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Sökning: WFRF:(Freire Garabal Manuel)

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1.
  • Carbajales, Carlos, et al. (författare)
  • Structure-Based Design of New KSP-Eg5 Inhibitors Assisted by a Targeted Multicomponent Reaction
  • 2014
  • Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 15:10, s. 1471-1480
  • Tidskriftsartikel (refereegranskat)abstract
    • An integrated multidisciplinary approach that combined structure-based drug design, multicomponent reaction synthetic approaches and functional characterization in enzymatic and cell assays led to the discovery of new kinesin spindle protein (KSP) inhibitors with antiproliferative activity. A focused library of new benzimidazoles obtained by a Ugi + Boc removal/cyclization reaction sequence generated low-micromolar-range KSP inhibitors as promising anticancer prototypes. The design and functional studies of the new chemotypes were assessed by computational modeling and molecular biology techniques. The most active compounds-20 (IC50=1.49 mu m, EC50=3.63 mu m) and 22 (IC50=1.37 mu m, EC50=6.90 mu m)-were synthesized with high efficiency by taking advantage of the multicomponent reactions.
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2.
  • Majellaro, María, et al. (författare)
  • 3,4-Dihydropyrimidin-2(1H)-ones as Antagonists of the Human A2B Adenosine Receptor : Optimization, Structure–Activity Relationship Studies, and Enantiospecific Recognition
  • 2021
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:1, s. 458-480
  • Tidskriftsartikel (refereegranskat)abstract
    • We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A2BAR, with a number of potent and selective antagonists further confirmed by functional cyclic adenosine monophosphate experiments. The series was analyzed with one of the most exhaustive free energy perturbation studies on a GPCR, obtaining an accurate model of the structure–activity relationship of this chemotype. The stereospecific binding modeled for this scaffold was confirmed by resolving the two most potent ligands [(±)-47, and (±)-38Ki = 10.20 and 23.6 nM, respectively] into their two enantiomers, isolating the affinity on the corresponding (S)-eutomers (Ki = 6.30 and 11.10 nM, respectively). The assessment of the effect in representative cytochromes (CYP3A4 and CYP2D6) demonstrated insignificant inhibitory activity, while in vitro experiments in three prostate cancer cells demonstrated that this pair of compounds exhibits a pronounced antimetastatic effect.
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  • Resultat 1-2 av 2

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