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Publications by Madalena Pinto

Research paper thumbnail of Bioactive xanthones with effect on P-glycoprotein and prediction of intestinal absorption

Medicinal Chemistry Research, 2013

Abstract Our research group has been focusing in the discovery of potential antitumor small molec... more Abstract Our research group has been focusing in the discovery of potential antitumor small molecules based on the xanthone scaffold. However, a serious obstacle in the field of cancer therapy is the multidrug resistance (MDR) phenotype, most often caused by the ...

Papers by Madalena Pinto

Research paper thumbnail of Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition

Research paper thumbnail of Metabolites from Marine-Derived Fungi as Potential Antimicrobial Adjuvants

Marine Drugs, Aug 25, 2021

Research paper thumbnail of Development of Triazolyl Acetophenone Hybrids as a New Strategy for the Prevention of Marine Biofouling

Research paper thumbnail of BDDE-Inspired Chalcone Derivatives as New Antimicrobial Adjuvants

Research paper thumbnail of Quantification of a Sulfated Marine-Inspired Antifouling Compound in Several Aqueous Matrices: Biodegradation Studies and Leaching Assays from Polydimethylsiloxane Coatings

Marine Drugs

The development of marine-inspired compounds as non-toxic antifouling (AF) agents has been pursue... more The development of marine-inspired compounds as non-toxic antifouling (AF) agents has been pursued in the last years. Sulfur is the third most common element in seawater. Sulfur is present in oxygenated seawater as sulfate anion (SO42−), which is the most stable combination of sulfur in seawater, and several promising AF secondary metabolites with sulfate groups have been described. However, sulfated compounds proved to be an analytical challenge to quantify by HPLC. Taking these facts into consideration, this work presents the development and validation of a method for the quantification of gallic acid persulfate (GAP) in seawater and ultrapure water matrix, based on hydrophilic interaction liquid chromatography (HILIC). This method was used to evaluate GAP stability following several abiotic and biotic degradation assays, and to quantify its release in seawater from room-temperature-vulcanizing polydimethylsiloxane commercial coating. GAP was very stable in several water matrices,...

Research paper thumbnail of Synthesis of New Chiral Derivatives of Xanthones with Enantioselective Effect on Tumor Cell Growth and DNA Crosslinking

ChemistrySelect

A new series of thirty‐two new enantiomerically pure derivatives of xanthones (3–34) were synthes... more A new series of thirty‐two new enantiomerically pure derivatives of xanthones (3–34) were synthesized for antitumor evaluation. Two carboxyxanthones (1 and 2) were used as chemical substrates and coupled with selected chiral building blocks (43–62), achieving yields and enantiomeric excess (ee) values higher than 92 and 99 %, respectively. Carboxyxanthones 1 and 2 were synthesized, by a multi‐step synthetic pathway via diaryl ether intermediate (Ullman reaction), being compound 2 described here for the first time. The evaluation of the growth inhibitory activity allowed to find active chiral compounds for all the tested cells lines, and to establish structure‐activity relationship (SAR) considerations. In some cases, the growth inhibitory effects demonstrated to be dependent on the stereochemistry of the compounds. Interestingly, the most active compound (12) and its enantiomer (11) demonstrated high enantioselectivity for MCF‐7 breast adenocarcinoma cell line. In addition, in vitro...

Research paper thumbnail of Insights of chalcone-triazole hybrids in bacterial resistance modulation

Proceedings of 7th International Electronic Conference on Medicinal Chemistry, 2021

Research paper thumbnail of BP-C4: A new diarylpentanoid with potential activation of the p53 pathway

Proceedings of 7th International Electronic Conference on Medicinal Chemistry, 2021

Research paper thumbnail of BP-M345, a New Diarylpentanoid with Promising Antimitotic Activity

