306 shared publications
REQUIMTE/LAQV, Laboratory of Pharmacognosy, Departament of Chemistry, Faculty of Pharmacy, University of Porto, R. Jorge Viterbo Ferreira, no. 228, 4050-313 Porto, Portugal
229 shared publications
REQUIMTE/LAQV, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
206 shared publications
Department of Nutrition, Food Sciences and Gastronomy, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB) and Institute of Theoretical and Computational Chemistry (IQTC), University of Barcelona, Av. Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain
205 shared publications
Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
196 shared publications
University of Porto
(2002 - 2019)
Natural flavonoid and xanthone glycosides display several biological activities [1-3], with the glycoside moiety playing an important role in the mechanisms of action of these metabolites. Herein, to give further insights into the inhibitory cell growth activity of these classes of compounds, the synthesis of new flavonoid and xanthone derivatives containing one or more acetoglycoside moieties was carried out to evaluate their in vitro cell growth inhibitory activity in human tumor cell lines.
The introduction of one or two acetoglycoside moieties in the skeleton of a hydroxylated flavonoid was performed using three synthetic methods: Michael reaction, Koenigs-Knorr reaction, and through a copper-catalyzed azide-alkyne cycloaddition. Acetyl groups were introduced in rutin, diosmin, and mangiferin using acetic anhydride under microwave irradiation. The in vitro cell growth inhibitory activity of seven synthesized compounds was investigated in six human tumor cell lines: A375- C5 (malignant melanoma IL-1 insensitive), MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), U251 (glioblastoma astrocytoma), U373 (glioblastoma astrocytoma), and U87MG (glioblastoma astrocytoma). The most active compound in all tumor cell lines tested was a flavonoside and showed GI50 values below 10 μM.
 Leong, C.N.A., et al., Food Chemistry, 2008. 109(2): p. 415-420.
 Kumar, M., et al., Fitoterapia, 2010. 81(4): p. 234-242.
 Reutrakul, V., et al., Planta Medica, 2007. 73(7): p. 683-688.
The authors want to thank Fundação da Ciência e Tecnologia (FCT/MCTES, PIDDAC) and European Regional Development Fund (ERDF) for funding this research through the COMPETE – Programa Operacional Factores de Competitividade (POFC) programme (POCI-01-0145‐FEDER-016790 and POCI-01-0145-FEDER-016793), Reforçar a Investigação, o Desenvolvimento Tecnológico e a Inovação (RIDTI, Project 3599 and 9471), and INNOVMAR, reference NORTE-01-0145-FEDER-000035, Research Line NOVELMAR, under the projects PTDC/ MAR-BIO/4694/2014 and PTDC/AAG-TEC/0739/2014 and the Strategic Funding UID/Multi/04423/2013 through national funds provided by FCT and ERDF, in the framework of the programme PT2020. Ana R. Neves wants to thank FCT for the Ph.D. fellowship (SFRH/BD/114856/2016).
Antimicrobial resistance is one of the most pressing health issues of our days. The marine environment has proven to be a very rich source of diverse natural products with broad-spectra of biologically activities being a very helpful resource in the search for novel antimicrobial compounds. These structurally distinct molecules are revealing promising biological activities against a very large number of drug-resistant pathogenic bacteria and fungi, catching marine natural products attention in the discovery of new antimicrobial agents. Inspired by antimicrobial lichen xanthones  and fungi-derived alkaloids, two series of marine natural products mimics were prepared. The synthesized compounds were evaluated for their antimicrobial activity. Both series produced interesting compounds active against E. faecalis (ATCC 29212 and 29213) and S. aureus (ATCC 29213) with some synthetic alkaloids being active against a MRSA strain. Some revealed a potent fungistatic and fungicidal activity against dermatophytes clinical strains (T. rubrum, M. canis, and E. floccosum). These results highlight the potential of marine natural products as a source of new antimicrobial agents to revert resistance.
 D. I. S. P. Resende, P. Pereira-Terra, Â. S. Inácio, P. M. Costa, E. Pinto, E. Sousa, M. M. M. Pinto. Lichen Xanthones as Models for New Antifungal Agents. Molecules 2018, 23, 2617; doi:10.3390/molecules23102617
Acknowledgments: 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). Solida Long thanks Erasmus Mundus Action 2 (LOTUS+, LP15DF0205) for full PhD scholarship. 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).
