Chemical Approaches to Targeting Cancer

The presentation will regard the efforts of the last years in the fields of the synthesis of anticancer compounds. Two different approaches will be discussed. The first one is based on the use of anticancer natural products as building blocks or as lead compounds.1 Chemical modifications permits the generation of small libraries of new compounds with the aim to find new biological activity, to improve the delivery and to help the understanding of the biological mechanisms.2 For what regards the delivery, preliminary results in the field of the nanoassemblies will be discussed.3 The second approach regards the de novo synthesis of new compounds on the base of isosteric substitutions and scaffold decoration of known totally synthetic anticancer compounds guided by modeling studies.4 The considered biological targets include: Tubulin, Topoisomerases, HDAC, Tyrosine Kinases (cMet, Abl), p53, Sirtuin, Hedgehog. The recent results in the field of “in situ” target guided synthesis will be presented for the case of tubulin5 and Abl tyrosine kinase. The discussion will take into consideration the coordination of two COST network projects regarding the inhibition of Angiogenesis6 and the targeting of drug resistance in Cancer Stem Cells.7 1. For a recent example see: M. S. Christodoulou , F. Zunino, V. Zuco, S. Borrelli, D. Comi, G. Fontana, M. Martinelli, J. Lorens, L. Evensen, M. Sironi, S. Pieraccini, L. Dalla Via, O. M. Gia, D. Passarella “Camptothecin-7-yl-methanthiole: Semisynthesis and Biological Evaluation” ChemMedChem DOI: 10.1002/cmdc.201200322 2. E. Riva, M. Mattarella, S. Borrelli, M. S. Christodoulou, D. Cartelli, M. Main, S. Faulkner, D. Sykes, G. Cappelletti, J. S. Snaith, D. Passarella ”Preparation of Fluorescent Tubulin Binders” ChemPlusChem. Accepted for publication 3. S. Borrelli, F. Dosio, D. Passarella unpublished results 4. For a recent example see: F. Arioli, S. Borrelli, F. Colombo, F. Falchi, I. Filippi, E. Crespan, A. Naldini, G. Scalia, A. Silvani, G. Maga, F. Carraro, M. Botta, D. Passarella “N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine as a Scaffold for the Synthesis of Inhibitors of Bcr-Abl” ChemMedChem 2011, 6, 2009 - 2018 5. For the case of tubulin see: G. Cappelletti, D. Cartelli, B. Peretto, M. Ventura, M. Riccioli, F. Colombo, J. S. Snaith, S. Borrelli, D. Passarella “Tubulin-guided dynamic combinatorial library of thiocolchicine-podophyllotoxin conjugates” Tetrahedron 2011, 67, 7354 – 7357 6. COST Action CM0602 “Inhibitors of Angiogenesis: Design, Synthesis and Biological Exploitation” – www.angiokem.org 7. COST Action CM1106 “Chemical Approaches to Targenting Drug Resistance in Cancer Stem Cells” – www.stemchem.org