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1. Pharmacological Treatment of Malaria

Author

Lopes, Elizabeth A., Santos, Maria M. M., Mori, Mattia, Bernstein, Peter R., Series Editor, Garner, Amanda L., Series Editor, Georg, Gunda I., Series Editor, Laufer, Stefan, Series Editor, Lowe, John A., Series Editor, Meanwell, Nicholas A., Series Editor, Saxena, Anil Kumar, Series Editor, Supuran, Claudiu T., Series Editor, Zhang, Ao, Series Editor, Tschammer, Nuska, Series Editor, Poulsen, Sally-Ann, Series Editor, and Vermelho, Alane Beatriz, editor

Published
2022
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8. Editorial: Women in experimental pharmacology and drug discovery 2023.

Author

Rijo, Patricia, Timucin, Emel, Santos, Maria M. M., and Bruno, Valeria

Subjects
DRUG discovery, HERMETIA illucens, BONE health, INTERNATIONAL Women's Day, COVID-19 pandemic
Abstract

This document is an editorial published in Frontiers in Pharmacology titled "Women in experimental pharmacology and drug discovery 2023." The editorial highlights the achievements of women scientists in the field of pharmacology and drug discovery, showcasing their diverse and impactful research endeavors. It also discusses the importance of promoting gender equality in science and encouraging girls and women to pursue careers in STEM fields. The editorial features several key studies conducted by women scientists, covering topics such as hepatoprotective potential, sustainable ingredients, antioxidative components, and the role of certain molecules in disease treatment. The document emphasizes the need to support and celebrate the work of women scientists to foster a more inclusive and innovative scientific community. [Extracted from the article]

Published
2024
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13. Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

Author

Fundação para a Ciência e a Tecnologia (Portugal), Ministerio de Ciencia, Innovación y Universidades (España), Espadinha, Margarida, Barcherini, Valentina, Gonçalves, Lídia M., Molins, Elies, Antunes, Alexandra M. M., Santos, Maria M. M., Fundação para a Ciência e a Tecnologia (Portugal), Ministerio de Ciencia, Innovación y Universidades (España), Espadinha, Margarida, Barcherini, Valentina, Gonçalves, Lídia M., Molins, Elies, Antunes, Alexandra M. M., and Santos, Maria M. M.

Abstract

Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol-derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therapeutic target in cancer. In this work, we developed a novel series of enantiomerically pure tryptophanol-derived small molecules to target human gastric adenocarcinoma (AGS) cells. From an initial screening of fourteen compounds in AGS cell line, a hit compound was selected for optimization, leading to two derivatives selective for AGS gastric cells over other types of cancer cells (MDA-MB-231, A-549, DU-145, and MG-63). More importantly, the compounds were non-toxic in normal cells (HEK 293T). Additionally, we show that the growth inhibition of AGS cells induced by these compounds is mediated by apoptosis. Stability studies in human plasma and human liver microsomes indicate that the compounds are stable, and that the major metabolic transformations of these molecules are mono- and di-hydroxylation of the indole ring.

Published
2021

14. Hybrid molecules of protoflavones and spirooxindole derivatives with selective cytotoxicity against triple-negative breast cancer cellsElectronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3md00251a

Author

Girst, Gábor, Lopes, Elizabeth A., Gonçalves, Lídia M., Espadinha, Margarida, Kúsz, Norbert, Wang, Hui-Chun, Santos, Maria M. M., and Hunyadi, Attila

Abstract

The combination of compounds with complementary bioactivities into hybrid molecules is an emerging concept in drug discovery. In this study, we aimed to synthesize new hybrid compounds based on p53-MDM2/X protein–protein interaction spiropyrazoline oxindole-based inhibitors and ataxia telangiectasia and Rad3-related (ATR) protoflavone-based inhibitors through copper(i) catalysed azide–alkyne cycloaddition. Five new hybrids were prepared along with three representative reference fragments. The compounds were tested against human breast cancer cell lines MCF-7 (hormone-dependent, wild-type p53) and MDA-MB-231 (triple-negative, mutant p53). Most of the new hybrids were more cytotoxic than their reference fragments and several showed 2–4 times selective toxicity against MDA-MB-231 cells. Relevant pharmacological benefit gained from the hybrid coupling was further confirmed by virtual combination index calculations using the Chou method. Compound 13modulated doxorubicin-induced DNA damage response through inhibiting the ATR-dependent activation of Chk-1, while increasing the activation of Chk-2. Our results suggest that the new hybrids may serve as new leads against triple negative breast cancer.