Molecules, 2021

Previously, we reported the in vitro growth inhibitory effect of diarylpentanoid BP-M345 on human... more Previously, we reported the in vitro growth inhibitory effect of diarylpentanoid BP-M345 on human cancer cells. Nevertheless, at that time, the cellular mechanism through which BP-M345 exerts its growth inhibitory effect remained to be explored. In the present work, we report its mechanism of action on cancer cells. The compound exhibits a potent tumor growth inhibitory activity with high selectivity index. Mechanistically, it induces perturbation of the spindles through microtubule instability. As a consequence, treated cells exhibit irreversible defects in chromosome congression during mitosis, which induce a prolonged spindle assembly checkpoint-dependent mitotic arrest, followed by massive apoptosis, as revealed by live cell imaging. Collectively, the results indicate that the diarylpentanoid BP-M345 exerts its antiproliferative activity by inhibiting mitosis through microtubule perturbation and causing cancer cell death, thereby highlighting its potential as antitumor agent.

Research paper thumbnail of Tryptophan derived natural marine alkaloids and synthetic derivatives as promising antimicrobial agents

European Journal of Medicinal Chemistry, 2021

Research paper thumbnail of New chalcone analogues with potential bacterial efflux pump inhibitory effect

Proceedings of 6th International Electronic Conference on Medicinal Chemistry, 2020

Research paper thumbnail of Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection

Pharmaceuticals, 2020

SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, ... more SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients. In addition, we aimed to identify drugs that could be repurposed to inhibit GRP78, thus with potential anti-SARS-CoV-2 activity. Gene expression studies were performed in 10 SARS-CoV-2 (−) and 24 SARS-CoV-2 (+) pneumonia patients. A structure-based virtual screen was performed with 10,761 small molecules retrieved from DrugBank, using the GRP78 nucleotide binding domain and substrate binding domain as molecular targets. Results indicated that GRP78 mRNA levels were approximately four times higher in the blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients, further suggesting that GRP78 might be a good molecular target to treat Covid-19. In addition, a total of 409 compound...

Research paper thumbnail of Targeting neuroblastoma with a new inhibitor of the TAp73 interaction with MDM2 and mutant p53

Proceedings of 5th International Electronic Conference on Medicinal Chemistry, 2019

Research paper thumbnail of New chalcone derivatives with suitable drug-like lipophilicity targeting mitosis

Proceedings of 5th International Electronic Conference on Medicinal Chemistry, 2019

Research paper thumbnail of New chiral stationary phases for liquid chromatography based on small molecules: Development, enantioresolution evaluation and chiral recognition mechanisms

Research paper thumbnail of Enantioseparation, recognition mechanisms and binding of xanthones on human serum albumin by liquid chromatography

Bioanalysis, 2019

Aim: To develop a method for enantioseparation of several chiral derivatives of xanthones (CDXs) ... more Aim: To develop a method for enantioseparation of several chiral derivatives of xanthones (CDXs) by LC using a human serum albumin-chiral stationary phase (HSA-CSP) and screening CDX-HSA affinity. Additionally, recognition mechanisms were investigated. Materials & methods: The influence of organic modifier, buffer type, pH and ionic strength of mobile phase, and temperature were explored. The affinity was determined by measuring the retention times and further calculation of bound percentage. Chiral recognition mechanisms were investigated by docking. Results: Enantioselectivity and resolution values ranged from 1.40 to 9.16 and 1.51 to 4.97. Bound percentages ranged from 79.02 to 99.99%. Conclusion: LC systematic study and binding affinity of CDXs on HSA-CSP are presented here for the first time, expanding the applications of HSA-CSP for this class of compounds.

