamo pertanto preparato una nuove serie di derivati.

In this preliminary study we report the activity of 3-methyl-9-substituted-6-oxo-6,9-dihydro-3H-[1,2,3]-triazolo[4,5-h]quinolone-carboxylic acids and their esters as a new class of antiinfective agents against MDR Mycobacterium tuberculosis. In antitubercular screening against H37Rv and 11 clinically isolated strains of M. tuberculosis several derivatives (1o,3a,c,i,j,p) showed MIC90 in the range 0.5–3.2μg/mL. 3c showed no cytotoxicity and proved to be the most potent derivative exhibiting MIC90=0.5μg/mL against all M. tuberculosis strains and infected human macrophages (J774-A1) tested.

An effective approach for the synthesis of new substituted mono and diaminoquinolines is described. Two known quinolines 7,8-dichloro-6-nitroquinoline (1) and 7,8-dichloro-6-nitrohydroquinolin-4-one (9) were used as key intermediates.

In recent years, a number of newer designer drugs have entered the illicit drug market. The methylenedioxy-derivates of amphetamine represent the largest group of designer drugs. This paper describes a method for screening for and quantification of ten 2,5-methylenedioxy-derivates of amphetamine and phenylethylamine in human urine, using capillary electrophoresis coupled to electrospray ionisation–mass spectrometry (CE–ESI–MS). Prior to CE–MS analysis, a simple solid-phase extraction (SPE) was used for sample cleanup. The method was validates according to international guidelines.