Currently, one of the most urgent threats is antimicrobial resistance, which leads to the inefficacy of drugs in therapeutics, and can arise from several reasons, being the overexpression of efflux pumps one of them. These pumps are ubiquitous in bacteria, and their overexpression allows bacteria to develop multidrug resistance, through the extrusion of antimicrobial drugs. They can be divided into five families, being the resistance-nodulation-division (RND) family and the major facilitator superfamily (MFS) the most relevant. Efforts have been put towards a selective, efficient efflux pump inhibitor (EPI), and although some progress has been achieved, in the therapeutic scenario no EPIs have been approved.1
Our group has experience in molecular docking and synthesis of aminated thioxanthones with modulatory activity in the mammal efflux pump P-glycoprotein (P-gp), which is also useful in the detoxification of xenobiotics.2,3 Taking this into account, the aim of this work was the design of a virtual library of approximately 1.000 aminated (thio)xanthones, the performance of docking studies in bacterial efflux pumps whose crystal structure has been elucidated and available in the Protein Data Bank and in a model of the human P-gp. For the docking studies bacterial efflux pumps chosen were both from the RND family: AcrB, from the AcrAB-TolC efflux system,4 and MexB, from the MexAB-OprM efflux system.5
The compounds that will be selected for synthesis are the ones that virtually displayed good scores for the bacterial referred efflux pumps and lower scores for P-gp, since this would mean that, in vivo, these compounds would efficiently reduce antimicrobial resistance while not interfering with human detoxification pathways.
Acknowledgements: This research was developed under Project No. POCI-01-0145-FEDER-028736, co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds.
- Durães, F.; Pinto, M.; Sousa, E., Medicinal Chemistry Updates on Bacterial Efflux Pump Modulators. Curr Med Chem 2018, Feb 9. doi: 10.2174/0929867325666180209142612.
- Palmeira, A.; Vasconcelos, M. H.; Paiva, A.; Fernandes, M. X.; Pinto, M.; Sousa, E., Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones. Biochem Pharmacol 2012, 83 (1), 57-68.
- Palmeira, A.; Rodrigues, F.; Sousa, E.; Pinto, M.; Vasconcelos, M. H.; Fernandes, M. X., New uses for old drugs: pharmacophore-based screening for the discovery of P-glycoprotein inhibitors. Chem Biol Drug Des 2011, 78 (1), 57-72.
- Yu, E. W.; Aires, J. R.; McDermott, G.; Nikaido, H., A periplasmic drug-binding site of the AcrB multidrug efflux pump: a crystallographic and site-directed mutagenesis study. J Bacteriol 2005, 187 (19), 6804-15.
- Sennhauser, G.; Bukowska, M. A.; Briand, C.; Grutter, M. G., Crystal structure of the multidrug exporter MexB from Pseudomonas aeruginosa. Journal of molecular biology 2009, 389 (1), 134-45.
Several biological activities from nearly 150 marine-derived sulfated steroids have been reported with both pharmacological (antimicrobial, antitumor, cardiovascular and/ or anti-inflammatory activities) and environmental (antifouling activity) applications . Sulfation is used in Nature to avoid toxicity and therefore marine-inspired sulfated steroids could be an interesting strategy for drug discovery. The sulfated aminosterol squalamine, isolated from the internal organs of the dogfish shark, is in phase III of clinical trials as anti-angiogenic drug , which evidences the potential of sulfated steroids.
Sulfation of small molecules using sulfur trioxide-amine complexes entails several advantages, such as persulfation, low degradation, and feasibility in the work-up . Moreover, these complexes appear to be suitable for sulfation of alcohol groups present in steroids . In this direction, sulfation of four sterols was achieved using triethylamine-sulfur trioxide adduct in dimethylacetamide under heating, with yields ranging from 3% to 93%. Purification involved insolubilization with diethyl ether followed by several methods to obtain the sulfated derivatives free of inorganic impurities, including dialysis and/ or chromatographic processes. Structure elucidation of these new compounds was established by infrared (IR), nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HRMS). Biological activities will be further studied.
This work was supported through national funds provided by FCT/MCTES - Foundation for Science and Technology from the Ministry 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 projects PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599–PPCDT), PTDC/AAGTEC/0739/2014 (reference POCI-01-0145-FEDER-016793; Project 9471-RIDTI) and POCI-01-0145-FEDER-028736 in the framework of the programme PT2020. Carvalhal F also acknowledges FCT for the grant PTDC/AAG- TEC/0739/2014-018.
 Carvalhal, F., M. Correia-da-Silva, M.E. Sousa, M. Pinto, and A. Kijjoa, Journal of Molecular Endocrinology, 2018, 61(2) 211-231.
 NCT02727881 (https://clinicaltrials.gov/ct2/show/NCT02727881, October 15, 2018)
 Correia-da-Silva, M., E. Sousa, and M.M. Pinto, Medicinal Research Reviews, 2014, 34(2) 223-79.
 Al-Horani, R.A., and U.R. Desai, Chemical Sulfation of Small Molecules - Advances and Challenges.Tetrahedron, 2010, 66(16), 2907-2918