Mimicking the Nature: Diverse Heterocyclic Peptidomimetics Libraries

VIKTOR KRCHNAK; MIRTA P. MISCHNE; AGUSTINA LA VENIA

La Plata

Workshop; International Workshop on Drug Design and Neglected Tropical Diseases; 2016

Laboratory of Research and Development of Bioactives (LIDeB), Faculty of Exact Sciences, University of La Plata

Title: Mimicking the Nature: Diverse HeterocyclicPeptidomimetics LibrariesAuthors: Agustina La Venia,1 Mirta P. Mischne,1Viktor Krchňák2,31 Instituto de Química Rosario - IQUIR (CONICET),Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional deRosario, Suipacha 531, Rosario, S2002LRK, Argentina2 Department of Organic Chemistry and Institute ofMolecular and Translational Medicine, Palacký University, Tr. 17.listopadu 12,771 46 Olomouc, Czech Republic.3 Departmentof Chemistry and Biochemistry, 251 Nieuwland Science Center, University ofNotre Dame, Notre Dame, IN 46556, USA.Purpose: Design and synthesis of diversefused and bridged ring systems on solid phase using a combinatorial approach toobtained constrained peptidomimetics.1 The synthetic strategiesshould be robust but, stereo-, regio- and chemoselective; as well as compatiblewith peptide synthesis on solid-phase and capable of generating tridimensionalstructures.Methodology: a) Synthetic strategies:Traditional Merrifield solid-phase synthesis of peptide, Tandem iminium ioncyclization - nucleophilic addition, Metal-promoted cyclization. b) Monitoringreactions and compound characterization: IR, NMR, LC/MS. c) Purification ofcompounds: Flash chromatography, HPLC. Results:We have developed a powerful regio- and stereoselective synthetic route onsolid-phase with a common key intermediate Iwhich, via tandem N-acyliminium ioncyclization - nucleophilic addition, leads to structurally diverse fused andbridged heterocyclic molecular scaffolds (IIa-i).2These bicyclic scaffolds were formed by new heteroatom-carbon bonds as well asnew carbon-carbon bonds and provided diversity with respect to the heteroatomsincluded in the heterocyles and the size of the rings. Conclusions:The complex bi-, tri- and tetracyclic molecular scaffolds can mimic variety ofnatural products, providing access to pharmacologically relevant drug-likechemical entities. In addition, these cyclic systems can be incorporated inpeptide backbones to generate constrained peptidomimetics (III). Studies related to their biological activity and theirpotential applications as peptide constraint units are currently in progress,as well as new methodologies applying gold catalysis. References:1.a) J. Vagner, H. Qu, V. J. Hruby, CurrentOpinion in Chemical Biology 2008, 292; b) A. L. Harvey, Drug Discovery today 2008, 894.2.a) A. La-Venia, B.Lemrova, and V. Krchnak, ACS Comb. Sci.,2013, 15 (1), 59; b) A. La-Venia, B. Dolensky, V. Krchňák, ACS Comb. Sci., 2013, 15 (3), 162; c) P. Ventosa-Andres, L. Hradilova, V. Krchnak, ACS Comb. Sci., 2014,16 (7), 359; d) A. La-Venia, P. Ventosa-Andres, L. Hradilova, V. Krchnak, J. Org. Chem., 2014, 79(21), 10378; e) P.Ventosa-Andrés, A. La-Venia, C. A. Barea Ripoll, L. Hradilová,V. Krchňák, Chem. Eur. J., 21 (37), 2015, 13112.