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1. Benchmarking Strategies of Sustainable Process Chemistry Development: Human-Based, Machine Learning, and Quantum Mechanics

Author

Almeida, A. Filipa, primary, Branco, Sofia, additional, Carvalho, Luisa C. R., additional, Dias, Andre Raposo Moreira, additional, Leitão, Emília P. T., additional, Loureiro, Rui M. S., additional, Lucas, Susana D., additional, Mendonça, Ricardo F., additional, Oliveira, Rudi, additional, Rocha, Inês L. D., additional, Sardinha, Joao, additional, Silva, Saúl, additional, Sobral, Luís M. S., additional, Lourenço, Nuno M. T., additional, and Valente, Pedro C., additional

Published
2024
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5. Chemoproteomik‐basierte Identifikation von 4‐Oxo‐β‐lactamen als Inhibitoren der Dipeptidylpeptidasen 8 und 9

Author

Carvalho, Luís A. R., primary, Ross, Breyan, additional, Fehr, Lorenz, additional, Bolgi, Oguz, additional, Wöhrle, Svenja, additional, Lum, Kenneth M., additional, Podlesainski, David, additional, Vieira, Andreia C., additional, Kiefersauer, Reiner, additional, Félix, Rita, additional, Rodrigues, Tiago, additional, Lucas, Susana D., additional, Groß, Olaf, additional, Geiss‐Friedlander, Ruth, additional, Cravatt, Benjamin F., additional, Huber, Robert, additional, Kaiser, Markus, additional, and Moreira, Rui, additional

Published
2022
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6. Chemoproteomics‐Enabled Identification of 4‐Oxo‐β‐Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9

Author

Carvalho, Luís A. R., primary, Ross, Breyan, additional, Fehr, Lorenz, additional, Bolgi, Oguz, additional, Wöhrle, Svenja, additional, Lum, Kenneth M., additional, Podlesainski, David, additional, Vieira, Andreia C., additional, Kiefersauer, Reiner, additional, Félix, Rita, additional, Rodrigues, Tiago, additional, Lucas, Susana D., additional, Groß, Olaf, additional, Geiss‐Friedlander, Ruth, additional, Cravatt, Benjamin F., additional, Huber, Robert, additional, Kaiser, Markus, additional, and Moreira, Rui, additional

Published
2022
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7. Cover Picture: Chemoproteomics‐Enabled Identification of 4‐Oxo‐β‐Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9 (Angew. Chem. Int. Ed. 47/2022)

Author

Carvalho, Luís A. R., primary, Ross, Breyan, additional, Fehr, Lorenz, additional, Bolgi, Oguz, additional, Wöhrle, Svenja, additional, Lum, Kenneth M., additional, Podlesainski, David, additional, Vieira, Andreia C., additional, Kiefersauer, Reiner, additional, Félix, Rita, additional, Rodrigues, Tiago, additional, Lucas, Susana D., additional, Groß, Olaf, additional, Geiss‐Friedlander, Ruth, additional, Cravatt, Benjamin F., additional, Huber, Robert, additional, Kaiser, Markus, additional, and Moreira, Rui, additional

Published
2022
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8. Titelbild: Chemoproteomik‐basierte Identifikation von 4‐Oxo‐β‐lactamen als Inhibitoren der Dipeptidylpeptidasen 8 und 9 (Angew. Chem. 47/2022)

Author

Carvalho, Luís A. R., primary, Ross, Breyan, additional, Fehr, Lorenz, additional, Bolgi, Oguz, additional, Wöhrle, Svenja, additional, Lum, Kenneth M., additional, Podlesainski, David, additional, Vieira, Andreia C., additional, Kiefersauer, Reiner, additional, Félix, Rita, additional, Rodrigues, Tiago, additional, Lucas, Susana D., additional, Groß, Olaf, additional, Geiss‐Friedlander, Ruth, additional, Cravatt, Benjamin F., additional, Huber, Robert, additional, Kaiser, Markus, additional, and Moreira, Rui, additional

Published
2022
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11. Synthesis, Biological Evaluation, and Docking Studies of Open-Chain Carbohydrate Amides as Acetylcholinesterase Inhibitors

Author

Gonçalves-Pereira, Rita, Figueiredo, Jose A., Lucas, Susana D., García-Moreno, Maria I., Mellet, Carmen O., Rauter, Amelia P., and Ismael, Maria I.

