Pedro Besada

Instituto de Investigación Biomédica de A Coruña, La Corogne, Galicia, Spain

Are you Pedro Besada?

Claim your profile

Publications (42)100.19 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: New series of pyridazinone derivatives (4, 5 and 6) were synthesized in good yields following a synthetic strategy based on singlet oxygen oxidation of alkyl furans, in which a suitable β(α)-substituted γ-hydroxybutenolide (10 or 11) or a bicyclic lactone (12 or 13) was the key intermediate. The synthesized compounds were tested in vitro as antiplatelet agents and some of them (compounds 4b, 4d and 5b) exhibited potent inhibitory effects on collagen-induced platelet aggregation with IC50 values in the low μM range. Studies performed with the most active compound of these series (4b) demonstrated its lack of activity as inhibitor of platelet aggregation induced by other agonists as thrombin, ionomycin or U-46619 suggesting a selective action on the biochemical mechanisms triggered by collagen in the platelets. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 03/2015; 94:113-122. DOI:10.1016/j.ejmech.2015.02.061 · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Phthalazinones are an important kind of nitrogen atom containing heterocyclic compounds due to their synthetic and pharmacological versatility. This fused heterocycle system represents a common structural feature for many bioactive compounds showing a variety of pharmacological activities such as anticancer, anti-diabetic, anti-asthmatic, antihistaminic, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant or antimicrobial agents, which makes it an attractive scaffold for the design and development of new drugs. This review summarizes detailed and updated information, described in recent non-patent literature, about the most relevant pharmacological properties of phthalazinone derivatives, highlighting the application of this potent pharmacophore in drug discovery. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 11/2014; DOI:10.1016/j.ejmech.2014.11.043 · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the title compound, C21H24N2O2Si, the carbonyl group of the heterocyclic ring and the O atom of the silyl ether group are placed toward opposite sides and the tert-butyl and pyridazinone moieties are anti-oriented across the Si—O bond [torsion angle = −168.44 (19)°]. In the crystal, mol­ecules are assembled into inversion dimers through co-operative N—H⋯O hydrogen bonds between the NH groups and O atoms of the pyridazinone rings of neighbouring mol­ecules. The dimers are linked by π–π inter­actions involving adjacent pyridazinone rings [centroid–centroid distance = 3.8095 (19) Å], generating ladder-like chains along the b-axis direction. The chains are further linked into a two-dimensional network parallel to the ab plane through weak C—H⋯π inter­actions.
    Acta Crystallographica Section E Structure Reports Online 11/2013; 69(12). DOI:10.1107/S1600536813032212 · 0.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The title N-benzyl-phthalimide derivative, C16H13NO3, consists of two planar moieties, viz. the phthalimide system (r.m.s. deviation = 0.007 Å) and the phenyl ring, which make a dihedral angle of 84.7 (6)°. The meth-oxy group is almost coplanar with the phathalimide ring, as shown by the C-C-O-C torsion angle of -171.5 (2)°. In the crystal, the mol-ecules are self-assembled via non-classical C-H⋯O hydrogen bonds, forming a tape motif along [110].
    Acta Crystallographica Section E Structure Reports Online 01/2013; 69(Pt 10):o1594-o1595. DOI:10.1107/S160053681302638X · 0.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A total synthesis of a Greek tobacco lactonic natural product and three of its analogues has been achieved using a commercially available starting material and our furan approach to oxacyclic systems, the proven scope of which is thus broadened.
    Tetrahedron Letters 08/2012; 53(33):4293–4295. DOI:10.1016/j.tetlet.2012.05.151 · 2.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Several pyridazin-3(2H)-one derivatives were synthesized starting from alkyl furans using oxidation with singlet oxygen to give 4-methoxy or 4-hydroxybutenolides, key intermediates of the synthetic strategy followed. For all pyridazinones reported, a complete assignment of the (1)H and (13)C NMR spectra using one- and two-dimensional NMR spectroscopic methods, which included NOE, DEPT, COSY, HSQC and HMBC experiments, was accomplished. Correlations between the chemical shifts of the heterocyclic ring atoms and substituents at N-2 and C-6 were analyzed.
    Magnetic Resonance in Chemistry 07/2011; 49(7):437-42. DOI:10.1002/mrc.2755 · 1.56 Impact Factor
  • ChemInform 12/2010; 32(49). DOI:10.1002/chin.200149233
  • [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 10/2010; 30(42). DOI:10.1002/chin.199942247
  • [Show abstract] [Hide abstract]
