Sara Cravo

A new cyclic hexapeptide and a new isocoumarin derivative from the marine sponge-associated fungus Aspergillus similanensis KUFA 0013.

A new isocoumarin derivative, similanpyrone C (1), a new cyclohexapeptide, similanamide (2), and a new pyripyropene derivative, named pyripyropene T (3) were isolated from the ethyl acetate extract of the culture of the marine sponge-associated fungus Aspergillus similanensis KUFA 0013. The structures of the compounds were established based on 1D and 2D NMR spectral analysis, and in the case of compound 2 the stereochemistry of its amino acid constituents was determined by chiral HPLC analysis of the hydrolysate by co-injection with the d and l amino acids standards. Compounds 2 and 3 were evaluated for their in vitro growth inhibitory activity against MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A373 (melanoma) cell lines, as well as antibacterial activity against reference strains and the environmental multidrug-resistant isolates (MRS and VRE). Only compound 2 exhibited weak activity against the three cancer cell lines, and neither of them showed antibacterial activity.

New Cyclotetrapeptides and a New Diketopiperzine Derivative from the Marine Sponge-Associated Fungus Neosartorya glabra KUFA 0702

Two new cyclotetrapeptides, sartoryglabramides A (5) and B (6), and a new analog of fellutanine A (8) were isolated, together with six known compounds including ergosta-4, 6, 8 (14), 22-tetraen-3-one, ergosterol 5, 8-endoperoxide, helvolic acid, aszonalenin (1), (3R)-3-(1H-indol-3-ylmethyl)-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (2), takakiamide (3), (11aR)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione (4), and fellutanine A (7), from the ethyl acetate extract of the culture of the marine sponge-associated fungus Neosartorya glabra KUFA 0702. The structures of the new compounds were established based on extensive 1D and 2D spectral analysis. X-ray analysis was also used to confirm the relative configuration of the amino acid constituents of sartoryglabramide A (5), and the absolute stereochemistry of the amino acid constituents of sartoryglabramide A (5) and sartoryglabramides B (6) was determined by chiral HPLC analysis of their hydrolysates by co-injection with the d- and l- amino acids standards. Compounds 1–8 were tested for their antibacterial activity against Gram-positive (Escherichia coli ATCC 25922) and Gram-negative (Staphyllococus aureus ATCC 25923) bacteria, as well as for their antifungal activity against filamentous (Aspergillus fumigatus ATCC 46645), dermatophyte (Trichophyton rubrum ATCC FF5) and yeast (Candida albicans ATCC 10231). None of the tested compounds exhibited either antibacterial (MIC > 256 μg/mL) or antifungal activities (MIC > 512 μg/mL).

Lipophilicity assessement in drug discovery: Experimental and theoretical methods applied to xanthone derivatives

For the last several years, searching of new xanthone derivatives (XDs) with potential pharmacological activities has remained one of the main areas of interest of our group. The optimization of biological activity and drug-like properties of hits and leads is crucial at early stage of the drug discovery pipeline. Lipophilicity is one of the most important drug-like properties having a great impact in both pharmacokinetics and pharmacodynamics processes. In this work, we describe the lipophilicity of a small library of bioactive XDs, previously synthesized by our group, using different methods: computational, vortex-assisted liquid-liquid microextraction coupled with high-performance liquid chromatography (VALLME-HPLC), reversed-phase high-performance thin layer chromatography (RP-HPTLC), reversed-phase high-performance liquid chromatography (RP-HPLC), and biomembrane model by the partition between micelles and aqueous phase. The different results obtained by the used methods were compared and discussed. The methodologies and data gathered in this study will expand the investigation of lipophilicity of XDs, an important class of compounds in medicinal chemistry.

Data analysis of “krokodil” samples obtained by street-like synthesis

The data described in this work is related to be the subject of an article in the Forensic Science International, titled: “The harmful chemistry behind “krokodil”: street-like synthesis and product analysis” (http://dx.doi.org/10.1016/j.forsciint.2015.07.042) [1]. The data presented here provides additional description of the chemical profile of “krokodil”. Physicochemical and organoleptic characteristics, TLC profile, UV/Vis, 1H NMR and FTIR spectrum are presented. These data validate the proposed synthetic procedure and pathway and give further information about the contaminants present in “krokodil”.

