Diana Alonso

Synthesis and potential muscarinic receptor binding and antioxidant properties of 3-(thiadiazolyl)pyridine 1-oxide compounds.

The synthesis of two different series of 3‐(thiadiazolyl)pyridine 1‐oxides containing 1,2,5‐ and 1,2,4‐thiadiazole moiety respectively is described. The potential muscarinic receptor binding together with the antioxidant properties of the new compounds were evaluated.

Evidence for a new binding mode to GSK-3: allosteric regulation by the marine compound palinurin.

Glycogen synthase kinase 3β (GSK-3β) is widely recognised as a relevant player in the pathogenesis of several highly prevalent disorders such as Alzheimers disease, mood disorders, diabetes and cancer. Therefore, this enzyme constitutes a highly attractive therapeutic target for the development of selective inhibitors as new promising drugs for the treatment of these pathologies. We describe here the isolation and biochemical characterization of the marine natural sesquiterpene palinurin as a GSK-3β inhibitor. Experimental studies performed for characterizing the inhibitory mechanism indicate that GSK-3β inhibition by palinurin cannot be competed out by ATP nor peptide substrate. Molecular modelling techniques have enabled us to propose an unconventional binding mode to GSK-3β. Moreover, molecular dynamics simulations have identified an allosteric mechanism by which binding of palinurin leads to GSK-3β inhibition. The inhibitory activities determined for a series of structurally related analogues support the proposed binding mode of palinurin, which is the first compound described to target this allosteric site. The results offer new opportunities for designing and developing selective inhibitors with novel mechanisms of action.

Marine compounds for the therapeutic treatment of neurological disorders

The marine environment has proven to be a very rich source of extremely potent compounds that demonstrate significant biological activities. In general, recently published literature reviews organise the marine compound patents phylogenetically. However, this review focuses on the potential of marine natural compounds as a source for new drugs to treat neurological disorders. Patents covering the period 1998 – 2004 are examined and two pathologies arise with success in this area: Alzheimer’s disease and neuropathic pain, which will be the focus of this review.

Effect of Porins and Plasmid-Mediated AmpC beta-Lactamases on the Efficacy of beta-Lactams in Rat Pneumonia Caused by Klebsiella pneumoniae

ABSTRACT The in vivo activities of imipenem, meropenem, and cefepime were studied in a model of rat pneumonia caused by a plasmid-mediated AmpC β-lactamase ACT-1-producing Klebsiella pneumoniae strain (K. pneumoniae strain 12) and a derivative porin-deficient mutant (K. pneumoniae strain 12dp). No differences between these activities were seen with K. pneumoniae 12. Only meropenem showed an activity slightly better than that of imipenem with K. pneumoniae 12dp.

Enzymatic alcoholysis of SO2-uracil analog diacyclonucleosides. Long-distance effect of the substituents on the regioselectivity

Abstract Diacetoxy SO 2 -uracil analog diacyclonucleosides have been deprotected via lipase-mediated alcoholysis. The reactivity and regioselectivity of the reaction are dependent on the steric hindrance of distant 5-substituents, even if they are as small as a methyl or a 4,5-trimethylene chain, and, in a lesser extent, the electronic or hydrogen bond interactions of 3-carbonyl and hydroxyl-chain groups.