    ABSTRACT: New 6-substituted and 2,6-disubstituted pyridazinone derivatives were obtained starting from easily accessible alkyl furans by using oxidation with singlet oxygen to give 4-methoxy or 4-hydroxybutenolides, key intermediates of this synthetic strategy. The new pyridazinone derivatives have been studied as vasorelaxant and antiplatelet agents. Analysis of biological data revealed the silyl ethers (4a-i) and N,O-dibenzyl derivatives (6g-i) as the most active compounds.
    Bioorganic & medicinal chemistry letters 09/2010; 20(22):6624-7. DOI:10.1016/j.bmcl.2010.09.031 · 2.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Several new purine nucleosides derivatives of allofuranose were prepared according to Vorbrüggen method, starting from 1,2,5,6-di-O-isopropylidene-α-D-allofuranose and using 1,2,3,5,6-pentaacetoxy-β-D-allofuranose as key intermediate. The synthesized allofuranosyl nucleosides, as well as some acetyl derivatives, were evaluated for their cytotoxicity in vitro in three human cancer cell lines (MCF-7, Hela-229 and HL-60). Among the studied compounds the 9-(2,3,5,6-tetra-O-acetyl-β-D-allofuranosyl)-2,6-dichloropurine (9) was the most potent one on the three cell lines evaluated, being its activity against HL-60 cells similar to cisplatin.
    European Journal of Medicinal Chemistry 09/2010; 45(12):6114-9. DOI:10.1016/j.ejmech.2010.09.046 · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: New tetrahydropyran isonucleoside derivatives of purine, with cis or trans configuration, were stereoselectively synthesized in moderate yield by a convergent strategy based on Mitsunobu coupling. The key starting material was a bicyclic lactone.
    Synthesis 02/2010; 3(3):425-430. DOI:10.1055/s-0029-1217142 · 2.44 Impact Factor
  • Pedro Besada, Tamara Costas, Carmen Terán
    [Show abstract] [Hide abstract]
    ABSTRACT: (1)H and (13)C NMR chemical shifts of cis and trans isonucleoside analogues of purine in which the furanose moiety is substituted by a tetrahydropyran ring were completely assigned using one- and two-dimensional NMR experiments that include NOE, DEPT, COSY and HSQC. The significant (1)H and (13)C NMR signals differentiating between the cis and trans stereoisomers were compared.
    Magnetic Resonance in Chemistry 01/2010; 48(6):483-5. DOI:10.1002/mrc.2589 · 1.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We describe an efficient new approach for the synthesis of highly substituted chiral tetrahydrothiophenes, based on the oxidation of a chiral furan substrate with singlet oxygen, followed by intramolecular hetero Michael addition.
    Tetrahedron Letters 12/2009; 50(50):6941–6943. DOI:10.1016/j.tetlet.2009.09.104 · 2.39 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of the study was to determine whether novel, selective antagonists of human A3 adenosine receptors (ARs) derived from the A3-selective agonist Cl-IB-MECA lower intraocular pressure (IOP) and act across species. IOP was measured invasively with a micropipette by the Servo-Null Micropipette System (SNMS) and by non-invasive pneumotonometry during topical drug application. Antagonist efficacy was also assayed by measuring inhibition of adenosine-triggered shrinkage of native bovine nonpigmented ciliary epithelial (NPE) cells. Five agonist-based A3AR antagonists lowered mouse IOP measured with SNMS tonometry by 3-5 mm Hg within minutes of topical application. Of the five agonist derivatives, LJ 1251 was the only antagonist to lower IOP measured by pneumotonometry. No effect was detected pneumotonometrically over 30 min following application of the other four compounds, consonant with slower, smaller responses previously measured non-invasively following topical application of A3AR agonists and the dihydropyridine A3AR antagonist MRS 1191. Latanoprost similarly lowered SNMS-measured IOP, but not IOP measured non-invasively over 30 min. Like MRS 1191, agonist-based A3AR antagonists applied to native bovine NPE cells inhibited adenosine-triggered shrinkage. In summary, the results indicate that antagonists of human A3ARs derived from the potent, selective A3 agonist Cl-IB-MECA display efficacy in mouse and bovine cells, as well. When intraocular delivery was enhanced by measuring mouse IOP invasively, five derivatives of the A3AR agonist Cl-IB-MECA lowered IOP but only one rapidly reduced IOP measured non-invasively after topical application. We conclude that derivatives of the highly-selective A3AR agonist Cl-IB-MECA can reduce IOP upon reaching their intraocular target, and that nucleoside-based derivatives are promising A3 antagonists for study in multiple animal models.
    Experimental Eye Research 10/2009; 90(1):146-54. DOI:10.1016/j.exer.2009.10.001 · 3.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformationally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed.