Research paper thumbnail of Potential of synthetic chalcone derivatives to prevent marine biofouling

Science of The Total Environment, 2018

Biofouling represents a major economic, environmental and health concern for which new eco-friend... more Biofouling represents a major economic, environmental and health concern for which new eco-friendly solutions are needed. International legislation has restricted the use of biocidal-based antifouling coatings, and increasing efforts have been applied in the search for environmentally friendly antifouling agents. This research work deals with the assessment of the interest of a series of synthetic chalcone derivatives for antifouling applications. Sixteen chalcone derivatives were synthesized with moderate yields (38-85%). Antifouling bioactivity of these compounds was assessed at different levels of biological organization using both anti-macrofouling and anti-microfouling bioassays, namely an anti-settlement assay using mussel (Mytilus galloprovincialis) larvae, as well as marine bacteria and microalgal biofilms growth inhibition bioassays. Results showed that three compounds (11, 12, and 16) were particularly active against the settlement of mussel larvae (EC50 7.24-34.63 μM), being compounds 12 and 16 also able to inhibit the growth of microfouling species (EC50 4.09-20.31 μM). Moreover, the most potent compounds 12 and 16 were found to be non-toxic to the non-target species Artemia salina (<10% mortality at 25 μM). A quantitative structure-activity relationship model predicted that descriptors describing the ability of molecules to form hydrogen bonds and encoding the shape, branching ratio and constitutional diversity of the molecule were implied in the antifouling activity against the settlement of mussel larvae. This work elucidates for the first time the relevance of synthesizing chalcone derivatives to generate new non-toxic products to prevent marine biofouling.

Research paper thumbnail of Curcumin: A Natural Lead for Potential New Drug Candidates

Current Medicinal Chemistry, 2015

Research paper thumbnail of 953 Discovery of a New Inhibitor of P53/MDM2 Interaction Using a Yeast Target-based Screening Strategy

European Journal of Cancer, 2012

Research paper thumbnail of Bioactive xanthones with effect on P-glycoprotein and prediction of intestinal absorption

Medicinal Chemistry Research, 2013

Abstract Our research group has been focusing in the discovery of potential antitumor small molec... more Abstract Our research group has been focusing in the discovery of potential antitumor small molecules based on the xanthone scaffold. However, a serious obstacle in the field of cancer therapy is the multidrug resistance (MDR) phenotype, most often caused by the ...

Research paper thumbnail of Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition

Research paper thumbnail of Metabolites from Marine-Derived Fungi as Potential Antimicrobial Adjuvants

Marine Drugs, Aug 25, 2021

Research paper thumbnail of Development of Triazolyl Acetophenone Hybrids as a New Strategy for the Prevention of Marine Biofouling

Research paper thumbnail of BDDE-Inspired Chalcone Derivatives as New Antimicrobial Adjuvants

Research paper thumbnail of Quantification of a Sulfated Marine-Inspired Antifouling Compound in Several Aqueous Matrices: Biodegradation Studies and Leaching Assays from Polydimethylsiloxane Coatings

Marine Drugs

The development of marine-inspired compounds as non-toxic antifouling (AF) agents has been pursue... more The development of marine-inspired compounds as non-toxic antifouling (AF) agents has been pursued in the last years. Sulfur is the third most common element in seawater. Sulfur is present in oxygenated seawater as sulfate anion (SO42−), which is the most stable combination of sulfur in seawater, and several promising AF secondary metabolites with sulfate groups have been described. However, sulfated compounds proved to be an analytical challenge to quantify by HPLC. Taking these facts into consideration, this work presents the development and validation of a method for the quantification of gallic acid persulfate (GAP) in seawater and ultrapure water matrix, based on hydrophilic interaction liquid chromatography (HILIC). This method was used to evaluate GAP stability following several abiotic and biotic degradation assays, and to quantify its release in seawater from room-temperature-vulcanizing polydimethylsiloxane commercial coating. GAP was very stable in several water matrices,...

