Modeling and Biological Investigations of an Unusual Behavior of Novel Synthesized Acridine‐Based Polyamine Ligands in the Binding of Double Helix and G‐Quadruplex DNA

Three novel 2,7‐substituted acridine derivatives were designed and synthesized to investigate the effect of this functionalization on their interaction with double‐stranded and G‐quadruplex DNA. Detailed investigations of their ability to bind both forms of DNA were carried out by using spectrophotometric, electrophoretic, and computational approaches. The ligands in this study are characterized by an open‐chain (L1) or a macrocyclic (L2, L3) framework. The aliphatic amine groups in the macrocycles are joined by ethylene (L2) or propylene chains (L3). L1 behaved similarly to the lead compound m‐AMSA, efficiently intercalating into dsDNA, but stabilizing G‐quadruplex structures poorly, probably due to the modest stabilization effect exerted by its protonated polyamine chains. L2 and L3, containing small polyamine macrocyclic frameworks, are known to adopt a rather bent and rigid conformation; thus they are generally expected to be sterically impeded from recognizing dsDNA according to an intercalative binding mode. This was confirmed to be true for L3. Nevertheless, we show that L2 can give rise to efficient π–π and H‐bonding interactions with dsDNA. Additionally, stacking interactions allowed L2 to stabilize the G‐quadruplex structure: using the human telomeric sequence, we observed the preferential induction of tetrameric G‐quadruplex forms. Thus, the presence of short ethylene spacers seems to be essential for obtaining a correct match between the binding sites of L2 and the nucleobases on both DNA forms investigated. Furthermore, current modeling methodologies, including docking and MD simulations and free energy calculations, provide structural evidence of an interaction mode for L2 that is different from that of L3; this could explain the unusual stabilizing ability of the ligands (L2>L3>L1) toward G‐quadruplex that was observed in this study.

[1]  C. Giorgi,et al.  Exploring the binding ability of phenanthroline-based polyammonium receptors for anions: hints for design of selective chemosensors for nucleotides. , 2009, The Journal of organic chemistry.

[2]  C. Sangregorio,et al.  Cu(ii) complexation with an acridine-containing macrocycle. Assembly of water cluster chains within the cavity of tetranuclear metallomacrocycles. , 2009, Dalton transactions.

[3]  A. J. Blake,et al.  Interaction of mixed-donor macrocycles containing the 1,10-phenanthroline subunit with selected transition and post-transition metal ions: metal ion recognition in competitive liquid-liquid solvent extraction of Cu(II), Zn(II), Pb(II), Cd(II), Ag(I), and Hg(II). , 2008, Inorganic chemistry.

[4]  Danzhou Yang,et al.  Polymorphism of human telomeric quadruplex structures. , 2008, Biochimie.

[5]  Stephen Neidle,et al.  Structural basis of DNA quadruplex recognition by an acridine drug. , 2008, Journal of the American Chemical Society.

[6]  C. Macrae,et al.  Mercury CSD 2.0 – new features for the visualization and investigation of crystal structures , 2008 .

[7]  Julie E Reed,et al.  Stabilisation of human telomeric quadruplex DNA and inhibition of telomerase by a platinum-phenanthroline complex. , 2007, Chemical communications.

[8]  J. Mergny,et al.  G‐Quadruplex Recognition by Quinacridines: a SAR, NMR, and Biological Study , 2007, ChemMedChem.

[9]  M. Drew,et al.  Evaluation of the binding ability of a novel dioxatetraazamacrocyclic receptor that contains two phenanthroline units: selective uptake of carboxylate anions. , 2007, The Journal of organic chemistry.

[10]  S. Neidle,et al.  Structure-based design of benzylamino-acridine compounds as G-quadruplex DNA telomere targeting agents. , 2007, Bioorganic & medicinal chemistry letters.

[11]  G. Parkinson,et al.  Structural basis for binding of porphyrin to human telomeres. , 2007, Biochemistry.

[12]  C. Lodeiro,et al.  Basicity and coordination properties of a new phenanthroline-based bis-macrocyclic receptor. , 2006, Dalton transactions.

[13]  G. Parkinson,et al.  Predictive modelling of topology and loop variations in dimeric DNA quadruplex structures , 2006, Nucleic acids research.

[14]  C. Renner,et al.  Neomycin-capped aromatic platforms: quadruplex DNA recognition and telomerase inhibition. , 2006, Organic & biomolecular chemistry.

[15]  James M. Morrell,et al.  Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding. , 2004, Bioorganic & medicinal chemistry letters.

[16]  B. Guyen,et al.  Synthesis, biophysical and biological evaluation of 3,6-bis-amidoacridines with extended 9-anilino substituents as potent G-quadruplex-binding telomerase inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[17]  Wei Zhang,et al.  A point‐charge force field for molecular mechanics simulations of proteins based on condensed‐phase quantum mechanical calculations , 2003, J. Comput. Chem..

[18]  James M. Morrell,et al.  Trisubstituted acridine derivatives as potent and selective telomerase inhibitors. , 2003, Journal of medicinal chemistry.

[19]  S. Neidle,et al.  A G-quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. , 2002, Molecular pharmacology.

