Browsing by Author "Moreira, Rui"
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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.
- Amino acids as selective acylating agentsPublication . Vale, Nuno; Matos, Joana; Moreira, Rui; Gomes, PaulaThe acylation of bioactive primaquine-based imidazolidin-4-ones was studied using N-chi-Boc-protected glycine as acylating agent. Two synthesis routes, eight different coupling methods and seven distinct solvents were compared. Mild carbodiimide-based couplings on high dielectric constant solvents such as DMF or MeCN increased acylation yields, whereas alcohols inhibited carbodiimide-mediated acylations to take place. Achievement of the synthetic goals was limited by the size of the imidazolidin-4-one ring substituents R-1, R-2 and R-3, but resort to MW-assisted synthesis allowed overcoming such obstacle, though with very modest reaction yields. All reactions involving a Boc-protected amino acid were regioselective, independent of reaction conditions employed. In contrast, regioselective acetylation of the imidazolidin-4-ones could only be achieved by resort to very mild coupling procedures. (C) 2008 Elsevier Ltd. All rights reserved.. - Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) ; PTDC/QUI [65142/ 2006]; SFRH/BD [17754/2004]; CIQUP ; CECF ; CEM Corporation (USA) ; QLabo (Portugal) ; CEM DiscoverSUPTM/SUP system. - Thanks are due to Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) for financial Support through Project PTDC/QUI/65142/ 2006. N.V. thanks FCT for Ph.D.grant SFRH/BD/17754/2004. P.G. and R.M. thank FCT for financial support to CIQUP and CECF, respectively. Thanks are also due to CEM Corporation (USA) and QLabo (Portugal) for providing a CEM DiscoverSUPTM/SUP system for a trial period.
- Aminocarbonyloxymethyl ester prodrugs of flufenamic acid and diclofenacPublication . Ribeiro, Lina; Silva, Nuno; Iley, Jim; Rautio, Jarkko; Jarvinen, Tomi; Mota-Filipe, Helder; Moreira, Rui; Mendes, EduardaAminocarbonyloxymethyl ester prodrugs are known to undergo rearrangement in aqueous solutions to form the corresponding N-acylamine side product via an 0 - N intramolecular acyl transfer from the carbamate conjugate base. Novel aminocarbonyloxymethyl esters of diclofenac and flufenamic acid containing amino acid amide carriers were synthesized and evaluated as potential prodrugs displaying less ability to undergo rearrangement. These compounds were prepared in reasonable yield by a four-step synthetic method that uses the appropriate N-Boc-protected amino acid N-hydroxysuccinimide ester and secondary amine and chloromethyl chloroformate as key reactants. Their reactivity in pH 7.4 buffer and 80% human plasma at 37 degrees C was assessed by RP-HPLC. The aminocarbonyloxymethyl esters containing a secondary carbamate group derived from amino acids such as glycine or phenylalanine were hydrolyzed quantitatively to the parent drug both in non-enzymatic and enzymatic conditions, with no rearrangement product being detected. The oral bioavailability in rats was determined for selected diclofenac derivatives. These derivatives displayed a bioavailability of 25 to 68% relative to that of diclofenac, probably due to their poor aqueous solubility and lipophilicity. These results suggest that further optimization of aminocarbonyloxymethyl esters as potential prodrugs for non-steroidal anti-inflammatory drugs require the use of amino acid carriers with ionizable groups to improve aqueous solubility.
- Anti-tumoral activity of imidazoquines, a new class of antimalarials derived from primaquinePublication . Fernandes, Iva; Vale, Nuno; de Freitas, Victor; Moreira, Rui; Mateus, Nuno; Gomes, PaulaThe growth inhibitory activity of imidazoquines, antimalarial imidazolidin-4-ones derived from primaquine, on human cancer cell lines HT-29, Caco-2, and MCF-7 has been evaluated. Primaquine, N-dipeptidyl-primaquine derivatives, and other quinolines have been included in the study for comparison purposes. Primaquine and some of its derivatives were significantly active against the MCF-7 human breast cancer cell line, so these compounds might represent useful leads targeted at the development of novel specific agents against breast cancer. Conversely, all compounds were generally inactive against HT-29, with only one of the imidazoquines having IC50 below 50 mu M. Activities against the Caco-2 cell line were modest and did not follow any defined trend. (C) 2009 Elsevier Ltd. All rights reserved.. - Portuguese Foundation for Science and Technology (FCT) [PTDC/QUI/65142/2006, PTDC/QUI/65501/2006, CONC-REEQ/275/QUI, REDE/1517/RMN/2005, SFRH/BPD/48345/2008, SFRH/BD/38883/2007]. - Thanks are due to the Portuguese Foundation for Science and Technology (FCT) for financial support through Project Grants PTDC/QUI/65142/2006, PTDC/QUI/65501/2006, CONC-REEQ/275/QUI and REDE/1517/RMN/2005. N.V. and I. F. thank FCT for, respectively, Post-Doc Grant SFRH/BPD/48345/2008 and Ph.D. Grant SFRH/BD/38883/2007.