Abstract

Introduction: Alzheimer’s disease is a multifactorial syndrome, which is not yet fully understood, causing memory loss, dementia, and, ultimately, death. Acetylcholinesterase inhibitors are the mainstay drugs that are used in disease-symptomatic treatment. In this work, we report a new synthetic route yielding sugar amides as low to moderate acetylcholinesterase inhibitors. Methods: Commercially available diacetone glucose was converted into perbenzyl D-glucono-1,4- lactone, which reacted with aromatic or aliphatic amines to afford the corresponding new amides in a high isolated yield. Docking studies of the most promising hydroxybutylamide and benzylamide were performed to assign binding interactions with acetylcholinesterase and determine the key features for bioactivity. Results: The inhibitors are accommodated in enzyme gorge, blocking the access to Ser203 mainly due to π-π stacking interactions of sugar benzyl groups with the aromatic gorge residues, Tyr337 and Tyr341 for both inhibitors and Trp439 only for the hydroxybutylamide. Conclusion: Bonding is also significant through sugar interaction with the residues Tyr124 and Ser125-OH in both inhibitors. Flexibility of these open-chain structures seems to be quite relevant for the observed binding to acetylcholinesterase.

Published
2023
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15. 3-Oxo-β-sultam as a Sulfonylating Chemotype for Inhibition of Serine Hydrolases and Activity-Based Protein Profiling

Author

Carvalho, Luís A. R., primary, Almeida, Vanessa T., additional, Brito, José A., additional, Lum, Kenneth M., additional, Oliveira, Tânia F., additional, Guedes, Rita C., additional, Gonçalves, Lídia M., additional, Lucas, Susana D., additional, Cravatt, Benjamin F., additional, Archer, Margarida, additional, and Moreira, Rui, additional

Published
2020
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21. Wittig Reaction: Domino Olefination and Stereoselectivity DFT Study. Synthesis of the Miharamycins’ Bicyclic Sugar Moiety

Author

Cachatra, Vasco, primary, Almeida, Andreia, additional, Sardinha, João, additional, Lucas, Susana D., additional, Gomes, Ana, additional, Vaz, Pedro D., additional, Florêncio, M. Helena, additional, Nunes, Rafael, additional, Vila-Viçosa, Diogo, additional, Calhorda, Maria José, additional, and Rauter, Amélia P., additional

Published
2015
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28. Cytotoxic bile acids, but not cytoprotective species, inhibit the ordering effect of cholesterol in model membranes at physiologically active concentrations

Author

Mello-Vieira, João, primary, Sousa, Tânia, additional, Coutinho, Ana, additional, Fedorov, Aleksander, additional, Lucas, Susana D., additional, Moreira, Rui, additional, Castro, Rui E., additional, Rodrigues, Cecília M.P., additional, Prieto, Manuel, additional, and Fernandes, Fábio, additional

Published
2013
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30. Synthesis and Evaluation of the Biological Profile of Novel Analogues of Nucleosides and of Potential Mimetics of Sugar Phosphates and Nucleotides.

Author

Xavier, Nuno M., Lucas, Susana D., Jorda, Radek, Schwarz, Stefan, Loesche, Anne, Csuk, René, and Oliveira, M. Conceição

Subjects
*NUCLEOSIDE synthesis, *SUGAR phosphates, *GLYCOSYLATION, *REGIOSELECTIVITY (Chemistry), *CARBONIC anhydrase
Abstract

The synthesis of purine/triazole 6'-isonucleosides and of glucuronic acid/glucuronamide-derived N-glycosylsulfonohydrazides through efficient and stereo- or regioselective methodologies is described. Their structures were envisaged to mimic nucleosides, sugar phosphates, or nucleotides, and were expected to provide potential inhibitors of therapeutically relevant enzymes, the active sites of which could potentially bind their structural fragments or functional groups. Such enzymes include cholinesterases, carbonic anhydrase II (CA-II) and cyclin-dependent kinase 2 (CDK-2). A (triazolyl)methyl amide-linked disaccharide nucleoside, based on a new prospective structural framework for analogues of nucleoside diphosphate sugars, was synthesized. The synthetic strategies employed unprotected or partially protected carbohydrate derivatives as precursors, including ribose, glucuronic acid, glucuronolactone, and glycopyranosides and relied on stereoselective N-glycosylation, regioselective Mitsunobu coupling and 'click chemistry' approaches. Some 6'-isonucleosides and triazole-containing glycoderivatives displayed moderate selective acetylcholinesterase inhibitory activities. The best inhibitor was an aminomethyltriazole 6'-isonucleoside with a Ki value of 11.9 μM. N-Glucuronylsulfonohydrazide showed good inhibition of CA-II (Ki = 9.5 μM). Molecular docking of the most active compounds into the effected enzymes showed interactions with key amino acid residues for substrate recognition. In addition, the tested compounds did not show toxicity to normal cells. [ABSTRACT FROM AUTHOR]

Published
2015
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35. Optimization of O3-Acyl Kojic Acid Derivatives as Potent and SelectiveHuman Neutrophil Elastase Inhibitors.