Published
2023
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15. Targeting p53 for Melanoma Treatment: Counteracting Tumour Proliferation, Dissemination and Therapeutic Resistance

Author

Loureiro, Joana B., primary, Raimundo, Liliana, additional, Calheiros, Juliana, additional, Carvalho, Carla, additional, Barcherini, Valentina, additional, Lima, Nuno R., additional, Gomes, Célia, additional, Almeida, Maria Inês, additional, Alves, Marco G., additional, Costa, José Luís, additional, Santos, Maria M. M., additional, and Saraiva, Lucília, additional

Published
2021
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17. Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders

Author

Fundação para a Ciência e a Tecnologia (Portugal), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Instituto de Salud Carlos III, Espadinha, Margarida, Viejo, L., Lopes, R. M. R. M., Herrera-Arozamena, Clara, Molins, E., dos Santos, D. J. V. A., Gonçalves, Lídia M., Rodríguez-Franco, María Isabel, Ríos, C. d. l., Santos, Maria M. M., Fundação para a Ciência e a Tecnologia (Portugal), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Instituto de Salud Carlos III, Espadinha, Margarida, Viejo, L., Lopes, R. M. R. M., Herrera-Arozamena, Clara, Molins, E., dos Santos, D. J. V. A., Gonçalves, Lídia M., Rodríguez-Franco, María Isabel, Ríos, C. d. l., and Santos, Maria M. M.

Abstract

N-Methyl-D-aspartate receptors (NMDARs) are crucial for the normal function of the central nervous system (CNS), and fundamental in memory and learning-related processes. The overactivation of these receptors is associated with numerous neurodegenerative and psychiatric disorders. Therefore, NMDAR is considered a relevant therapeutic target for many CNS disorders. Herein, we report the synthesis and pharmacological evaluation of a new scaffold with antagonistic activity for NMDAR. Specifically, a chemical library of eighteen 1-aminoindan-2-ol tetracyclic lactams was synthesized and screened as NMDAR antagonists. The compounds were obtained by chiral pool synthesis using enantiomerically pure 1-aminoindan-2-ols as chiral inductors, and their stereochemistry was proven by X-ray crystallographic analysis of two target compounds. Most compounds reveal NMDAR antagonism, and eleven compounds display IC values in a Ca entry-sensitive fluo-4 assay in the same order of magnitude of memantine, a clinically approved NMDAR antagonist. Docking studies suggest that the novel compounds can act as NMDAR channel blockers since there is a compatible conformation with MK-801 co-crystallized with NMDAR channel. In addition, we show that the tetracyclic 1-aminoindan-2-ol derivatives are brain permeable and non-toxic, and we identify promising hits for further optimization as modulators of the NMDAR function.

Published
2020

21. Improving anticancer activity towards colon cancer cells with a new p53‐activating agent

Author

Raimundo, Liliana, Espadinha, Margarida, Soares, Joana, Loureiro, Joana B, Alves, Marco G, Santos, Maria M M, and Saraiva, Lucília

Subjects
Lactams, Tryptophan, Nuclear Proteins, Antineoplastic Agents, Cell Cycle Proteins, Proto-Oncogene Proteins c-mdm2, Research Papers, Cell Movement, Doxorubicin, Drug Resistance, Neoplasm, Cell Line, Tumor, Proto-Oncogene Proteins, Colonic Neoplasms, Humans, Tumor Suppressor Protein p53
Abstract

BACKGROUND AND PURPOSE: Impairment of the tumour suppressor p53 pathway is a major event in human cancers, making p53 activation one of the most attractive therapeutic strategies to halt cancer. Here, we have identified a new selective p53 activator and investigated its potential as an anticancer agent. EXPERIMENTAL APPROACH: Anti‐proliferative activity of the (R)‐tryptophanol‐derived bicyclic lactam SYNAP was evaluated in a range of human cancer cells with different p53 status. The anticancer activity and mechanism of action of SYNAP was studied in two‐ and three‐dimensional models of human colon adenocarcinoma HCT116 cells with wild‐type p53 and corresponding p53‐null isogenic derivative cells, alone and in combination with known chemotherapeutic agents. KEY RESULTS: SYNAP showed anti‐proliferative effect in human cancer cells dependent on p53 status. In HCT116 cells, SYNAP caused p53‐dependent growth inhibition, associated with cell cycle arrest and apoptosis, anti‐migratory activity and regulation of the expression of p53 transcriptional targets. Data also indicated that SYNAP targeted p53, inhibiting its interaction with its endogenous inhibitors, murine double minute (MDM)2 and MDMX. Moreover, SYNAP sensitized colon cancer cells to the cytotoxic effect of known chemotherapeutic agents. SYNAP did not induce acquired or cross‐resistance and re‐sensitized doxorubicin‐resistant colon cancer cells to chemotherapy. Additionally, SYNAP was non‐genotoxic and had low cytotoxicity against normal cells. CONCLUSION AND IMPLICATIONS: SYNAP revealed encouraging anticancer activity, either alone or in combination with known chemotherapeutic agents, in colon cancer cells. Apart from its promising application in cancer therapy, SYNAP may provide a starting point for improved p53 activators.

