Browsing by Author "Guedes, Rita C."
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- 3-Oxo-ß-sultam as a Sulfonylating Chemotype for Inhibition of Serine Hydrolases and Activity-Based Protein ProfilingPublication . Carvalho, Luís; Almeida, Vanessa Tavares; Brito, José A.; Lum, Kenneth; Oliveira, Tânia F.; Guedes, Rita C.; Gonçalves, Lídia; Lucas, Susana Dias; Cravatt, Benjamin; Archer, Margarida; Moreira, Rui3-Oxo-β-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-β-sultam inhibitors and show, through crystallographic data, that they are regioselective sulfonylating electrophiles, covalently binding to the catalytic serine of human and porcine elastases through the sulfur atom. Application of 3-oxo-β-sultam-derived activity-based probes in a human proteome revealed their potential to label disease-related serine hydrolases and proteasome subunits. Activity-based protein profiling applications of 3-oxo-β-sultams should open up new opportunities to investigate these classes of enzymes in complex proteomes and expand the toolbox of available sulfur-based covalent protein modifiers in chemical biology.
- Azetidine-2,4-diones (4-oxo-beta-lactams) as scaffolds for designing elastase inhibitorsPublication . Mulchande, Jalmira; Guedes, Rita C.; Tsang, Wing-Yin; Page, Michael I.; Moreira, Rui; Iley, JimA new class of inhibitors 4-oxo-beta-lactams (azetidine-2,4-diones), containing the required structural elements for molecular recognition, inhibit porcine pancreatic elastase (PPE) but show a dramatically lower reactivity toward hydroxide compared with the analogous inhibitors 3-oxo-beta-sultams. Inhibition is the result of acylation of the active site serine and electron-withdrawing substituents at the N-(4-aryl) position in 3,3-diethyl-N-aryl derivatives increasing the rate of enzyme acylation and generating a Hammett p-value of 0.65. Compared with a p-value of 0.96 for the rates of alkaline hydrolysis of the same series, this is indicative of an earlier transition state for the enzyme-catalyzed reaction. Docking studies indicate favorable noncovalent interactions of the inhibitor with the enzyme. Compound 2i, the most potent inhibitor against PPE, emerged as a very potent HLE inhibitor, with a second-order rate for enzyme inactivation of similar to 5 x 10(5) M-1 s(-1).
- Design, synthesis and evaluation of 3-methylene-substituted indolinones as antimalarialsPublication . Kumar, S. Praveen; Gut, Jiri; Guedes, Rita C.; Rosenthal, Philip J.; Santos, Maria M. M.; Moreira, RuiThe design, synthesis and evaluation of 3-methylene-substituted indolinones as falcipain inhibitors and antiplasmodial agents are described. These compounds react readily with thiols via an addition-elimination mechanism, indicating their potential as cysteine protease inhibitors. Several indolinones containing a Leu-i-amyl recognition moiety were found to be moderate inhibitors of the Plasmodium falciparum cysteine protease falcipain-2, but not of the related protease falcipain-3, and displayed antiplasmodial activity against the chloroquine-resistant P. falciparum W2 strain in the low micromolar range. Coupling a 7-chloroquinoline moiety to the 3-methylene-substituted indolinone scaffold led to a significant improvement in antiplasmodial activity.
- Design, synthesis and structure-activity relationships of (1H-pyridin-4-ylidene)amines as potential antimalarialsPublication . Rodrigues, Tiago; Guedes, Rita C.; dos Santos, Daniel J. V. A.; Carrasco, Marta; Gut, Jiri; Rosenthal, Philip J.; Moreira, Rui; Lopes, Francisca(1H-Pyridin-4-ylidene)amines containing lipophilic side chains at the imine nitrogen atom were prepared as potential clopidol isosteres in the development of antimalarials. Their antiplasmodial activity was evaluated in vitro against the Plasmodium falciparum W2 (chloroquine-resistant) and FCR3 (atovaquone-resistant) strains. The most active of these derivatives, 4m, had an IC50 of 1 mu M against W2 and 3 mu M against FCR3. Molecular modeling studies suggest that (1H-pyridin-4-ylidene) amines may bind to the ubiquinol oxidation Q(o) site of cytochrome bc(1). (C) 2009 Elsevier Ltd. All rights reserved.. - Funda ao para a Ciencia e Tecnologia (FCT, Portugal) ; Doris Duke Charitable Foundation Distinguished Clinical Scientist [SFRH/BD/30689/2006]. - This work was supported by Funda ao para a Ciencia e Tecnologia (FCT, Portugal); T. R. acknowledges FCT for the Ph. D. grant SFRH/BD/30689/2006. P.J.R. is a Doris Duke Charitable Foundation Distinguished Clinical Scientist.
- Dipeptide vinyl sultamsPublication . Valente, Claudia; Guedes, Rita C.; Moreira, Rui; Iley, Jim; Gut, Jiri; Rosenthal, Philip J.The synthesis of phosphonate derivatives of N-phenyl- and N-benzyl-gamma and delta-sultams, and their application in the Wittig-Horner reaction with N-BOC-L-phenylalanine aldehyde to afford E- and Z-isomers, are described. These compounds were further processed to provide five dipeptide vinyl sultams, which were found to be inactive against papain at concentrations up to 50 mu M. In contrast, vinyl sultams demonstrated weak activity against recombinant falcipain-2 and Plasmodium falciparum W2. (c) 2006 Elsevier Ltd. All rights reserved.
