Synthesis of 1,2,3-triazolo fused natural product derivatives with anticancer and antiviral activity

Techniques to be learned : organic (semi)synthesis, multicomponent synthesis and characterisation (NMR, MS, IR, UV, etc..). HPLC separations, advanced NMR characterisation techniques In the laboratory of Organic synthesis at the Department of Chemistry in KU Leuven, several abundant natural products with known biological activities are being modified to heterocyclic analogs with the aim of improving the biological properties. The Ph D student of the current project will be asked to prepare a library of derivatives of such analogies using the most logical points of modification. The biological activities are screened in collaboration with the Department of Pharmacy, the Rega Institute or other groups at KU Leuven. Novel multicomponent reactions involving appropriately functionalized natural products as starting materials are the methodology of choice to lead to a fast acquisition of a collection of compounds. In particular we will use the several 1,2,3-triazole forming reactions we have discovered recently. The structures below (combretastatin, colchicine, betulinic acid) represent some of the lead structures that are used in the projects that are running currently in the laboratory and around which the research will center. Biological properties that we are aiming to enhance are anticancer/antitumor activities involving the inhibition of tubulin polymerization. One of the issues is the enhancement of the therapeutic window of the compounds. The copromotor of this project is therefore Prof Sandra Liekens (KU Leuven, Laboratory of Virology and Chemotherapy). The properties of the compounds will be investigated in her laboratory, and the feedback we receive will guide us in further synthesis. The results from this project will, when appropriate, be protected under the form of patent applications and then published at international conferences and in internationally reknown journals. Combretastatin Colchicine betulinic acid (For intellectual property reasons, no new structures are shown or further details can be given) References on recent work on natural products W. Dehaen, A. A. Mashentseva, T. S. Seitembetov "Allobetulin and its Derivatives: Synthesis and Biological Activity " Molecules 2011, 16, 2443-2466. N. Moons, W. De Borggraeve, W. Dehaen, "Isosteviol as a starting material in organic synthesis" Curr. Org. Chem. 2011, 15, 2731-2741 D. M. Gonzalez Mosquera, Y. H. Ortega, A. Kilonda, W. Dehaen, L. Pieters, S. Apers, "Evaluation of the in vivo anti-inflammatory activity of a flavonoid glycoside from Boldoa purpurascens" Phytochem. Lett. 2011, 4, 231-234. J. Alen, B. Ngan Truong, V. H. Hung, W. Dehaen, "Synthesis, reactions, and biological activity of 11-azaartemisinin and derivatives" ARKIVOC 2011, 346-369. A. A. Mashentseva, W. Dehaen, T. S. Seitembeitov, A. J. Seitembova, "Comparison of the antioxidant activity of the different Betula pendula Roth. Extracts from northern Kazakhstan", J. Phytol. 2011, 3, 18-25. N. Moons, W. De Borggraeve, W. Dehaen, "Stevioside and steviol as a starting materials in organic synthesis" Curr. Org. Chem. 2012, 16, 1986-1995. N. Moons, D. Goyens, J. Jacobs, L. Van Meervelt, W. De Borggraeve, W. Dehaen, "Fused derivatives of (iso)steviol via pericyclic reactions", Tetrahedron Lett. 2012, 53, 6806-6809 D. M. González Mosquera,Y. Hernandez Ortega, B. By, L. Vicet Muro, Y. Saucedo Hernandez, R. Grau Ábalos, W. Dehaen, L. Pieters, S. Apers, "Antihyperglycemic Activity of Extracts from Boldoa purpurascens Leaves in Alloxan-Induced Diabetic Rats ", Phytochem. Res. 2013, 27, 721-724 A. M. Orellana-Paucar, T. Afrikanova, J. Thomas, Y. K. Aibuldinov, W. Dehaen, P. A. M. de Witte, Camila V. Esguerra, "Insights from Zebrafish and Mouse Models on the Activity and Safety of Ar-Turmerone as a Potential Drug Candidate for the Treatment of Epilepsy" PLOS one, 2013, 8, e81634, 1-14. S. Obeid, J. Alen, N.V. Nguyen, C. P. Van, P. Meuleman, C. Pannecouque, T. N. Le, J. Neyts, W. Dehaen, J. Paeshuyse, "Artemisinin analogues as potent inhibitors of in vitro hepatitis C virus replication" PLOS one, 2013, 8 e81783, 1-6. T.D. Ngoc, W. Dehaen, N. Moons, Y. Kim, W ; De Borggraeve, A. Mashentseva, G. Andrei, R. Snoeck, J. Balzarini, W. Dehaen, " Synthesis of triterpenoid triazine derivatives of allobetulone and betulonic acid with biological activities" Bioorg. Med. Chem. 2014, 22, 3292-3300. T.D. Ngoc, W. Dehaen, "Selective functionalization of 2-oxoallobetulin" Tetrahedron 2014, 70, 1836-1840.status: publishe