Author

Lucas, Susana D., Gonçalves, Lídia M., Carvalho, Luís A.R., Correia, Henrique F., Da Costa, Eduardo M. R., Guedes, Romina A., Moreira, Rui, and Guedes, Rita C.

Subjects
*LEUCOCYTE elastase, *ACYL group, *MATHEMATICAL optimization, *INFLAMMATION, *LUNG disease treatment, *CELL-mediated cytotoxicity
Abstract

Humanneutrophil elastase (HNE) is an attractive target for treating chronicand acute inflammatory lung diseases. An optimization campaign ofthe kojic acid scaffold to develop new potent HNE inhibitors is reported. O3-Pivaloyl derivatives were shown to be themost potent inhibitors with IC5ovalues down to 80 nM.These compounds presented excellent selectivity and cytotoxicity profileswith suitable ligand efficiency. [ABSTRACT FROM AUTHOR]

Published
2013
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36. Targeting COPD: advances on low-molecular-weight inhibitors of human neutrophil elastase.

Author

Lucas, Susana D., Costa, Elsa, Guedes, Rita C., and Moreira, Rui

Abstract

Chronic obstructive pulmonary disease (COPD) is a major increasing health problem and the World Health Organization (WHO) reports COPD as the fifth leading cause of death worldwide. COPD refers to a condition of inflammation and progressive weakening of the structure of the lung as well as irreversible narrowing of the airways. Current treatment is only palliative and no available drug halts the progression of the disease. Human neutrophil elastase (HNE) is a serine protease, which plays a major role in the COPD inflammatory process. The protease/anti-protease imbalance leads to an excess of extracellular HNE hydrolyzing elastin, the structural protein that confers elasticity to the lung tissue. Although HNE was identified as a therapeutic target for COPD more than 30 years ago, only Sivelestat (ONO-5046), an HNE inhibitor from Ono Pharmaceutical, has been approved for clinical use. Nevertheless, Sivelestat is only approved in Japan and its development in the USA was terminated in 2003. Other inhibitors in pre-clinical or phase I trials were discontinued for various reasons. Hence, there is an urgent need for low-molecular-weight synthetic elastase inhibitors and the present review discusses the recent advances on this field covering acylating agents, transition-state inhibitors, mechanism-based inhibitors, relevant natural products, and major patent disclosures. [ABSTRACT FROM AUTHOR]

Published
2013
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37. KINETIC STUDY OF MINERAL ACID-CATALYZED CONVERSION OF 7-ETHYLTRIPTOPHOL TO METHYL ESTER OF ETODOLAC

Author

Car, Željka, Ribić, Rosana, Habinovec, Iva, Biljan, Ivana, Galić, Nives, Novak, Predrag, Tomić, Srđanka, Rauter, Amélia P., Martins, Alice, Matos, Ana M., Dias, Catarina, Xavier, Nuno M., Nunes, Rafael, Lucas, Susana D., Cachatra, Vasco, Paiva, Ana P., and Batista, Daniela

Subjects
Oxa Pictet Spengler reaction, mineral acid promoter, kinetic study
Abstract

Etodolac, 1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano- [3, 4-b]indole-1-acetic acid is a non-steroidal antiinflamatory antirheumatic drug. A key intermediate in the synthesis of Etodolac is its methyl ester which can be obtained by oxa- Pictet-Spengler reaction, starting from 7- ethyltriptophol. Pyrano[3, 4-b]indole ring is closed in the reaction of 7-ethyltriptophol and β-ketoester, methyl 3-oxo-pentanoate. For the preparation of oxacycle (pyranic ring) different Brönsted and Lewis acids can be employed.[1] Typically, aqueous hydrochloric or sulfuric acid, as well as boron trifuoride etherate, gasous hydrochloride, p- toluensulfonic acid, zink chloride, aluminium chloride and tin(IV) chloride in organic solvents are used to promote the reaction. Catalyst such as boron trifuoride etherate is expensive and is stable only in a perfectly anhydrous environment, which is difficult to manage, especially in productions on a larger scale. Therefore, the processes in which inorganic mineral acids can be used are preferred.[2] We report the kinetic study of conversion of 7-ethyltriptophol to methyl ester of Etodolac in methanol in the presence of concentrated hydrochloric and sulfuric acids. In order to optimize the synthetic procedure, kinetic profiles of reactions promoted with different molar ratios of acids (with respect to the β-ketoester) were determined using HPLC as a method of choice.