    Purinergic Signalling in Neuron-Glia Interactions: Novartis Foundation Symposium 276, 10/2008: pages 58 - 72; , ISBN: 9780470032244
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Activation of the G(q)-coupled P2Y(6) receptor heterologously expressed in astrocytes significantly attenuates apoptosis induced by tumor necrosis factor alpha (TNFalpha). We have extended the analysis of P2Y(6) receptor-induced cytoprotection to mouse skeletal muscle cells endogenously expressing this receptor. The endogenous P2Y(6) receptor agonist UDP and synthetic agonist MRS2693 protected C2C12 skeletal muscle cells against apoptosis in a concentration-dependent manner (0.1-10 nM) as determined by propidium iodide staining, histochemical analysis using hematoxylin and Hoechst 33258, and DNA fragmentation. The insurmountable P2Y(6) receptor antagonist MRS2578 blocked the protection. TNFalpha-induced apoptosis in C2C12 cells correlated with activation of the transcription factor NF-kappaB. The NF-kappaB activation was attenuated by 10nM MRS2693, which activated the antiapoptic ERK1/2 pathway. In an in vivo mouse hindlimb model, MRS2693 protected against skeletal muscle ischemia/reperfusion injury. The P2Y(6) receptor is a novel cytoprotective receptor that deserves further exploration in ameliorating skeletal muscle injury.
    Pharmacological Research 09/2008; 58(3-4):232-9. DOI:10.1016/j.phrs.2008.08.004 · 3.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The synthesis of phosphonate 1.2-disubstituted carbocyclic nucleosides with a cyclopentane ring is described following two different strategies: inclusion of the phosphonomethyl group before or after coupling of the carbocyclic moiety with the heterocyclic base. The diethyl [(trifluoromethanesulfonyl)oxy]methanephosphonate is the key phosphonylating agent for both the strategies.
    Synthesis 08/2008; 2008(15):2363-2368. DOI:10.1055/s-2008-1067166 · 2.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modification, found previously to enhance P2Y(2) receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y(2) receptor, in the form of Up(4)-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, alpha,beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1]glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P(1)-(uridine-5')-P(4)-(2'-deoxycytidine-5')tetraphosphate), a potent and selective P2Y(2) receptor agonist.
    Bioorganic & medicinal chemistry 07/2008; 16(12):6319-32. DOI:10.1016/j.bmc.2008.05.013 · 2.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have prepared a caged form (MRS2703) of a potent dual agonist of the P2Y(1) and P2Y(12) nucleotide receptors, 2-MeSADP, by blocking the beta-phosphate group with a 1-(3,4-dimethyloxyphenyl)eth-1-yl phosphoester. Although MRS2703 is itself inactive at human P2Y(1) and P2Y(12) receptors expressed heterologously in 1321N1 astrocytoma cells or in washed human platelets, this derivative readily regenerates the parent agonist upon mild irradiation with long-wave UV light (360 nm). The functional effect of the regenerated agonist was demonstrated by a rise in intracellular calcium mediated by either P2Y(1) or P2Y(12) receptors in transfected cells. Washed human platelets exposed to a solution of MRS2703 were induced to aggregate upon UV irradiation. At 1.0 microM MRS2703, full aggregation was achieved within 1 min of irradiation. Thus, this caged nucleotide promises to be a useful probe for potent P2Y receptor activation with light-directed spatial and temporal control.
    Biochemical pharmacology 04/2008; 75(6):1341-7. DOI:10.1016/j.bcp.2007.10.037 · 4.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Combined discriminant and regression analysis was carried out on a series of 167 A1 adenosine receptor agonists to identify the best linear and nonlinear models for the design of new compounds with a better biological profile. On the basis of the best linear discriminant analysis and both linear and nonlinear Multi Layer Perceptron neural networks regression, we have designed and synthesized 14 carbonucleoside analogues of adenosine. Their biological activities were predicted and experimentally measured to demonstrate the capability of our model to avoid the prediction of false positives. A good agreement was found between the calculated and observed biological activity.
    Bioorganic & medicinal chemistry 03/2008; 16(4):1658-75. DOI:10.1016/j.bmc.2007.11.026 · 2.82 Impact Factor

Publication Stats

415 Citations
100.19 Total Impact Points

Institutions

  • 2015
    • Instituto de Investigación Biomédica de A Coruña
      La Corogne, Galicia, Spain
  • 1999–2014
    • University of Vigo
      • Department of Organic Chemistry
      Vigo, Galicia, Spain
  • 2004–2009
    • National Institutes of Health
      • Laboratory of Bioorganic Chemistry (LBC)
      Maryland, United States
  • 2006–2008
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States