Browsing by Author "Iley, Jim"
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- 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.
- 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).
- Crystallization and preliminary diffraction studies of porcine pancreatic elastase in complex with a novel inhibitorPublication . Oliveira, Tania F.; Mulchande, Jalmira; Moreira, Rui; Iley, Jim; Archer, MargaridaPorcine pancreatic elastase (PPE) was crystallized in complex with a novel inhibitor at pH 5 and X-ray diffraction data were collected at a synchrotron source to 1.66 angstrom. Crystals belong to the orthorhombic space group P2(1)2(1)2(1), with unit cell parameters a = 50.25 angstrom, b = 57.94 angstrom and c = 74.69 angstrom. PPE is often used as model for drug target, due to its structural homology with the important therapeutic target human leukocyte elastase (HLE). Elastase is a serine protease that belongs to the chymotrypsin family, which has the ability to degrade elastin, an important component in connective tissues. Excessive elastin proteolysis leads to a number of pathological diseases.
- 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.
- Dopamine- and tyramine-based derivatives of triazenesPublication . Perry, M. Jesus; Mendes, Eduarda; Simplicio, Ana Luisa; Coelho, Ana; Soares, Ricardo V.; Iley, Jim; Moreira, Rui; Francisco, Ana PaulaA range of triazene derivatives were synthesized and investigated as prodrug candidates for melanocyte-directed enzyme prodrug therapy (MDEPT). The prodrugs contained a tyramine or dopamine promoiety required for tyrosinase activation and this was joined via a urea functional group to the cytotoxic triazene. The stability of each of the prodrugs in phosphate buffer, human plasma and in mushroom tyrosinase is discussed. The identification of the main peak formed after the tyrosinase reaction was attempted by LC-MS and the conversion of prodrug to the quinone was confirmed. (C) 2009 Elsevier Masson SAS. All rights reserved.. - Fundacao para a Ciencia e Tecnologia (Portugal). - The authors thank the Fundacao para a Ciencia e Tecnologia (Portugal) for financial support through their pluriannual funding to the iMed.UL research unit.
- Facile synthesis of Naphtho[2,3-d]isoxazole-4,9-diones derivativesPublication . Santos, Maria MM; Iley, Jim; Moreira, Rui
- Reaction of naphthoquinones with substituted nitromethanes. Facile synthesis and antifungal activity of naphtho[2,3- d]isoxazole-4,9-dionesPublication . Santos, Maria M. M.; Faria, Natália; Iley, Jim; Coles, Simon J.; Hursthouse, Michael B.; Martins, M. Luz; Moreira, RuiWe report here a simple entry into naphtho[2,3-d]isoxazole-4,9-dione system containing a EWG in position 3 using the readily available 2,3-dichloro-1,4-naphthoquinone and nitromethyl derivatives in the presence of base. Antifungal activity of synthesised naphthoquinones was evaluated against ATCC and PYCC reference strains of Candida. The results suggest that the naphtho[2,3-d]isoxazole-4,9-dione scaffold has the potential to be developed into novel and safe therapeutic antifungal agents.
- Reactivity of imidazolidin-4-one derivatives of primaquinePublication . Chambel, Paula; Capela, Rita; Lopes, Francisca; Iley, Jim; Morais, Jose; Gouveia, Luis; Gomes, Jose R. B.; Gomes, Paula; Moreira, RuiIn contrast to peptide-based imidazolidin-4-ones, those synthesized from N-(alpha-aminoacyl) derivatives of the antimalarial drug, primaquine and ketones are unexpectedly stable in pH 7.4 at 37 degrees C. The kinetics of hydrolysis of primaquine-based imidazolidin-4-ones were investigated in the pH range 0.3-13.5 at 60 degrees C. The hydrolysis to the parent alpha-aminoacylprimaquine is characterized by sigmoidal-shaped pH-rate profiles, reflecting the spontaneous decomposition of both unionized and protonated (at N-1) forms of the imidazolidin-4-one. The kinetically determined pK(a) values are ca. 3.6-4.0, i.e., 4 pKa units lower than those of amino acid amides, thus implying that hydrolysis of imidazolidin-4-ones at pH 7.4 involves the unionized form. Reactivity of this form decreases with the steric crowding of the amino acid alpha-substituent. In contrast, the rate constant for the spontaneous decomposition of the unionized form increases sharply for imidazolidin-4-ones derived from cyclic ketones, an observation that can be explained by the I-strain (internal strain) effect. These results are consistent with a mechanism of hydrolysis involving an S(N)1-type unimolecular cleavage of the imidazolidin-4-one C2-N3 bond with departure of an amide-leaving group. The mechanism for the decomposition of the protonated imidazolidin-4-one is likely to involve an amide-carbonyl oxygen protonated species, followed by the C2-N3 bond scission, as supported by computational studies. The results herein presented suggest that imidazolidin-4-ones derived from simple N-alkyl alpha-aminoamides are too stable and therefore, may be useful as slow drug release prodrugs. (c) 2006 Elsevier Ltd. All rights reserved.
- Synthesis and Evaluation of triazene prodrugs as candidate for Melanocyte-Directed Enzyme Prodrug Therapy (MDEPT)Publication . Mendes, Eduarda; Iley, Jim; Moreira, Rui; Perry, MJesus
- The 1,4-naphthoquinone scaffold in the design of cysteine protease inhibitorsPublication . Valente, Claudia; Moreira, Rul; Guedes, Rita C.; Iley, Jim; Jaffar, Mohammed; Douglas, Kenneth T.A series of 1,4-naphthoquinone derivatives diversely substituted at C-2, C-3, C-5 and C-8, prepared by reaction of amines, amino acids and alcohols with commercial 1,4-naphthoquinones, has been evaluated against papain and bovine spleen cathepsin B. These 1,4-naphthoquinone derivatives were found to be irreversible inhibitors for both cysteine proteases, with second-order rate constants, k(2), ranging from 0.67 to 35.4 M-1 s(-1) for papain, and from 0.54 to 8.03 M-1 s(-1) for cathepsin B. Some derivatives display a hyperbolic dependence of the first-order inactivation rate constant, k(obs) with the inhibitor concentration, indicative of a specific interaction process between enzyme and inhibitor. The chemical reactivity of the compounds towards cysteine as a model thiol is dependent on the naphthoquinone LUMO energy, whereas papain inactivation is not. The 1,4-naphthoquinone derivatives are inactive against the serine protease, porcine pancreatic elastase. (c) 2007 Elsevier Ltd. All rights reserved.