- Artemisinin-dipeptidyl vinyl sulfone hybrid moleculesPublication . Capela, Rita; Oliveira, Rudi; Goncalves, Lidia M.; Domingos, Ana; Gut, Jiri; Rosenthal, Philip J.; Lopes, Francisca; Moreira, RuiA series of artemisinin-vinyl sulfone hybrid molecules with the potential to act in the parasite food vacuole via endoperoxide activation and falcipain inhibition was synthesized and screened for antiplasmodial activity and falcipain-2 inhibition. All conjugates were active against the Plasmodium falciparum W2 strain in the low nanomolar range and those containing the Leu-hPhe core inhibited falcipain-2 in low micromolar range. (C) 2009 Elsevier Ltd. All rights reserved.. - FCT (Portugal) [SFRH/BD/30418/2006]; National Institutes of Health. - This work was supported by FCT (Portugal) and the National Institutes of Health; R. C. acknowledges FCT for the PhD grant SFRH/BD/30418/2006. PJR is a Doris Duke Charitable Foundation Distinguished Clinical Scientist.
- Aspartic vinyl sulfones: inhibitors of a caspase-3-dependent pathwayPublication . Glória, Paulo M. C.; Coutinho, Isabel; Gonçalves, Lídia M.; Baptista, Cristina; Soares, Joana; Newton, Ana S.; Moreira, Rui; Saraiva, Lucília; Santos, Maria M. M.In this article we describe an expanded structureeactivity relationship study for vinyl sulfones as caspase-3 inhibitors, a topic virtually unexplored in the existing literature. Most remarkably, and to our surprise, tripeptidyl vinyl sulfones were not active for caspase-3, opposite to other examples described in literature for peptidyl vinyl sulfones as potent cysteine protease inhibitors of clan CA. Moreover, the caspase-3 inhibitory activity of vinyl sulfones using an in vitro assay was then confirmed using a yeast cell-based assay. The results show that Fmoc-protected vinyl sulfones containing only the Asp moiety are inhibitors of a caspase-3-dependent pathway and the IC50 values obtained in the yeast assay are in the same order of magnitude of that obtained with the caspase-3 inhibitor tetrapeptidyl chloromethyl ketone, Ac-DEVD-CMK. This observation is consistent with appropriate cell permeability properties displayed by the vinyl sulfone inhibitors, as reflected by log P values ranging from 1.1 to 3.4. Overall, these results suggest that vinyl sulfones containing Asp at P1 should be considered for further optimization as caspase inhibitors and modulators of caspase-3-dependent pathways.
- Aza vinyl sulfones: Synthesis and evaluation as antiplasmodial agentsPublication . Glória, Paulo M. C.; Gut, Jiri; Gonçalves, Lídia M.; Rosenthal, Philip J.; Moreira, Rui; Santos, Maria M. M.A series of novel aza vinyl sulfones were designed, synthesized in good yields and evaluated as antiplasmodial agents. Tested compounds did not show activity against papain or the Plasmodium falciparum cysteine protease falcipain-2. However, a number of the new compounds effectively inhibited the in vitro development of P. falciparum. Compounds containing a squaramide group were the most active, with IC50 values between 0.95 and 4.5 μM, suggesting that these are potential lead compounds for the development of new antimalarial agents.
- 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).
- Bis{(E)-3-[(diethylmethylammonio)methyl]-N-[3-(N,N-dimethylsulfamoyl)-1-methylpyridin-4-ylidene]-4-methoxyanilinium} tetraiodide pentahydratePublication . Rodrigues, Tiago; Moreira, Rui; Dacunha-Marinho, Bruno; Lopes, FranciscaThe title compound, 2C(21)H(34)N(4)O(3)S(2+)center dot 4I(-)center dot 5H(2)O, was prepared exclusively as the E isomer by methylation of the corresponding N-phenylpyridin-4-amine. There are two symmetry-independent molecules in the asymmetric unit with no significant differences in bond lengths and angles. The aromatic rings are not coplanar with the pyridin-4-imine groups, as indicated by the C-N-C-C torsion angles of 47.7 (7) and 132.6 (5)degrees.. - Fundacao para a Ciencia e Tecnologia (FCT, Portugal) [SFRH/BD/30689/2006]. - Intensity measurements were performed at the Unidade de Raios X, RIAIDT, University of Santiago de Compostela, SPAIN. This work was supported by Fundacao para a Ciencia e Tecnologia (FCT, Portugal); TR acknowledges the FCT for the PhD grant SFRH/BD/30689/2006.
- Cell death targets and potential modulators in Alzheimer’s diseasePublication . Castro, Rui E.; Santos, Maria M. M.; Glória, Paulo M. C.; Ribeiro, Carlos J. A.; Ferreira, Duarte M. S.; Xavier, Joana M.; Moreira, Rui; Rodrigues, Cecília M. P.Apoptosis is now recognized as a normal feature in the development of the nervous system and may also play a role in neurodegenerative disorders, such as Alzheimer’s disease. Cell surface receptors, caspases, mitochondrial factors or p53 participate in the modulation and execution of cell death. Therefore, the ability to understand and manipulate the cell death machinery is an obvious goal of medical research. Potential therapeutic approaches to modulate disease by regulating apoptosis are being tested, and include the traditional use of small molecules to target specific players in the apoptosis cascade. As our understanding of apoptosis increases, further opportunities will arise for more specific therapies that will result in improved efficacy. This review focuses on molecular mechanisms of apoptosis in Alzheimer’s disease and highlights the potential use of small molecule modulators to treat neurodegenerative disorders.