Identification of Lead Compounds As Antagonists of Protein Bcl-x(L) with a Diversity-Oriented Multidisciplinary Approach
ABSTRACT We report on the use of a diversity oriented synthesis (DOS) approach that resulted in the generation of a set of libraries of compounds presenting novel structural cores. These chemical cores have been employed to design potential antagonists of the antiapoptotic protein Bcl-x(L) through reiterated steps of molecular docking calculations followed by experimental verification of binding. Our data suggest that the DOS approach is suitable to generate novel scaffolds, which can be employed to target protein-protein interactions.
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ABSTRACT: N6-isopentenyladenosine (i6A), a modified nucleoside belonging to the cytokinin family has shown in human many biological actions, including antitumoral effects through the modulation of the farnesyl pyrophosphate synthase activity. To investigate the relationship between i6A and farnesyl pyrophosphate synthase (FPPS), we undertook an inverse virtual screening computational target searching, testing i6A on a large panel of 3D protein structures involved in cancer processes. Experimentally, we performed an NMR investigation of i6A in the presence of FPPS protein. Both inverse virtual screening and saturation transfer difference (STD) NMR outcomes provided evidence of the structural interaction between i6A and FPPS, pointing to i6A as a valuable lead compound in the search of new ligands endowed with antitumoral potential and targeting FPPS protein.Journal of Medicinal Chemistry 09/2014; · 5.48 Impact Factor
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ABSTRACT: N-Allyl 3-endo-amino-7-oxabicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid has been synthesized and has been employed in a Ugi-5-centre-4-component reaction (U-5C-4CR) with various aldehydes and isocyanides; by employing a mixture of methanol and trifluoroethanol the reaction was completely stereoselective. The resulting products have been employed in an unprecedented ring-opening/ring-closing metathesis process with Ru catalyst, to afford stereochemically defined, polysubstituted cis-fused hexahydrofuro[3,2-b]pyridine derivatives in moderate to good yields. This straightforward procedure allows to assemble in just two synthetic steps natural product-like compounds having the 2-aza-7-oxabicyclo[4.3.0]nonane framework, displayed by various alkaloids.Tetrahedron Letters 11/2012; 53(48):6516–6518. · 2.39 Impact Factor
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ABSTRACT: How can diversity-oriented strategies for chemical synthesis provide chemical tools to help shape our understanding of complex cancer pathways and progress anti-cancer drug discovery efforts? This review (surveying the literature from 2003 to the present) considers the applications of diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS) and associated strategies to cancer biology and drug discovery, summarising the syntheses of novel and often highly complex scaffolds from pluripotent or synthetically versatile building blocks. We highlight the role of diversity-oriented synthetic strategies in producing new chemical tools to interrogate cancer biology pathways through the assembly of relevant libraries and their application to phenotypic and biochemical screens. The use of diversity-oriented strategies to explore structure-activity relationships in more advanced drug discovery projects is discussed. We show how considering appropriate and variable focus in library design has provided a spectrum of DOS approaches relevant at all stages in anti-cancer drug discovery.Molecules 10/2014; 19:17221-17255. · 2.10 Impact Factor