- Probing the aurone scaffold against Plasmodium falciparum: design, synthesis and antimalarial activityPublication . Carrasco, Marta; Newton, Ana; Gonçalves, Lídia; Góis, Ana; Machado, Marta; Gut, Jiri; Nogueira, Fátima; Hanscheid, Thomas; Guedes, Rita C.; dos Santos, Daniel J.V.A.; Rosenthal, Philip J.; Moreira, RuiA library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds.
- Properties and Permeability of Hypericin and Brominated Hypericin in Lipid MembranesPublication . Eriksson, Emma S. E.; dos Santos, Daniel J. V. A.; Guedes, Rita C.; Eriksson, Leif A.The promising photosensitizing properties of hypericin, a substituted phenanthroperylene quinone naturally found in Saint John's wort, has led to the proposal that it can be utilized in photodynamic therapy, Structurally modified derivatives are at the present time being investigated to generate a more effective hypericin photosensitizer. Neither the detailed mechanism behind the powerful action of hypericin, arising as a result of light excitation, nor the intracellular localization and transportation is still fully understood. In the present work, molecular dynamics simulations have been performed to study the properties and the permeability of hypericin and modifications thereof, substituted with one or four bromine atoms, in a dipalmitoylphosphatidylcholine lipid membrane. The molecules were found to accumulate in the most dense region of the lipids due to competing interactions with the hydrophobic lipid interior and the polar aqueous environment. This was confirmed by analyzing the radial distribution functions and by the density profiles of the system components. Calculated free energy profiles display large negative changes in free energy for the transport process of the molecules into the lipids, which also support this finding. Permeability coefficients show overall fastest diffusion in the membrane system for hypericin containing one bromine.. - Modelling and Simulation Research Center (ESEE) ; Swedish Research Council ; Faculty of Science and Technology at Orebro University ; National University of Ireland, Galway ; The Portuguese Fundacao para a Ciencia e a Tecnologia. - Financial Support from the Modelling and Simulation Research Center (ESEE), the Swedish Research Council, the Faculty of Science and Technology at Orebro University, and the National University of Ireland, Galway (LAE), is gratefully acknowledged. We also acknowledge generous grants of computing time at the National Supercomputing Center (NSC) in Linkoping. The Portuguese Fundacao para a Ciencia e a Tecnologia is also acknowledged for financial support.
- Redox and debromination reactions of brominated hypericinPublication . Eriksson, Emma S. E.; Guedes, Rita C.; Eriksson, Leif A.Phototoxic and radical-generating debromination reactions of monobrominated hypericin with bromine at one of four possible positions were investigated using density functional theory. The study was performed on two closely lying conformational isomers, differing in the relative orientations of the two anthracene units of the hypericin core. Calculated adiabatic electron affinities show that the molecules have the ability to, in aqueous solution, extract an electron from the surrounding. The electron might then be passed on to molecular oxygen, forming reactive superoxide radical anions. If electron extraction from the molecule does not occur in this step, the molecule might dissociate, generating a negatively charged bromine as a leaving group and a hypericin radical capable of forming direct binding to biological molecules. This reaction was found possible for those species substituted by Br at two of the four positions, with barriers of similar to 13 kcal/mol in aqueous solution. Debromination was not found energetically possible for neither the neutral ground state compounds nor the bay-deprotonated species. (c) 2008 Wiley Periodicals, Inc.
- Substituent effects on O-H and S-H bond dissociation enthalpies of disubstituted phenols and thiophenolsPublication . dos Santos, Daniel J. V. A.; Newton, Ana S.; Bernardino, Raul; Guedes, Rita C.The O-H and S-H homolytic bond dissociation enthalpies of a set of disubstituted phenols and thiophenols (NH2, OH, CH3, Cl, CF3, and NO2) have been computed by a density functional theory procedure with the 6-311++G(d,p) basis set. A very good agreement between our results and available experimental ones is observed. The effect of substituents on structure, charges and BDEs are investigated and their correlation with Hammett parameters is studied. (c) 2007 Wiley Periodicals, Inc.
- Synthesis and evaluation of vinyl sulfones as caspase-3 inhibitors. A structure-activity studyPublication . Newton, Ana S.; Glória, Paulo M. C.; Gonçalves, Lídia M.; Santos, Daniel J. V. A. dos; Moreira, Rui; Guedes, Rita C.; Santos, Maria M. M.The first structure–activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P1, as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CH CH–SO2Me was the most potent inhibitor of caspase-3 in the series, with a IC50 of 29 μM and a second-order rate constant of inactivation, kinact/Ki, of 1.5 M−1 s−1. Computational studies suggest that the second amino acid occupies position S3 of the enzyme. In addition, Fmoc-Val-Asp-trans-CH CH–SO2Ph was inactive for caspase-7 for the tested concentrations.