Xanthone and Flavone Derivatives as Dual Agents with Acetylcholinesterase Inhibition and Antioxidant Activity as Potential Anti-Alzheimer Agents

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that is associated with the elderly. The current therapy that is used to treat AD is based mainly on the administration of acetylcholinesterase (AChE) inhibitors. Due to their low efficacy there is a considerable need for other therapeutic strategies. Considering that the malfunctions of different, but interconnected, biochemical complex pathways play an important role in the pathogenesis of this disease, a promising therapy may consist in administration of drugs that act on more than a target on biochemical scenery of AD. In this work, the synthesis and evaluation of xanthone and flavone derivatives as antioxidants with AChE inhibitory activity were accomplished. Among the obtained compounds, Mannich bases 3 and 14 showed capacity to inhibit AChE and antioxidant property, exerting dual activity. Moreover, for the most promising AChE inhibitors, docking studies on the target have been performed aiming to predict the binding mechanism. The results presented here may help to identify new xanthone and flavone derivatives as dual anti-Alzheimer agents with AChE inhibitory and antioxidant activities.

GC-MS Method for the Analysis of Thirteen Opioids, Cocaine and Cocaethylene in Whole Blood Based on a Modified Quechers Extraction

1 UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; 2 Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, Porto, Portugal; 3 EPSJV – Polythecnical School of Health Joaquim Venâncio, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 4 Center of Medical Chemistry (CEQUIMED-UP), Faculty of Pharmacy, University of Porto, Porto, Portugal; 5 Interdisciplinary Center of Marine and Enviromental Investigation (CIIMAR/CIMAR), Porto, Portugal; 6 Department of Analytical Chemistry, Chemistry Institute, Fluminense Federal University, Niterói, Brazil; 7 IINFACTS Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal

Enantiomeric Resolution and Docking Studies of Chiral Xanthonic Derivatives on Chirobiotic Columns

A systematic study of enantioresolution of a library of xanthonic derivatives, prepared “in-house”, was successfully carried out with four commercially available macrocyclic glycopeptide-based columns, namely ChirobioticTM T, ChirobioticTM R, ChirobioticTM V and ChirobioticTM TAG. Evaluation was conducted in multimodal elution conditions: normal-phase, polar organic, polar ionic and reversed-phase. The effects of the mobile phase composition, the percentage of organic modifier, the pH of the mobile phase, the nature and concentration of different mobile phase additives on the chromatographic parameters are discussed. ChirobioticTM T and ChirobioticTM V, under normal-phase and reversed-phase modes, respectively, presented the best chromatographic parameters. Considering the importance of understanding the chiral recognition mechanisms associated with the chromatographic enantioresolution, and the scarce data available for macrocyclic glycopeptide-based columns, computational studies by molecular docking were also carried out.

Repeated subcutaneous administrations of krokodil causes skin necrosis and internal organs toxicity in Wistar rats: putative human implications

“Krokodil” is the street name for an impure homemade drug mixture used as a cheap substitute for heroin, containing desomorphine as the main opioid. Abscesses, gangrene, thrombophlebitis, limb ulceration and amputations, jaw osteonecrosis, skin discoloration, ulcers, skin infections, and bleeding are some of the typical reported signs in humans. This study aimed to understand the toxicity of krokodil using Wistar male rats as experimental model.

New chiral stationary phases based on xanthone derivatives for liquid chromatography

Six chiral derivatives of xanthones (CDXs) were covalently bonded to silica, yielding the corresponding xanthonic chiral stationary phases (XCSPs). The new XCSPs were packed into stainless-steel columns with 150 x 4.6 mm i.d. Moreover, the greening of the chromatographic analysis by reducing the internal diameter (150 x 2.1 mm i.d.) of the liquid chromatography (LC) columns was also investigated. The enantioselective capability of these phases was evaluated by LC using different chemical classes of chiral compounds, including several types of drugs. A library of CDXs was evaluated in order to explore the principle of reciprocity as well as the chiral self-recognition phenomenon. The separation of enantiomeric mixtures of CDXs was investigated under multimodal elution conditions. The XCSPs provided high specificity for the enantiomeric mixtures of CDXs evaluated mainly under normal-phase elution conditions. Furthermore, two XCSPs were prepared with both enantiomers of the same xanthonic selector in order to confirm the inversion order elution.

Multi-milligram resolution and determination of absolute configuration of pentedrone and methylone enantiomers

The enantioresolution of pentedrone and methylone was carried out at a multi-milligram scale by liquid chromatography on a Chiralpak AS® stationary phase. The excellent enantioresolution using this column allowed to collect highly pure enantiomeric fractions, achieving enantiomeric ratios higher than 98%. An overall recovery of 72% was achieved for pentedrone enantiomers and 80% for methylone. Furthermore, the absolute configuration of the enantiomers of both cathinones was determined for the first time by electronic circular dichroism (ECD) spectroscopy, with the aid of theoretical calculations, as (+)‑(S) and (-)‑(R)-pentedrone, and (-)‑(S) and (+)‑(R)‑methylone.