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 
Abstract: 

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.