Seminars 2014

Title:Small Molecules for Targeting Nucleic Acid Structures From Chemical Biology tools to Drug Discovery
Speaker:Dr Marie-Paule Teulade-Fichou
Date:9 January 2014 
Time:2.30pm to 4.00pm 
Venue: NTU SPMS CBC Building Level 2, Conference Room
Host:Associate Professor Phan Anh Tuan 

For many years our research efforts have been focused on the design of structure and fluorescence probes for nucleic acids. Our targets are more specifically alternative secondary structures such as G-quadruplexes that can be found in G-rich regions. These structures are involved in various genomic dysfunctions and may ultimately cause genetic instability related to cancer development. Our aim is to provide chemical biology tools for a better understanding of the roles of these structures and of their processing by proteins.[1-2] In parallel quadruplextargeted compounds may be considered as prototypes for anticancer drug development. A large number of compounds have been developed to target quadruplexes but few display the required criteria of high affinity and high selectivity. [2-3] In addition the current challenge is to design compounds able to discriminate between various quadruplexes originating from different genomic domains in order to correlate phenotypic effects with quadruplex formation at a given site.[4] We will detail recent data on bifunctional ligands able to both recognize quadruplexes and to establish covalent or quasi-covalent bonding inside their binding pocket via photoinduced alkylation or metal coordination to heterocyclic bases.[5-6] These functional systems represent tools for trapping quadruplex structures in cells and thus offer supplementary advantages with regard to the currently available quadruplex binders that operate via a reversible non covalent process. We will give a short overview of the synthetic approaches of these two classes of hybrid compounds; their in vitro DNA bindingbehaviour and their cellular effects.

References: . [1] a) A. Piazza et al. Genetic instability triggered by G-quadruplex interacting Phen-DC compounds in Saccharomyces cerevisiae Nucleic Acid Res 2010, 38,4337-4348 b) J. Lopez et al. G-quadruplex-induced instability during leading strand replication EMBO J. 2011, 30, 4033 – 4046. [2] D. Monchaud et al; A Hitchiker guide to G-quadruplex ligands, Org.Biomol.Chem. 2008,6, 627-636 [3] a) De Cian et al Highly efficient Bisquinolinum compounds for quadruplex recognition J.Amer. Chem.Soc. 2007, 129, 1856. b) W.J Chung et al. Solution structure of a G- quadruplex bound to the Bisquinolium compound Phe nDC3. Angew.Chem. Int.Ed. 2013 in press. [4] F.Hamon et al. An acyclic oligoheteroaryle that discriminates strongly between diverse G-quadruplex topologies, Angew. Chem. Int.Ed. 2011, 50, 8745 –8749. [5] D.Verga et al. Photocrosslinking Probes for Trapping G-Quadruplex DNA Angew.Chem.Int.Ed. 2013 in Press. [6] H. Bertrand et al. S, Exclusive platination of loop adenine Org. Biomol. Chem. 2009, 7, 2864-2871. E.Largy et al. Tridentate N-donor Palladium (II) Complexes as Efficient Coordinating Quadruplex-DNA binders Chem.Eur.J.2011, 17,13274-13283.