Biopolym. Cell. 2018; 34(5):387-399.
http://dx.doi.org/10.7124/bc.00098B
Bioorganic Chemistry
Interaction of cationic porphyrin-imidazophenazine conjugates with DNA quadruplex: FID assay and quantum-chemical modeling
1, 2Didan Yu. V., 1Ilchenko M. M., 1Negrutska V. V., 1Dubey L. V., 3Ryazanova O. A., 1Dubey I. Ya.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143
  2. Delft University of Technology
    9 van der Maasweg, Delft 2629HZ, Netherlands
  3. B. I. Verkin Institute for Low Temperature Physics and Engineering, NAS of Ukraine
    47, Prospekt Nauky, Kharkiv, Ukraine, 61103

Abstract

Aim. To study the efficiency of tricationic porphyrin–imidazo[4,5-b]phenazine conjugate and its Zn(II) and Mn(III) complexes as G-quadruplex (G4) DNA ligands. Methods. FID (Fluorescent Intercalator Displacement) assay was used to evaluate the affinity of compounds for a model duplex and Tel22 quadruplex DNA at various ionic strengths. Molecular modeling of the conjugate interaction with G4 DNA was performed using the Density Functional Theory (DFT) calculations with M06-2X functional and 6-31G(d) basis set. Guanine octet stabilized with K+ ion was used as a G4 model. Results. DC50 values and dissociation constants were determined for the complexes of three conjugates with duplex and quadruplex DNA. The structures and energetic parameters of G-octet complexes with Zn-metalated conjugate were obtained. Conclusions. All complexes have a strong affinity to the Tel22 quadruplex. The increase of ionic strength results in an increase in selectivity for quadruplex over duplex DNA and the decrease of binding affinity of the ligands. The structure of ligand–G4 complexes is determined by stacking interaction of porphyrin fragment with G-quartet, rather than an intercalative binging of the ligand.
Keywords: G-quadruplex, ligands, porphyrins, imidazophenazine, FID, DFT
Full text: (PDF, in English)

References

[1] Burge S, Parkinson GN, Hazel P, Todd AK, Neidle S. Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res. 2006;34(19):5402-15.
[2] Xu Y. Chemistry in human telomere biology: structure, function and targeting of telomere DNA/RNA. Chem Soc Rev. 2011;40(5):2719-40.
[3] Ruden M, Puri N. Novel anticancer therapeutics targeting telomerase. Cancer Treat Rev. 2013;39(5):444-56.
[4] Crees Z, Girard J, Rios Z, Botting GM, Harrington K, Shearrow C, Wojdyla L, Stone AL, Uppada SB, Devito JT, Puri N. Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy. Curr Pharm Des. 2014;20(41):6422-37.
[5] Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266(5193):2011-5.
[6] Sekaran V, Soares J, Jarstfer MB. Telomere maintenance as a target for drug discovery. J Med Chem. 2014;57(3):521-38.
[7] Maji B, Bhattacharya S. Advances in the molecular design of potential anticancer agents via targeting of human telomeric DNA. Chem Commun (Camb). 2014;50(49):6422-38.
[8] Neidle S. Quadruplex nucleic acids as targets for anticancer therapeutics. Nat Rev Chem. 2017; 1(5):0041.
[9] Islam MK, Jackson PJ, Rahman KM, Thurston DE. Recent advances in targeting the telomeric G-quadruplex DNA sequence with small molecules as a strategy for anticancer therapies. Future Med Chem. 2016;8(11):1259-90.
[10] Rigo R, Palumbo M, Sissi C. G-quadruplexes in human promoters: A challenge for therapeutic applications. Biochim Biophys Acta Gen Subj. 2017;1861(5 Pt B):1399-1413.
[11] Cammas A, Millevoi S. RNA G-quadruplexes: emerging mechanisms in disease. Nucleic Acids Res. 2017;45(4):1584-1595.
[12] Rhodes D, Lipps HJ. G-quadruplexes and their regulatory roles in biology. Nucleic Acids Res. 2015;43(18):8627-37.
[13] Hänsel-Hertsch R, Di Antonio M, Balasubramanian S. DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential. Nat Rev Mol Cell Biol. 2017;18(5):279-284.
[14] Hasegawa D, Okabe S, Okamoto K, Nakano I, Shin-ya K, Seimiya H. G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells. Biochem Biophys Res Commun. 2016;471(1):75-81.
[15] Moruno-Manchon JF, Koellhoffer EC, Gopakumar J, Hambarde S, Kim N, McCullough LD, Tsvetkov AS. The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons. Aging (Albany NY). 2017;9(9):1957-1970.