[20]  Gary Parkinson,et al.  Telomere maintenance as a target for anticancer drug discovery , 2002, Nature Reviews Drug Discovery.

[21]  Laurence H. Hurley,et al.  DNA and its associated processes as targets for cancer therapy , 2002, Nature Reviews Cancer.

[22]  J. Chaires,et al.  Interaction of an Acridine Dimer with DNA Quadruplex Structures , 2001, Journal of biomolecular structure & dynamics.

[23]  Nathan A. Baker,et al.  Electrostatics of nanosystems: Application to microtubules and the ribosome , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Carol W. Greider,et al.  Telomere Dysfunction Increases Mutation Rate and Genomic Instability , 2001, Cell.

[25]  A. Masotti,et al.  Protonation and Zn(II) coordination by dipyridine-containing macrocycles with different molecular architecture. A case of pH-controlled metal jumping outside-inside the macrocyclic cavity. , 2001, Inorganic chemistry.

[26]  Stephen Neidle,et al.  Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  S Neidle,et al.  Molecular modeling studies on G-quadruplex complexes of telomerase inhibitors: structure-activity relationships. , 1999, Journal of medicinal chemistry.

[28]  S. Neidle,et al.  Human telomerase inhibition by substituted acridine derivatives. , 1999, Bioorganic & medicinal chemistry letters.

[29]  N. Maizels,et al.  The Saccharomyces cerevisiae Sgs1 helicase efficiently unwinds G-G paired DNAs. , 1999, Nucleic acids research.

[30]  P. Gans,et al.  Hyperquad simulation and speciation (HySS): a utility program for the investigation of equilibria involving soluble and partially soluble species , 1999 .

[31]  Jean-Louis Mergny,et al.  G-quadruplex DNA: A target for drug design , 1998, Nature Medicine.

[32]  N. Maizels,et al.  The Bloom’s Syndrome Helicase Unwinds G4 DNA* , 1998, The Journal of Biological Chemistry.

[33]  C. Harley,et al.  Extension of life-span by introduction of telomerase into normal human cells. , 1998, Science.

[34]  Nam W. Kim,et al.  Advances in quantification and characterization of telomerase activity by the telomeric repeat amplification protocol (TRAP) , 1997, Nucleic Acids Res..

[35]  P. Gans,et al.  Investigation of equilibria in solution. Determination of equilibrium constants with the HYPERQUAD suite of programs. , 1996, Talanta.

[36]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[37]  T. Darden,et al.  A smooth particle mesh Ewald method , 1995 .

[38]  C B Harley,et al.  Specific association of human telomerase activity with immortal cells and cancer. , 1994, Science.

[39]  K. Sharp,et al.  Accurate Calculation of Hydration Free Energies Using Macroscopic Solvent Models , 1994 .

[40]  P. Kollman,et al.  A well-behaved electrostatic potential-based method using charge restraints for deriving atomic char , 1993 .

[41]  C B Harley,et al.  Telomere loss: mitotic clock or genetic time bomb? , 1991, Mutation research.

[42]  D. Case,et al.  Langevin modes of macromolecules: Applications to crambin and DNA hexamers , 1990, Biopolymers.

[43]  C. Harley,et al.  Telomeres shorten during ageing of human fibroblasts , 1990, Nature.

[44]  G. Morin.  The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats , 1989, Cell.

[45]  Y. Pommier,et al.  DNA unwinding and inhibition of mouse leukemia L1210 DNA topoisomerase I by intercalators. , 1987, Nucleic acids research.

[46]  A. Bianchi,et al.  Solution chemistry of macrocycles. 5. Synthesis and ligational behavior toward hydrogen and copper(II) ions of the large polyazacycloalkane 1,4,7,10,13,16,19,22,25-nonaazacycloheptacosane ([27]aneN9) , 1987 .

[47]  Carol W. Greider,et al.  Identification of a specific telomere terminal transferase activity in tetrahymena extracts , 1985, Cell.

[48]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[49]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[50]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[51]  P. V. von Hippel,et al.  Theoretical aspects of DNA-protein interactions: co-operative and non-co-operative binding of large ligands to a one-dimensional homogeneous lattice. , 1974, Journal of molecular biology.

[52]  Jean-Louis Mergny,et al.  Targeting telomeres and telomerase. , 2008, Biochimie.

[53]  L. Hurley,et al.  Targeting telomeres and telomerase. , 2001, Methods in enzymology.

[54]  D. Crothers,et al.  Simultaneous measurement of binding constants and unwinding angles by gel electrophoresis. , 2001, Methods in enzymology.

[55]  A. Masotti,et al.  Phenanthroline-containing macrocycles as multifunctional receptors for nucleotide anions. A thermodynamic and NMR study† , 1999 .

[56]  H M Berman,et al.  The interaction of intercalating drugs with nucleic acids. , 1981, Annual review of biophysics and bioengineering.

[57]  S. Neidle.  The molecular basis for the action of some DNA-binding drugs. , 1979, Progress in medicinal chemistry.

[58]  M. Paabo,et al.  Use of the glass electrode in deuterium oxide and the relation between the standardized pD (paD) scale and the operational pH in heavy water , 1968 .