Research paper thumbnail of Synthesis of New Chiral Derivatives of Xanthones with Enantioselective Effect on Tumor Cell Growth and DNA Crosslinking

ChemistrySelect

A new series of thirty‐two new enantiomerically pure derivatives of xanthones (3–34) were synthes... more A new series of thirty‐two new enantiomerically pure derivatives of xanthones (3–34) were synthesized for antitumor evaluation. Two carboxyxanthones (1 and 2) were used as chemical substrates and coupled with selected chiral building blocks (43–62), achieving yields and enantiomeric excess (ee) values higher than 92 and 99 %, respectively. Carboxyxanthones 1 and 2 were synthesized, by a multi‐step synthetic pathway via diaryl ether intermediate (Ullman reaction), being compound 2 described here for the first time. The evaluation of the growth inhibitory activity allowed to find active chiral compounds for all the tested cells lines, and to establish structure‐activity relationship (SAR) considerations. In some cases, the growth inhibitory effects demonstrated to be dependent on the stereochemistry of the compounds. Interestingly, the most active compound (12) and its enantiomer (11) demonstrated high enantioselectivity for MCF‐7 breast adenocarcinoma cell line. In addition, in vitro...

Research paper thumbnail of Insights of chalcone-triazole hybrids in bacterial resistance modulation

Proceedings of 7th International Electronic Conference on Medicinal Chemistry, 2021

Research paper thumbnail of BP-C4: A new diarylpentanoid with potential activation of the p53 pathway

Proceedings of 7th International Electronic Conference on Medicinal Chemistry, 2021

Research paper thumbnail of BP-M345, a New Diarylpentanoid with Promising Antimitotic Activity

Molecules, 2021

Previously, we reported the in vitro growth inhibitory effect of diarylpentanoid BP-M345 on human... more Previously, we reported the in vitro growth inhibitory effect of diarylpentanoid BP-M345 on human cancer cells. Nevertheless, at that time, the cellular mechanism through which BP-M345 exerts its growth inhibitory effect remained to be explored. In the present work, we report its mechanism of action on cancer cells. The compound exhibits a potent tumor growth inhibitory activity with high selectivity index. Mechanistically, it induces perturbation of the spindles through microtubule instability. As a consequence, treated cells exhibit irreversible defects in chromosome congression during mitosis, which induce a prolonged spindle assembly checkpoint-dependent mitotic arrest, followed by massive apoptosis, as revealed by live cell imaging. Collectively, the results indicate that the diarylpentanoid BP-M345 exerts its antiproliferative activity by inhibiting mitosis through microtubule perturbation and causing cancer cell death, thereby highlighting its potential as antitumor agent.

Research paper thumbnail of Tryptophan derived natural marine alkaloids and synthetic derivatives as promising antimicrobial agents

European Journal of Medicinal Chemistry, 2021

Research paper thumbnail of New chalcone analogues with potential bacterial efflux pump inhibitory effect

Proceedings of 6th International Electronic Conference on Medicinal Chemistry, 2020

Research paper thumbnail of Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection

Pharmaceuticals, 2020

SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, ... more SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients. In addition, we aimed to identify drugs that could be repurposed to inhibit GRP78, thus with potential anti-SARS-CoV-2 activity. Gene expression studies were performed in 10 SARS-CoV-2 (−) and 24 SARS-CoV-2 (+) pneumonia patients. A structure-based virtual screen was performed with 10,761 small molecules retrieved from DrugBank, using the GRP78 nucleotide binding domain and substrate binding domain as molecular targets. Results indicated that GRP78 mRNA levels were approximately four times higher in the blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients, further suggesting that GRP78 might be a good molecular target to treat Covid-19. In addition, a total of 409 compound...