[16] Monchaud D, Teulade-Fichou MP. A hitchhiker's guide to G-quadruplex ligands. Org Biomol Chem. 2008;6(4):627-36.
[17] Wheelhouse RT, Sun D, Han H, Han FX, Hurley LH. Cationic porphyrins as telomerase inhibitors: the interaction of tetra-(N-methyl-4-pyridyl)porphine with quadruplex DNA. J Am Chem Soc. 1998; 120(13):3261-62.
[18] Han H, Langley DR, Rangan A, Hurley LH. Selective interactions of cationic porphyrins with G-quadruplex structures. J Am Chem Soc. 2001;123(37):8902-13.
[19] Mestre B, Pratviel G, Meunier B. Preparation and nuclease activity of hybrid "metallotris(methylpyridinium)porphyrin oligonucleotide" molecules having a 3'-loop for protection against 3'-exonucleases. Bioconjugate Chem. 1995; 6(4):466-72.
[20] Mezo G, Herényi L, Habdas J, Majer Z, Myśliwa-Kurdziel B, Tóth K, Csík G. Syntheses and DNA binding of new cationic porphyrin-tetrapeptide conjugates. Biophys Chem. 2011;155(1):36-44.
[21] Dixon IM, Lopez F, Estève JP, Tejera AM, Blasco MA, Pratviel G, Meunier B. Porphyrin derivatives for telomere binding and telomerase inhibition. Chembiochem. 2005;6(1):123-32.
[22] Zhao P, Hu L-C, Huang J-W, Fu D, Yu H-C, Ji L-N. Cationic porphyrin-anthraquinone dyads: modes of interaction with G-quadruplex DNA. Dyes Pigments 2009; 83(1):81-7.
[23] Dubey LV, Ilchenko MM, Zozulya VN, Ryazanova OA, Pogrebnoy PV, Dubey IYa. Synthesis, structure and antiproliferative activity of cationic porphyrin-imidazophenazine conjugate. Int Rev Biophys Chem. 2011; 2(4):147-52.
[24] Blagoi YuP, Zozulya VN, Voloshin IM, Makitruk VL, Shalamay AS, Shcherbakova AS. Investigation of phenazine derivatives interaction with DNA by polarized fluorescence method. Biopolym Cell. 1997; 13(1):22-9.
[25] Zozulya V, Shcherbakova A, Dubey I. Calculating helix-to-coil transitions of duplexes formed by phenazine-conjugated oligonucleotide, using fluorescence melting data. J Fluorescence 2000; 10(1):49-53.
[26] Zozulya V, Blagoi Yu, Dubey I, Fedoryak D, Makitruk V, Ryazanova O, Shcherbakova A. Anchorage of an oligonucleotide hybridization by a tethered phenazine nucleoside analogue. Biopolymers. 2003; 72(4):264-73.
[27] Dubey L, Ryazanova O, Zozulya V, Fedoryak D, Dubey I. Postsynthetic modification of oligonucleotides with imidazophenazine dye and its effect on duplex stability. Nucleosides Nucleotides Nucleic Acids. 2011;30(7-8):585-96.
[28] Negrutska VV, Dubey LV, Ilchenko MM, Dubey IYa. Design and study of telomerase inhibitors based on G-quadruplex ligands. Biopolym Cell. 2013; 29(3):169-76.
[29] Zozulya VN, Ryazanova OA, Voloshin IM, Dubey LV, Dubey IYa. Spectroscopic studies on binding of porphyrin-phenazine conjugate to intramolecular G-quadruplex formed by 22-mer oligonucleotide. Int Rev Biophys Chem. 2011; 2(4):112-9.
[30] Ryazanova O, Zozulya V, Voloshin I, Dubey L, Dubey I, Karachevtsev V. Spectroscopic Studies on Binding of Porphyrin-Phenazine Conjugate to Four-Stranded Poly(G). J Fluoresc. 2015;25(4):1013-21.
[31] Ryazanova O, Zozulya V, Voloshin I, Dubey L, Dubey I, Karachevtsev V. Binding of Metallated Porphyrin-Imidazophenazine Conjugate to Tetramolecular Quadruplex Formed by Poly(G): a Spectroscopic Investigation. J Fluoresc. 2015;25(6):1897-904.
[32] Boger DL, Fink BE, Brunette SR, Tse WC, Hedrick MP. A simple, high-resolution method for establishing DNA binding affinity and sequence selectivity. J Am Chem Soc. 2001;123(25):5878-91.
