Degree: Doctor

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FCUP

Bio

Fernanda Borges (FB) is an Associate Professor with habilitation at the Department of Chemistry and Biochemistry. She received her MSc and PhD (Pharmaceutical Chemistry) in Pharmacy from the Faculty of Pharmacy, University of Porto, Portugal. FB is the coordinator of the Medicinal and Biological Chemistry Group (https://drugdiscoveryup.pt/), of the Chemistry Research Centre of the University of Porto (CIQUP).  The Group is internationally competitive and rmultidisciplinary working at the chemistry–biology interface R&D areas related to human health and well-being. The team is composed of researchers with diverse backgrounds, from chemistry and biochemistry to pharmacy and nanotechnology, and has expertise in drug discovery, drug analysis, and drug delivery FB published 407 articles, 26 book chapters (H-index: 57; Scopus) and received 9 awards. Supervised/co-supervised (inter)national students at PhD (36) and MSc (35) thesis and 14 postDocs and researcher fellows/grant holders. FB is the principal Investigator (PI) and Co-PI of 33 national and european projects, and principal inventor in 8 (inter)national patents. Her research is focused in the design and development of new chemical entities for the prevention/therapy of neurodegenerative, liver, cancer or infectious diseases.




Publications
Showing 5 latest publications. Total publications: 327
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1. Mitochondria dysfunction induced by decyl-TPP mitochondriotropic antioxidant based on caffeic acid AntiOxCIN6 sensitizes cisplatin lung anticancer therapy due to a remodeling of energy metabolism, Amorim, R; Magalhaes, CC; Benfeito, S; Cagide, F; Tavares, LC; Santos, K; Sardao, VA; Datta, S; Cortopassi, GA; Baldeiras, I; Jones, JG; Borges, F Oliveira, PJ; Teixeira, J in BIOCHEMICAL PHARMACOLOGY, 2024, ISSN: 0006-2952,  Volume: 219, 
Article,  Indexed in: crossref, scopus, wos  DOI: 10.1016/j.bcp.2023.115953 P-00Z-ESJ
Abstract The pharmacological interest in mitochondria is very relevant since these crucial organelles are involved in the pathogenesis of multiple diseases, such as cancer. In order to modulate cellular redox/oxidative balance and enhance mitochondrial function, numerous polyphenolic derivatives targeting mitochondria have been developed. Still, due to the drug resistance emergence in several cancer therapies, significant efforts are being made to develop drugs that combine the induction of mitochondrial metabolic reprogramming with the ability to generate reactive oxygen species, taking into consideration the varying metabolic profiles of different cell types. We previously developed a mitochondria-targeted antioxidant (AntiOxCIN6) by linking caffeic acid to lipophilic triphenylphosphonium cation through a 10-carbon aliphatic chain. The antioxidant activity of AntiOxCIN6 has been documented but how the mitochondriotropic compound impact energy metabolism of both normal and cancer cells remains unknown. We demonstrated that AntiOxCIN6 increased antioxidant defense system in HepG2 cells, although ROS clearance was ineffective. Consequently, AntiOxCIN6 significantly decreased mitochondrial function and morphology, culminating in a decreased capacity in complex I-driven ATP production without affecting cell viability. These alterations were accompanied by an increase in glycolytic fluxes. Additionally, we demonstrate that AntiOxCIN6 sensitized A549 adenocarcinoma cells for CIS-induced apoptotic cell death, while AntiOxCIN6 appears to cause metabolic changes or a redox pre-conditioning on lung MRC-5 fibroblasts, conferring protection against cisplatin. We propose that length and hydrophobicity of the C10-TPP+ alkyl linker play a significant role in inducing mitochondrial and cellular toxicity, while the presence of the antioxidant caffeic acid appears to be responsible for activating cytoprotective pathways.

2. Biological and Medicinal Properties of Natural Chromones and Chromanones, Gaspar, A Garrido, EMPJ; Borges, F Garrido, JMPJ in ACS OMEGA, 2024, ISSN: 2470-1343, 
Review,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.1021/acsomega.4c00771 P-010-F4M
Abstract Emerging threats to human health require a concerted effort to search for new treatment therapies. One of the biggest challenges is finding medicines with few or no side effects. Natural products have historically contributed to major advances in the field of pharmacotherapy, as they offer special characteristics compared to conventional synthetic molecules. Interest in natural products is being revitalized, in a continuous search for lead structures that can be used as models for the development of new medicines by the pharmaceutical industry. Chromone and chromanones are recognized as privileged structures and useful templates for the design of diversified therapeutic molecules with potential pharmacological interest. Chromones and chromanones are widely distributed in plants and fungi, and significant biological activities, namely antioxidant, anti-inflammatory, antimicrobial, antiviral, etc., have been reported for these compounds, suggesting their potential as lead drug candidates. This review aims to update the literature published over the last 6 years (2018-2023) regarding the natural occurrence and biological activity of chromones and chromanones, highlighting the recent findings and the perspectives that they hold for future research and applications namely in health, cosmetic, and food industries.

3. Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction, Carradori, S; Chavarria, D Provensi, G; Leri, M; Bucciantini, M; Carradori, S; Bonardi, A; Gratteri, P; Borges, F Nocentini, A; Supuran, CT in JOURNAL OF MEDICINAL CHEMISTRY, 2024, ISSN: 0022-2623,  Volume: 67, 
Article,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.1021/acs.jmedchem.4c00045 P-010-2GH
Abstract We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer's disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-beta-peptide (A beta)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (K(I)s in the range of 0.1-90.0 nM) and MAO-B (IC50 in the range of 6.7-32.6 nM). Computational studies were conducted to elucidate the structure-activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented A beta-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs.

4. Bonding to Psychedelics: Synthesis of Molecularly Imprinted Polymers Targeting 4-Bromo-2,5-dimethoxyphenethylamine (2C-B), Martins, D; Fernandes, C; Mendes, RF; Cagide, F; Silva, AF; Borges, F Garrido, J in APPLIED SCIENCES-BASEL, 2024, ISSN: 2076-3417,  Volume: 14, 
Article,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.3390/app14041377 P-010-3S2
Abstract The increasing interest in utilizing psychedelics for therapeutic purposes demands the development of tools capable of efficiently monitoring and accurately identifying these substances, thereby supporting medical interventions. 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) has gained significant popularity as one of the most widely used psychedelic compounds in non-medical settings. In this study, we aimed to create a material with selective recognition of 2C-B by synthesizing a series of molecularly imprinted polymers (MIP) using 2C-B as the template and varying ratios of methacrylic acid (MAA) as the functional monomer (1:2, 1:3, and 1:4). Both thermal and microwave-assisted polymerization processes were employed. The molar ratio between the template molecule (2C-B) and functional monomer (MAA) was 1:4, utilizing a microwave-assisted polymerization process. Isotherm studies revealed a Langmuir's maximum absorption capacity (Bmax) value of 115.6 mu mol center dot mg-1 and Kd values of 26.7 mu M for this material. An imprint factor of 4.2 was determined for this material, against the corresponding non-imprinted polymer. The good selectivity against 14 other new psychoactive substances highlighted the material's potential for applications requiring selective recognition. These findings can contribute to the development of tailored materials for the detection and analysis of 2C-B, supporting advancements in non-medical use monitoring and potential therapeutic models involving psychedelics.

5. Rescuing a Troubled Tolcapone with PEGylated PLGA Nanoparticles: Design, Characterization, and Hepatotoxicity Evaluation, Pinto, M Machado, CS; Barreiro, S; Otero-Espinar, FJ; Remiao, F; Borges, F Fernandes, C in ACS APPLIED MATERIALS & INTERFACES, 2024, ISSN: 1944-8244,  Volume: 16, 
Article,  Indexed in: crossref, scopus, unpaywall, wos  DOI: 10.1021/acsami.4c00614 P-010-B1R
Abstract Tolcapone is an orally active catechol-O-methyltransferase (COMT) inhibitor used as adjuvant therapy in Parkinson's disease. However, it has a highly hepatotoxic profile, as recognized by the U.S. Food and Drug Administration. As a possible solution, nanoscience brought us several tools in the development of new functional nanomaterials with tunable physicochemical properties, which can be part of a solution to solve several drawbacks, including drug's short half-life and toxicity. This work aims to use PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a stable carrier with lower hydrodynamic size and polydispersity to encapsulate tolcapone in order to overcome its therapeutic drawbacks. Using the nanoprecipitation method, tolcapone-loaded nanoparticles with a DLC% of 5.7% were obtained (EE% of 47.0%) and subjected to a lyophilization optimization process to obtain a final shelf-stable formulation. Six different cryoprotectants in concentrations up to 10% (w/v) were tested. A formulation of PLGA nanoparticles with 3% hydroxypropyl-beta-cyclodextrin (HP beta CD) as a cryoprotectant (PLGA-HP@Tolc), presenting sub-200 nm sizes and low polydispersity (PdI < 0.200) was selected. Cytotoxicity assays, namely, MTT and SRB, were used to study the metabolic activity and cell density of tolcapone and PLGA-HP@Tolc-treated cells. In both assays, a hepatocarcinoma cell line (HepG2) growing in glucose or glucose-free media (galactose-supplemented medium) was used. The results demonstrated that the treatment with the PLGA-HP@Tolc formulation led to a decrease in cytotoxicity in comparison to free tolcapone-treated cells in both media tested. Moreover, the elected formulation also counteracted ATP-depletion and excessive ROS production induced by tolcapone. The results suggest that HP beta CD might have a dual function in the formulation: cryoprotectant and anticytotoxic agent, protecting cells from tolcapone-induced damage. Using an in vitro COMT inhibition assay, the PLGA-HP@Tolc formulation demonstrated to inhibit COMT as efficiently as free tolcapone. Overall, the results suggest that tolcapone-loaded PLGA NPs could be an interesting alternative to free tolcapone, demonstrating the same in vitro efficacy in inhibiting COMT but with a safer cytotoxic profile.