Published
2018

22. SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma

Author

Gomes, Sara, primary, Bosco, Bartolomeo, additional, Loureiro, Joana B., additional, Ramos, Helena, additional, Raimundo, Liliana, additional, Soares, Joana, additional, Nazareth, Nair, additional, Barcherini, Valentina, additional, Domingues, Lucília, additional, Oliveira, Carla, additional, Bisio, Alessandra, additional, Piazza, Silvano, additional, Bauer, Matthias R., additional, Brás, João P., additional, Almeida, Maria Inês, additional, Gomes, Célia, additional, Reis, Flávio, additional, Fersht, Alan R., additional, Inga, Alberto, additional, Santos, Maria M. M., additional, and Saraiva, Lucília, additional

Published
2019
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26. Uncovering the binding of the anticancer small molecule SLMP53-1 to mutant p53R280K

Author

Gomes, A. S., Gomes, S., Soares, Joana, Ramos, Helena, Oliveira, Carla, Freire, Filipe, Pinheiro, Benedita, Marcelo, Filipa, Espadinha, Margarida, Domingues, Lucília, Romão, Maria João, Carvalho, Ana Luísa, Santos, Maria M. M., Saraiva, Lucília, and Universidade do Minho

Abstract

Introduction: The tumor suppressor protein p53 is frequently mutated in human cancer, which is commonly related to poor prognosis. Thus, reactivation of wild-type functions to mutant p53 is an attractive anticancer therapeutic strategy (1). Indeed, many efforts have been developed to target mutant p53. In a recent work, our group discovered the small molecule SLMP53-1, which restores the wild-type activity to mutant p53R280K with promising in vitro and in vivo antitumor activity results (2; 3). Aims: The present work aims to unravel the binding of SLMP53-1 to mutant p53R280K. Materials and methods: With that purpose, two strategies were defined: i) to assess the thermal stabilization of mutant p53R280K, induced by the binding of SLMP53-1 to mutant p53, in a cellular context by Cellular Thermal Shift Assay (CETSA); and ii) to produce p53R280K for biophysical binding assays, including MicroScale Thermophoresis (MST), Saturation-Transfer Difference NMR (STD-NMR) and X-ray crystallography. Results: By CETSA, we showed that SLMP53-1 induces p53R280K thermal stabilization, confirming the binding of SLMP53-1 to p53R280K. Recombinant p53R280K protein (core domain) was successfully produced and purified from E. coli BL21(DE3). So far, crystals of apo p53R280K and with SLMP53-1 were obtained. Co-crystallization optimization, MST and STD-NMR experiments are underway. Conclusions: With this work, the SLMP53-1 binding to p53R280K was confirmed and its characterization is in progress. This integrated study will contribute to understand the biology and pharmacology of p53 mutant forms and to the rational design of improved reactivators of mutant p53., info:eu-repo/semantics/publishedVersion

Published
2017

28. SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner.

Author

Ramos, Helena, Calheiros, Juliana, Almeida, Joana, Barcherini, Valentina, Santos, Sónia, Carvalho, Alexandra T. P., Santos, Maria M. M., and Saraiva, Lucília

Subjects
METABOLIC regulation, NEOVASCULARIZATION, P53 antioncogene, GLUCOSE metabolism, CANCER cell migration, CYTOCHROME oxidase, TUMOR growth, VASCULAR endothelial growth factors
Abstract

The Warburg effect is an emerging hallmark of cancer, which has the tumor suppressor p53 as its major regulator. Herein, we unveiled that p53 activation by (S)-tryptophanol-derived oxazoloisoindolinone (SLMP53-1) mediated the reprograming of glucose metabolism in cancer cells and xenograft human tumor tissue, interfering with angiogenesis and migration. Particularly, we showed that SLMP53-1 regulated glycolysis by downregulating glucose transporter 1 (GLUT1), hexokinase-2 (HK2), and phosphofructokinase-2 isoform 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase-3 (PFKFB3) (key glycolytic enzymes), while upregulating the mitochondrial markers synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase subunit 4 (COX4), and OXPHOS mitochondrial complexes. SLMP53-1 also downregulated the monocarboxylate transporter 4 (MCT4), causing the subsequent reduction of lactate export by cancer cells. Besides the acidification of the extracellular environment, SLMP53-1 further increased E-cadherin and reduced metalloproteinase-9 (MMP-9) expression levels in both cancer cells and xenograft human tumor tissue, which suggested the interference of SLMP53-1 in extracellular matrix remodeling and epithelial-to-mesenchymal transition. Consistently, SLMP53-1 depleted angiogenesis, decreasing endothelial cell tube formation and vascular endothelial growth factor (VEGF) expression levels. SLMP53-1 also exhibited synergistic growth inhibitory activity in combination with the metabolic modulator dichloroacetic acid. These data reinforce the promising application of the p53-activating agent SLMP53-1 in cancer therapy, by targeting p53-mediated pathways of growth and dissemination. [ABSTRACT FROM AUTHOR]