Research paper thumbnail of Targeting neuroblastoma with a new inhibitor of the TAp73 interaction with MDM2 and mutant p53

Proceedings of 5th International Electronic Conference on Medicinal Chemistry, 2019

Research paper thumbnail of New chalcone derivatives with suitable drug-like lipophilicity targeting mitosis

Proceedings of 5th International Electronic Conference on Medicinal Chemistry, 2019

Research paper thumbnail of New chiral stationary phases for liquid chromatography based on small molecules: Development, enantioresolution evaluation and chiral recognition mechanisms

Research paper thumbnail of Enantioseparation, recognition mechanisms and binding of xanthones on human serum albumin by liquid chromatography

Bioanalysis, 2019

Aim: To develop a method for enantioseparation of several chiral derivatives of xanthones (CDXs) ... more Aim: To develop a method for enantioseparation of several chiral derivatives of xanthones (CDXs) by LC using a human serum albumin-chiral stationary phase (HSA-CSP) and screening CDX-HSA affinity. Additionally, recognition mechanisms were investigated. Materials & methods: The influence of organic modifier, buffer type, pH and ionic strength of mobile phase, and temperature were explored. The affinity was determined by measuring the retention times and further calculation of bound percentage. Chiral recognition mechanisms were investigated by docking. Results: Enantioselectivity and resolution values ranged from 1.40 to 9.16 and 1.51 to 4.97. Bound percentages ranged from 79.02 to 99.99%. Conclusion: LC systematic study and binding affinity of CDXs on HSA-CSP are presented here for the first time, expanding the applications of HSA-CSP for this class of compounds.

Research paper thumbnail of Potential of synthetic chalcone derivatives to prevent marine biofouling

Science of The Total Environment, 2018

Biofouling represents a major economic, environmental and health concern for which new eco-friend... more Biofouling represents a major economic, environmental and health concern for which new eco-friendly solutions are needed. International legislation has restricted the use of biocidal-based antifouling coatings, and increasing efforts have been applied in the search for environmentally friendly antifouling agents. This research work deals with the assessment of the interest of a series of synthetic chalcone derivatives for antifouling applications. Sixteen chalcone derivatives were synthesized with moderate yields (38-85%). Antifouling bioactivity of these compounds was assessed at different levels of biological organization using both anti-macrofouling and anti-microfouling bioassays, namely an anti-settlement assay using mussel (Mytilus galloprovincialis) larvae, as well as marine bacteria and microalgal biofilms growth inhibition bioassays. Results showed that three compounds (11, 12, and 16) were particularly active against the settlement of mussel larvae (EC50 7.24-34.63 μM), being compounds 12 and 16 also able to inhibit the growth of microfouling species (EC50 4.09-20.31 μM). Moreover, the most potent compounds 12 and 16 were found to be non-toxic to the non-target species Artemia salina (<10% mortality at 25 μM). A quantitative structure-activity relationship model predicted that descriptors describing the ability of molecules to form hydrogen bonds and encoding the shape, branching ratio and constitutional diversity of the molecule were implied in the antifouling activity against the settlement of mussel larvae. This work elucidates for the first time the relevance of synthesizing chalcone derivatives to generate new non-toxic products to prevent marine biofouling.

Research paper thumbnail of Curcumin: A Natural Lead for Potential New Drug Candidates

Current Medicinal Chemistry, 2015

Research paper thumbnail of 953 Discovery of a New Inhibitor of P53/MDM2 Interaction Using a Yeast Target-based Screening Strategy

European Journal of Cancer, 2012

Research paper thumbnail of Bioactive Marine Xanthones: A Review

Marine Drugs, 2022

The marine environment is an important source of specialized metabolites with valuable biological... more The marine environment is an important source of specialized metabolites with valuable biological activities. Xanthones are a relevant chemical class of specialized metabolites found in this environment due to their structural variety and their biological activities. In this work, a comprehensive literature review of marine xanthones reported up to now was performed. A large number of bioactive xanthone derivatives (169) were identified, and their structures, biological activities, and natural sources were described. To characterize the chemical space occupied by marine-derived xanthones, molecular descriptors were calculated. For the analysis of the molecular descriptors, the xanthone derivatives were grouped into five structural categories (simple, prenylated, O-heterocyclic, complex, and hydroxanthones) and six biological activities (antitumor, antibacterial, antidiabetic, antifungal, antiviral, and miscellaneous). Moreover, the natural product-likeness and the drug-likeness of m...