Steroidal CYP17 Inhibitors for Prostate Cancer Treatment: From Concept to Clinic

The successful application of therapeutic strategies to block the known growth stimulation property of estrogen in breast cancer, namely the aromatase (CYP19) inhibitors formestane (4-OH) and exemestane (Aromasin) [1], has paved the way for the investigation of inhibitors of other P450 enzymes that might impart the growth of hormone-dependent cancers [2]. Cytochrome P450 17α-hydroxylase,C17,20-lyase (CYP17) is at the crossroads of androgen and corticoid biosynthesis and has become a valuable target in prostate cancer (PC) treatment [3-8]. Androgens, which are produced in steroidogenic tissues, bind to the androgen receptor (AR) and initiate transcription which in turn results in the synthesis of prostate-specific proteins, as well as in cell proliferation. Systemic ablation of androgen by castration, either surgical or chemical, is highly effective in treating PC when the disease is hormone-dependent

Catalytic, Tunable, One-Step Bismuth(III) Triflate Reaction with Alcohols : Dehydration Versus Dimerization

Bi(OTf)(3)center dot xH(2)O is a powerful catalyst for the dehydration of tertiary alcohols into alkenes in apolar solvents. The reaction proceeds smoothly and selectively, with amounts as low as 0.01 mol % catalyst, in yields up to 93%. Moreover, in polar solvents, Bi(OTf)(3)center dot xOH(2)O (0.1-1 mol %) selectively catalyzes the dimerization of the alcohols instead, forming new C-C bonds, in yields up to 96%. This mild, efficient, economic, and eco-friendly method is applicable across different chemical classes and amenable to several functional groups.Peer reviewe

Liquorice for pain?

Liquorice has a long history of use in traditional Chinese, Ayurvedic and herbal medicine. The liquorice plant contains numerous bioactive compounds, including triterpenes, flavonoids and secondary metabolites, with glycyrrhizin being the main active compound. Liquorice constituents have been found to have anti-inflammatory, antioxidant, antiviral, anticancer, hepatoprotective and neuroprotective properties. In addition, they appear to have antidepressant actions and effects on morphine tolerance. Glycyrrhizin, its metabolite glycyrrhetic (glycyrrhetinic) acid and other liquorice-derived compounds such as isoflavonoids and trans-chalcones, exert potent anti-inflammatory effects via a wide range of mechanisms including high mobility group box 1 protein (HMGB1) inhibition, gap junction blockade and alpha(2A)-adrenoceptor antagonism. These properties, together with an increasing body of preclinical studies and a long history of use in herbal medicine, suggest that liquorice constituents may be useful for pain management. Glycyrrhizin is used widely in the confectionary, food and tobacco industries, but has documented adverse effects that may limit clinical use. Whether liquorice plant-derived compounds represent a novel class of analgesics is yet to be established. Having a host of bioactive compounds with a broad range of mechanisms of effect, liquorice is a plant that, in the future, may give rise to new therapies for pain.Peer reviewe

Biodegradation of Carbamazepine and Diclofenac by Bacterial Strain Labrys portucalensis

The occurrence of pharmaceuticals in the environment has been a topic of increasing concern. Pharmaceuticals are not completely mineralized in the human body and are released on the sewage systems as the pharmaceutical itself and as their “biologically active” metabolites through excretion, as well as by improper elimination and disposal. Conventional wastewater treatment plants (WWTPs) are not designed to remove these emerging pollutants and they are thus released into the environment. The antiepileptic drug carbamazepine (CBZ) and the non-steroidal anti-inflammatory diclofenac (DCF) are two widely used pharmaceuticals, frequently detected in water bodies, including rivers and groundwater, in concentrations ranging from ng L 1 to mg L 1. These two compounds were classified as medium to high-risk pollutants in WWTP effluents and surface waters. Also, CBZ has been suggested as a molecular marker of wastewater contamination in surface water and groundwater and the European Union included DCF in the watch list of substances Directive to be monitored. In the present study, biodegradation of CBZ and DCF by the bacterial strain Labrys portucalensis F11, a strain able to degrade other pharmaceutical compounds, was assessed; tests were performed with F11 as single carbon and energy source, as well as in presence of 5.9mM of sodium acetate. In assays supplemented with 2.0 and 4.0 µM of CBZ, the compound was no longer detected in the bulk medium after 24hr and 5days, respectively. Complete degradation was achieved in 21 days for 11.0 µM and in 23 days for 21.0 µM. For the highest concentration tested (43.0 µM), 95% of degradation was achieved in 30days. Supplementation with acetate increased the degradation rate of CBZ, for all tested concentrations. In the case of DCF, when supplemented as a single carbon source, approximately 70% of DCF (1.7, 3.3, 8.4, 17.5 and 34.0 µM) was degraded in 30days. Complete degradation was achieved in the presence of acetate for all tested concentrations, at higher degradation rates. The detection of intermediates produced during DCF biodegradation was performed by UPLC-QTOF/MS/MS, which allowed the identification of a range of metabolites. Stoichiometric liberation of chorine occurred and no metabolites were detected at the end of the biodegradation assays suggesting a complete mineralization of DCF. Strain Labrys portucalensis F11 proved to be able to degrade these two top priority environmental contaminants and may be potentially useful for biotechnological applications/environment remediation.info:eu-repo/semantics/publishedVersio

