Lichen xanthones as models for new antifungal agents

Due to the emergence of multidrug-resistant pathogenic microorganisms, the search for new antimicrobial compounds plays an important role in current medicinal chemistry research. Inspired by lichen antimicrobial xanthones, a series of novel chlorinated xanthones was prepared using five chlorination methods (Methods A–E) to obtain different patterns of substitution in the xanthone scaffold. All the synthesized compounds were evaluated for their antimicrobial activity. Among them, 3-chloro-4,6-dimethoxy-1-methyl-9H-xanthen-9-one 15 showed promising antibacterial activity against E. faecalis (ATCC 29212 and 29213) and S. aureus ATCC 29213. 2,7-Dichloro-3,4,6-trimethoxy-1-methyl-9H-xanthen-9-one 18 revealed a potent fungistatic and fungicidal activity against dermatophytes clinical strains (T. rubrum, M. canis, and E. floccosum (MIC = 4–8 µg/mL)). Moreover, when evaluated for its synergistic effect for T. rubrum, compound 18 exhibited synergy with fluconazole (ΣFIC = 0.289). These results disclosed new hit xanthones for both antibacterial and antifungal activity.This work was partially supported through national funds provided by FCT/MCTES - Foundation for Science and Technology from the Ministry of Science, Technology, and Higher Education (PIDDAC) and the European Regional Development Fund (ERDF) through the COMPETE - Programa Operacional Factores de Competitividade (POFC) programme, under the Strategic Funding UID/Multi/04423/2013, the projects POCI-01-0145-FEDER-028736 and POCI-01-0145-FEDER-016790 (PTDC/MAR-BIO/4694/2014; 3599-PPCDT) in the framework of the programme PT2020, as well as by the project INNOVMAR - Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-0145-FEDER-000035, within Research Line NOVELMAR), supported by North Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Diana I. S. P. Resende also acknowledge for her grant (NOVELMAR/BPD_2/2016-019) and Patrícia Pereira-Terra for her grant (NOVELMAR/BPD/2017/012)

Chiral stationary phases for liquid chromatography based on chitin- and chitosan-derived marine polysaccharides

The development of chiral stationary phases (CSPs) for liquid chromatography (LC) revolutionized the enantioseparation and, nowadays, different types of CSPs are commercially available. Polysaccharide-based CSPs are one of the most versatile and widely used for both analytical and preparative applications and they are able to resolve several classes of racemates. Phenylcarbamates of amylose and cellulose derivatives are the most successful; however, polysaccharide-based CSPs comprising marine-derived polysaccharides are also described revealing high chiral recognition abilities and wider range of mobile phases. A literature survey covering the report on chitin and chitosan based CSPs is presented. The chemical structure of the chiral selectors, their development and applications in chiral LC are emphasized. © 2017 by the authors.Acknowledgments: This work was partially supported through national funds provided by FCT/ MCTES—Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE—Programa Operacional Factores de Competitividade (POFC) programme, under the Strategic Funding UID/Multi/04423/2013, the project PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599—Promover a Produção Científica e Desenvolvimento Tecnológico e a Constituição de Redes Temáticas (3599-PPCDT)) in the framework of the programme PT2020 as well as by the project INNOVMAR—Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-0145-FEDER-000035, within Research Line NOVELMAR), supported by North Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and Chiral_Drugs_CESPU_2017

Marine natural products as models to circumvent multidrug resistance

Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds. © 2016 by the authors.The authors thank to national funds provided by FCT-Foundation for Science and Technology and European Regional Development Fund (ERDF) and COMPETE under the projects PEst-C/MAR/LA0015/2013, PTDC/MAR-BIO/4694/2014, and INNOVMAR-Innovation and Sustainability in the Management and Exploitation of Marine Resources, reference NORTE-01-0145-FEDER-000035, Research Line NOVELMAR. S.L. thanks Erasmus Mundus Action 2 (LOTUS+, LP15DF0205) for full PhD scholarship

Marine natural peptides: Determination of absolute configuration using liquid chromatography methods and evaluation of bioactivities

Over the last decades, many naturally occurring peptides have attracted the attention of medicinal chemists due to their promising applicability as pharmaceuticals or as models for drugs used in therapeutics. Marine peptides are chiral molecules comprising different amino acid residues. Therefore, it is essential to establish the configuration of the stereogenic carbon of their amino acid constituents for a total characterization and further synthesis to obtain higher amount of the bioactive marine peptides or as a basis for structural modifications for more potent derivatives. Moreover, it is also a crucial issue taking into account the mechanisms of molecular recognition and the influence of molecular three-dimensionality in this process. In this review, a literature survey covering the report on the determination of absolute configuration of the amino acid residues of diverse marine peptides by chromatographic methodologies is presented. A brief summary of their biological activities was also included emphasizing to the most promising marine peptides. A case study describing an experience of our group was also included. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.This research was partially supported by the Strategic Funding UID/Multi/04423/2013 through national funds provided by FCT—Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the programme PT2020, the project PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599—Promover a Produção Científica e Desenvolvimento Tecnológico e a Constituição de Redes Temáticas (3599-PPCDT)) as well as by the project INNOVMAR— Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01- 0145-FEDER-000035, within Research Line NOVELMAR), supported by North Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the Europeann Regional Development Fund (ERDF), and Chiral_Drugs_CESPU_2017. Phyo thanks the Erasmus Mundus Action 2 (Lotus Plus project) for a PhD’s scholarship

Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies

Recently, thioxanthone derivatives were found to protect cells against toxic P-glycoprotein (P-gp) substrates, acting as potent inducers/activators of this efflux pump. The study of new P-gp chiral modulators produced from thioxanthone derivatives could clarify the enantioselectivity of this ABC transporter towards this new class of modulators. The aim of this study was to evaluate the P-gp modulatory ability of four enantiomeric pairs of new synthesized chiral aminated thioxanthones (ATxs) 1–8, studying the influence of the stereochemistry on P-gp induction/ activation in cultured Caco-2 cells. The data displayed that all the tested compounds (at 20 µM) significantly decreased the intracellular accumulation of a P-gp fluorescent substrate (rhodamine 123) when incubated simultaneously for 60 min, demonstrating an increased activity of the efflux, when compared to control cells. Additionally, all of them except ATx 3 (+), caused similar results when the accumulation of the P-gp fluorescent substrate was evaluated after pre-incubating cells with the test compounds for 24 h, significantly reducing the rhodamine 123 intracellular accumulation as a result of a significant increase in P-gp activity. However, ATx 2 (−) was the only derivative that, after 24 h of incubation, significantly increased P-gp expression. These results demonstrated a significantly increased P-gp activity, even without an increase in P-gp expression. Therefore, ATxs 1–8 were shown to behave as P-gp activators. Furthermore, no significant differences were detected in the activity of the protein when comparing the enantiomeric pairs. Nevertheless, ATx 2 (−) modulates P-gp expression differently from its enantiomer, ATx 1 (+). These results disclosed new activators and inducers of P-gp and highlight the existence of enantioselectivity in the induction mechanism. © 2018 by the authors.Acknowledgments: This research was partially supported by the Strategic Funding UID/Multi/04423/2013 through national funds provided by FCT—Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the programme PT2020, the project PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599—Promover a Produção Científica e Desenvolvimento Tecnológico e a Constituição de Redes Temáticas (3599-PPCDT)) as well as by the project INNOVMAR—Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-0145-FEDER-000035, within Research Line NOVELMAR), supported by North Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). The authors also thank Sara Cravo, Department of Chemistry, Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, for technical support in chiral HPLC. Renata Silva acknowledges Fundação para a Ciência e a Tecnologia (FCT) for her Post-doctoral grant (SFRH/BPD/110201/2015)

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. 2018 by the authors.Acknowledgments: This research was partially supported by the Strategic Funding UID/Multi/04423/2013 through national funds provided by FCT—Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the programme PT2020, the project PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599—Promover a Produçã

Drug-like properties and ADME of xanthone derivatives: The antechamber of clinical trials

Xanthone derivatives have been described as compounds with a privileged scaffold exhibiting diverse biological/pharmacological activities, what directed the interest to pursue the development of these derivatives into drug candidates. Nevertheless, to achieve this purpose it is crucial to study their pharmacokinetics and toxicity (PK/tox) properties as decision endpoints to continue or interrupt the development investment. This review aims to expose the most relevant analytical methods used in the physicochemical and PK/tox studies in order to detect, quantify, and identify different bioactive xanthones. Analyzing the main results from in vitro and in vivo systems towards ADME properties such as solubility, lipophilicity, pKa, chemical and metabolic stability, permeability, transporters modulation, and plasma protein binding, it is possible to uncover some threats governing the PK properties and to understand the bioavailability and drugability of xanthone derivatives. The last section of this review focuses on a case-study of the development of the drug candidate DMXAA, which has reached clinical trials, to provide the paths and the importance of PK/tox parameters of this scaffold. The data assembled in this review intends to guide for tackling issues in the design of potential lead compounds and drug candidates with a xanthone scaffold. © 2016 Bentham Science Publishers.This work was supported by ERDF, COMPETE, and FCT under the projects PTDC/AAG-TEC/0739/2014 (POCI-01-0145-FEDER-016793), PTDC/MARBIO/4694/2014 (POCI-01-0145-FEDER-016-790), and INNOVMAR - Innovation and Sustainability in the Management and Exploitation of Marine Resources, reference NORTE-01-0145-FEDER-000035, Research Line NOVELMAR and FCT through the FCT PhD Programmes and by Programa Operacional Potencial Humano (POCH), specifically by the BiotechHealth Programe (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences). FCT PhD Programmes with PhD student grants: A. S. Gomes (PD/BI/105912/2014 and PD/BD/114046/2015)