Published
2015

38. DEVELOPMENT OF HPLC METHOD FOR MONITORING ACID- CATALYZED CONVERSION OF 7-ETHYLTRYPTOPHOL TO METHYL ESTER OF ETODOLAC

Author

Habinovec, Iva, Car, Željka, Ribić, Rosana, Biljan, Ivana, Galić, Nives, Novak, Predrag, Tomić, Srđanka, Rauter, Amélia P., Martins, Alice, Matos, Ana M., Dias, Catarina, Xavier, Nuno M., Nunes, Rafael, Lucas, Susana D., Cachatra, Vasco, Paiva, Ana P., and Batista, Daniela

Subjects
HPLC method, kinetic study, Oxa Pictet Spengler reaction
Abstract

Etodolac methyl ester is a key intermediate in the synthesis of Etodolac, a non-steroidal anti-inflammatory drug. It can be obtained by oxa-Pictet-Spengler reaction, starting from 7- ethyltriptophol and using inorganic mineral acids as catalysts.[1] In order to get kinetic profiles of reactions catalyzed with different molar ratios of sulfuric and hydrochloric acid, a high performance liquid chromatography method with UV detection was developed for monitoring conversion of 7-ethyltryptophol to methyl ester of Etodolac. For that purpose different stationary phases (C18, Phenyl and NH2 column) were investigated for separation of 7-ethyltryptophol and Etodolac methyl ester. Elution was performed with three different solvent mixtures in isocratic and/or gradient mode. The best chromatographic separation was achieved isocratically using Waters Symmetry Shield RP 18 column with 55% acetonitrile and 45% water.

Published
2015

39. Chemoproteomics-Enabled Identification of 4-Oxo-β-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.

Author

Carvalho LAR, Ross B, Fehr L, Bolgi O, Wöhrle S, Lum KM, Podlesainski D, Vieira AC, Kiefersauer R, Félix R, Rodrigues T, Lucas SD, Groß O, Geiss-Friedlander R, Cravatt BF, Huber R, Kaiser M, and Moreira R

Subjects
beta-Lactams pharmacology, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Proteomics, Crystallography, X-Ray, Dipeptidases metabolism
Abstract

Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-β-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Published
2022
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40. Dipeptidyl Vinyl Sulfone as a Novel Chemical Tool to Inhibit HMGB1/NLRP3-Inflammasome and Inflamma-miRs in Aβ-Mediated Microglial Inflammation.

Author

Falcão AS, Carvalho LA, Lidónio G, Vaz AR, Lucas SD, Moreira R, and Brites D

Subjects
Animals, Cell Survival drug effects, Cells, Cultured, Cerebral Cortex cytology, Gene Expression Regulation drug effects, HMGB1 Protein genetics, Interleukin-1beta metabolism, Lipopolysaccharides pharmacology, Matrix Metalloproteinases metabolism, Mice, MicroRNAs genetics, MicroRNAs metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Phagocytes drug effects, Sulfones chemical synthesis, Sulfones chemistry, Amyloid beta-Peptides pharmacology, Anti-Inflammatory Agents pharmacology, HMGB1 Protein metabolism, Microglia drug effects, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Peptide Fragments pharmacology, Sulfones pharmacology
Abstract

Rapid microglial activation and associated inflammatory pathways contribute to immune-defense and tissue repair in the central nervous system (CNS). However, persistent activation of these cells will ultimately result in vast production of pro-inflammatory mediators and other neurotoxic factors, which may induce neuronal damage and contribute to chronic neurodegenerative diseases, as Alzheimer's disease (AD). Therefore, small molecules with immunomodulatory effects on microglia may be considered as potential tools to counteract their proinflammatory phenotype and neuroimmune dysregulation in such disorders. Indeed, reducing amyloid-β (Aβ)-induced microglia activation is believed to be effective in treating AD. In this study, we investigated whether dipeptidyl vinyl sulfone (VS) was able to attenuate Aβ-mediated inflammatory response using a mouse microglial (N9) cell line and a solution containing a mixture of Aβ aggregates. We show that low levels of VS are able to prevent cell death while reducing microglia phagocytosis upon Aβ treatment. VS also suppressed Aβ-induced expression of inflammatory mediators in microglia, such as matrix metalloproteinase (MMP)-2 and MMP-9, as well as high-mobility group box protein-1 (HMGB1), nod-like receptor protein 3 (NLRP3)-inflammasome, and interleukin (IL)-1β. Interestingly, increased expression of the two critical inflammation-related microRNAs (miR)-155 and miR-146a in microglia upon Aβ treatment was also prevented by VS coincubation. Taken together, VS emerges as a potential new therapeutic strategy worthy of further investigation in improved cellular and animal models of AD.

Published
2017
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