Biological removal processes in aerobic granular sludge exposed to diclofenac

Diclofenac is a worldwide consumed drug included in the watch list of substances to be monitored according to the European Union Water Framework Directive (Directive 2013/39/EU). Aerobic granular sludge sequencing batch reactors (AGS-SBR) are increasingly used for wastewater treatment but there is scant information on the fate and effect of micropollutants to nutrient removal processes. An AGS-SBR fed with synthetic wastewater containing diclofenac was bioaugmented with a diclofenac degrading bacterial strain and performance and microbial community dynamics was analysed. Chemical oxygen demand, phosphate and ammonia removal were not affected by the micropollutant at 0.03 mM (9.54 mg L-1). The AGS was able to retain the degrading strain, which was detected in the sludge throughout after augmentation. Nevertheless, besides some adsorption to the biomass, diclofenac was not degraded by the augmented sludge given the short operating cycles and even if batch degradation assays confirmed that the bioaugmented AGS was able to biodegrade the compound. The exposure to the pharmaceutical affected the microbial community of the sludge, separating the two first phases of reactor operation (acclimatization and granulation) from subsequent phases. The AGS was able to keep the bioaugmented strain and to maintain the main functions of nutrient removal even through the long exposure to the pharmaceutical, but combined strategies are needed to reduce the spread of micropollutants in the environment.info:eu-repo/semantics/acceptedVersio

(+)-Dehydroabietic Acid, an Abietane-Type Diterpene, Inhibits Staphylococcus aureus Biofilms in Vitro

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Drug repositioning : a machine-learning approach through data integration

Existing computational methods for drug repositioning either rely only on the gene expression response of cell lines after treatment, or on drug-to-disease relationships, merging several information levels. However, the noisy nature of the gene expression and the scarcity of genomic data for many diseases are important limitations to such approaches. Here we focused on a drug-centered approach by predicting the therapeutic class of FDA-approved compounds, not considering data concerning the diseases. We propose a novel computational approach to predict drug repositioning based on state-of-the-art machine-learning algorithms. We have integrated multiple layers of information: i) on the distances of the drugs based on how similar are their chemical structures, ii) on how close are their targets within the protein-protein interaction network, and iii) on how correlated are the gene expression patterns after treatment. Our classifier reaches high accuracy levels (78%), allowing us to re-interpret the top misclassifications as re-classifications, after rigorous statistical evaluation. Efficient drug repurposing has the potential to significantly impact the whole field of drug development. The results presented here can significantly accelerate the translation into the clinics of known compounds for novel therapeutic uses

Biodegradation of Carbamazepine by the bacterial strain Labrys portucalensis F11 – metabolism and toxicologic studies

Background Occurrence of pharmaceuticals in the environment is a topic of concern. Most pharmaceuticals are not completely mineralized and are released on the sewage systems through excretion and by improper elimination and disposal(1). Municipal wastewater treatment plants (WWTPs) are not designed to remove them and they are released into the environment(2). They are classified as persistent microcontaminants due to their continuous release even if at low concentrations (3). Carbamazepine (CBZ) is an widely used anticonvulsant and has been suggested as a molecular marker of contamination in surface water and groundwater(4). Method Biodegradation of CBZ by the bacterial strain Labrys portucalensis F11 was tested as sole carbon and energy source (0.04 mM) and in the presence of acetate as primary carbon source. Transformation products (TPs) were detected and identified by UPLCQTOF/MS/MS. Ecotoxicologiacl effects of CBZ and the TPs resultant from biodegradation were evaluated at different trophic levels, i) zooplanckton (Dapnhia magna) and ii) plants (Lipidium sativum). The 24–48 h immobilization of D. magna bioassays were performed following the Standard Operational Procedures of Daphtoxkit FTM. The toxicity was measured as the immobilization of D. magna according to the procedures OCED Guideline 202(5). The bioassay with L. sativum evaluated the potential toxicity considering the root elongation according to OECD Guideline 208(6). Results & Conclusions Strain F11 was able to degrade 95% of initial CBZ concentration during 30 days experiment. Supplementation with acetate increased degradation to 100% in 24 days. A group of 12 TPs formed in the microbial process were identified; CBZ degradation by strain F11 proceeds mainly by oxidation, hydroxilation and cleavage of the aromatic ring. The effect of whole biodegradation products on root elongation of L. sativum was practically neglectable; however the same exhibited toxicity to D. magna. Strain Labrys portucalensis F11 proved to be able to degrade CBZ and may be potentially useful for biotechnological applications.info:eu-repo/semantics/publishedVersio

Antiprotozoal activity of dehydroabietic acid derivatives against Leishmania donovani and Trypanosoma cruzi - SPECIAL ISSUE "NEW TALENT: EUROPE"

Derivatives of dehydroabietic acid bearing different amino acids scaffolds have potent antiprotozoal activity against Leishmania donovani and Trypanosoma cruzi, with good to high selectivity, and can therefore be regarded as good models for further development into new drugs to fight leishmaniasis and Chagas disease. Several of the tested compounds were able to kill parasites residing inside cells, with IC50 values ranging from 2.3 to 9 mu M (L. donovani) and 1.4 to 5.8 mu M (T. cruzi), reflecting their ability to fight these infections at the relevant stage responsible for disease. One of the compounds, bearing a 3-pyridyl-Dalanine side chain, was 1.5-fold more potent against T. cruzi amastigotes residing in L6 cells than the reference compound benznidazole.Peer reviewe

Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12

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