One step forward towards the development of eco-friendly antifouling coatings: Immobilization of a sulfated marine-inspired compound

Marine biofouling represents a global economic and ecological challenge and few eco-friendly antifouling agents are available. The aim of this work was to establish the proof of concept that a recently synthesized nature-inspired compound (gallic acid persulfate, GAP) can act as an eco-friendly and effective antifoulant when immobilized in coatings through a non-release strategy, promoting a long-lasting antifouling effect. The synthesis of GAP was optimized to provide quantitative yields. GAP water solubility was assessed, showing values higher than 1000 mg/mL. GAP was found to be stable in sterilized natural seawater with a half-life (DT50) of 7 months. GAP was immobilized into several commercial coatings, exhibiting high compatibility with different polymeric matrices. Leaching assays of polydimethylsiloxane and polyurethane-based marine coatings containing GAP confirmed that the chemical immobilization of GAP was successful, since releases up to fivefold lower than the conventional releasing systems of polyurethane-based marine coatings were observed. Furthermore, coatings containing immobilized GAP exhibited the most auspicious anti-settlement effect against Mytilus galloprovincialis larvae for the maximum exposure period (40 h) in laboratory trials. Overall, GAP promises to be an agent capable of improving the antifouling activity of several commercial marine coatings with desirable environmental properties.This research was funded by national funds through the Foundation for Science and Technology (FCT) within the scope of research unit grants to CIIMAR (UIDB/04423/2020 and UIDP/04423/2020), to BioISI (UIDB/04046/2020 and UIDP/04046/2020) and under the project PTDC/AAG-TEC/0739/2014 (reference POCI-01-0145-FEDER-016793) supported through national funds provided by FCT and the European Regional Development Fund (ERDF) via the Programa Operacional Factores de Competitividade (POFC/COMPETE) programme and the Reforçar a Investigação, o Desenvolvimento Tecnológico e a Inovação (RIDTI; project 9471)

New polyketides and new benzoic acid derivatives from the marine sponge-associated fungus Neosartorya quadricincta KUFA 0081

Two new pentaketides, including a new benzofuran-1-one derivative (1) and a new isochromen-1-one (5), and seven new benzoic acid derivatives, including two new benzopyran derivatives (2a, b), a new benzoxepine derivative (3), two new chromen-4-one derivatives (4b, 7) and two new benzofuran derivatives (6a, b), were isolated, together with the previously reported 2,3-dihydro-6-hydroxy-2,2-dimethyl-4H-1-benzopyran-4-one (4a), from the culture of the marine sponge-associated fungus Neosartorya quadricincta KUFA 0081. The structures of the new compounds were established based on 1D and 2D NMR spectral analysis, and in the case of compounds 1, 2a, 4b, 5, 6a and 7, the absolute configurations of their stereogenic carbons were determined by an X-ray crystallographic analysis. None of the isolated compounds were active in the tests for antibacterial activity against Gram-positive and Gram-negative bacteria, as well as multidrug-resistant isolates from the environment (MIC > 256 μg/mL), antifungal activity against yeast (Candida albicans ATTC 10231), filamentous fungus (Aspergillus fumigatus ATTC 46645) and dermatophyte (Trichophyton rubrum FF5) (MIC > 512 μg/mL) and in vitro growth inhibitory activity against the MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma) cell lines (GI50 > 150 μM) by the protein binding dye SRB method. © 2016 by the authors; licensee MDPI.This work was developed in the Natural Products Research Laboratory of the Department of Chemistry, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), of the University of Porto and partially supported through national funds provided by FCT-Foundation for Science and Technology and European Regional Development Fund (ERDF) and COMPETE, under the projects PEst-C/MAR/LA0015/2013, PTDC/MAR-BIO/4694/2014, as well as by the project INNOVMAR (Innovation and Sustainability in the Management and Exploitation of Marine Resources) (Reference NORTE-01-0145-FEDER-000035, within Research Line NOVELMAR/INSEAFOOD/ECOSERVICES), supported by the North Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). We thank Mrs. Júlia Bessa and Sara Cravo for technical support

Chiral derivatives of xanthones: Investigation of the effect of enantioselectivity on inhibition of cyclooxygenases (COX-1 and COX-2) and binding interaction with human serum albumin

Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx—Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(−)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.This work was partially supported through national funds provided by FCT/MCTES? Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE?Programa Operacional Factores de Competitividade (POFC) programme, under the Strategic Funding UID/Multi/04423/2013, the project PTDC/MAR-BIO/4694/205 (reference POCI-01-055-FEDER-016790; Project 3599?Promover a Produ??o Cient?fica e Desenvolvimento Tecnol?gico e a Constitui??o de Redes Tem?ticas (3599-PPCDT)) in the framework of the programme PT2020 as well as by the project INNOVMAR - Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-055-FEDER-000035, within Research Line NOVELMAR), supported by North Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) and COXANT-CESPU-2016