Published
2020
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31. DIMP53-1: a novel small-molecule dual inhibitor of p53-MDM2/X interactions with multifunctional p53-dependent anticancer properties

Author

Soares, Joana, primary, Espadinha, Margarida, additional, Raimundo, Liliana, additional, Ramos, Helena, additional, Gomes, Ana Sara, additional, Gomes, Sara, additional, Loureiro, Joana B., additional, Inga, Alberto, additional, Reis, Flávio, additional, Gomes, Célia, additional, Santos, Maria M. M., additional, and Saraiva, Lucília, additional

Published
2017
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35. VINYL SULFONES AS CASPASE INHIBITORS

Author

Santos, Maria M. M., Newton, Ana S., Coutinho, Isabel, Gloria, Paulo M. C., Saraiva, Lucilia, Moreira, Rui, and Repositório da Universidade de Lisboa

Subjects
Pharmacology & Pharmacy
Abstract

Made available in DSpace on 2015-12-30T10:18:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2009

Published
2009

36. Naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates

Author

Santos, Daniela M., Santos, Maria M. M., Viana, Ricardo J. S., Castro, Rui E., Moreira, Rui, Rodrigues, Cecilia M. R., and Repositório da Universidade de Lisboa

Subjects
Biochemistry & Molecular Biology, Pharmacology & Pharmacy, Toxicology
Abstract

Compounds containing a quinone moiety represent an important class of biologically active molecules that are widespread in nature, displaying anticancer, antibacterial, antimalarial, and fungicidal activities. In the course of designing 2,3-disubstituted-1,4-naphthoquinones derivatives as potential cysteine protease inhibitors, two naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates, 1a and 1b, were obtained. The antiapoptotic potential of 1a and 1b was then evaluated and compared to that of naphthoquinone 4. Primary rat hepatocytes were incubated with synthesized naphthoquinone derivatives and then exposed to the apoptotic stimulus camptothecin. Our results indicate that naphthol 2,3-dlisoxazole-4,9-dione-3-carboxylates 1a and 1b exerted a potent protective role in camptothecin-induced apoptosis in primary rat hepatocytes. Both 1a and 1b significantly increased cell viability, while reducing nuclear fragmentation, caspase-3, -8 and -9 activation, and cytochrome c release induced by camptothecin. In addition, 1a and 1b were shown to up-regulate Bcl-X-L, a pro-survival member of the Bcl-2 family of proteins, which modulates the mitochondrial pathway of apoptosis. Similar protective effects of quinone derivatives were seen in HuH-7 and PC12 cells incubated with distinct apoptotic stimuli, such as camptothecin, TGF-beta 1, or rotenone. Our results suggest that naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates 1a and 1b may act as potent, cytoprotective agents, through modulation of apoptotic pathways. (C) 2009 Elsevier Ireland Ltd. All rights reserved.. - Fundacao para a Ciencia e a Tecnologia (Portugal) [PTDC/SAU-FCF/67912/2006]. - This work was supported by Fundacao para a Ciencia e a Tecnologia (Portugal) through grant PTDC/SAU-FCF/67912/2006 (C.M.P.R.), and doctoral fellowships to D.M.S. and RJ.S.V. and postdoctoral fellowships to M.M.M.S. and R.E.C.

Published
2009

42. Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists.

Author

Pereira, Nuno A. L., Sureda, Francesc X., Pérez, Maria, Amat, Mercedes, and Santos, Maria M. M.

Subjects
QUINOLIZIDINES synthesis, ASPARTATES, AMINO alcohols, AMANTADINE, INDOLE
Abstract

Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl D-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic δ-oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors. [ABSTRACT FROM AUTHOR]

Published
2016
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47. Stereocontrolled Generation of Benzo[a]‐ and Indolo[2,3‐a]quinolizidines from (S)‐Tryptophanol and (S)‐(3,4‐Dimethoxyphenyl)alaninol‐Derived Lactams

Author

Pérez, Maria, primary, Arioli, Federica, additional, Rigacci, Gianna, additional, Santos, Maria M. M., additional, Gómez‐Esqué, Arantxa, additional, Escolano, Carmen, additional, Florindo, Pedro, additional, Ramos, Carlos, additional, Bosch, Joan, additional, and Amat, Mercedes, additional

Published
2011
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