[33] Boger DL, Tse WC. Thiazole orange as the fluorescent intercalator in a high resolution fid assay for determining DNA binding affinity and sequence selectivity of small molecules. Bioorg Med Chem. 2001;9(9):2511-8.
[34] Monchaud D, Allain C, Teulade-Fichou MP. Development of a fluorescent intercalator displacement assay (G4-FID) for establishing quadruplex-DNA affinity and selectivity of putative ligands. Bioorg Med Chem Lett. 2006;16(18):4842-5.
[35] Monchaud D, Allain C, Bertrand H, Smargiasso N, Rosu F, Gabelica V, De Cian A, Mergny JL, Teulade-Fichou MP. Ligands playing musical chairs with G-quadruplex DNA: a rapid and simple displacement assay for identifying selective G-quadruplex binders. Biochimie. 2008;90(8):1207-23.
[36] Largy E, Hamon F, Teulade-Fichou MP. Development of a high-throughput G4-FID assay for screening and evaluation of small molecules binding quadruplex nucleic acid structures. Anal Bioanal Chem. 2011;400(10):3419-27.
[37] Zhao Y, Truhlar DG. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Acc. 2008; 120(1):215-41.
[38] Ilchenko MM, Dubey IYa. Density functional study of the structure of guanine octets in aqueous medium. Int Rev Biophys Chem. 2011; 2(3):82-6.
[39] Barone V, Cossi M. Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model. J Phys Chem A 1998; 102(11):1995-2001.
[40] Cossi M, Rega N, Scalmani G, Barone V. Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J Comput Chem. 2003;24(6):669-81.
[41] Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian 16 Rev. B.01. Wallingford, CT2016.
[42] Tse WC, Boger DL. A fluorescent intercalator displacement assay for establishing DNA binding selectivity and affinity. Acc Chem Res. 2004;37(1):61-9.
[43] Glass LS, Bapat A, Kelley MR, Georgiadis MM, Long EC. Semi-automated high-throughput fluorescent intercalator displacement-based discovery of cytotoxic DNA binding agents from a large compound library. Bioorg Med Chem Lett. 2010;20(5):1685-8.
[44] Del Villar-Guerra R, Gray RD, Trent JO, Chaires JB. A rapid fluorescent indicator displacement assay and principal component/cluster data analysis for determination of ligand-nucleic acid structural selectivity. Nucleic Acids Res. 2018;46(7):e41.
[45] Tran PLT, Largy E, Hamond F, Teulade-Fichou M-P, Mergny J-L. Fluorescence intercalator displacement assay for screening G4 ligands towards a variety of G-quadruplex structures. Biochimie. 2011; 93(8):1288-96.
[46] Jamroskovic J, Livendahl M, Eriksson J, Chorell E, Sabouri N. Identification of compounds that selectively stabilize specific G-quadruplex structures by using a thioflavin T-displacement assay as a tool. Chem Eur J. 2016; 22(52):18932-43.
[47] Asare-Okai PN, Chow CS. A modified fluorescent intercalator displacement assay for RNA ligand discovery. Anal Biochem. 2011;408(2):269-76.
[48] Ruan TL, Davis SJ, Powell BM, Harbeck CP, Habdas J, Habdas P, Yatsunyk LA. Lowering the overall charge on TMPyP4 improves its selectivity for G-quadruplex DNA. Biochimie. 2017;132:121-130.
[49] Zhang S, Wu Y, Zhang W. G-quadruplex structures and their interaction diversity with ligands. ChemMedChem. 2014;9(5):899-911.
[50] Sponer J, Cang X, Cheatham TE 3rd. Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures. Methods. 2012;57(1):25-39.
[51] Haider S. Computational methods to study G-quadruplex–ligand complexes. J Ind Inst Sci. 2018; 98(3):325-39.
[52] Arba M, Kartasasmita RE, Tjahjono DH. Molecular docking and dynamics simulations on the interaction of cationic porphyrin-anthraquinone hybrids with DNA G-quadruplexes. J Biomol Struct Dyn. 2016;34(2):427-38.
[53] Bazzi S, Novotný J, Yurenko YP, Marek R. Designing a New Class of Bases for Nucleic Acid Quadruplexes and Quadruplex-Active Ligands. Chemistry. 2015;21(26):9414-25.
[54] Zaccaria F, Paragi G, Fonseca Guerra C. The role of alkali metal cations in the stabilization of guanine quadruplexes: why K+ is the best. Phys Chem Chem Phys. 2016; 18(31):20895-904.
[55] Radhika R, Shankar R, Vijayakumar S, Kolandaivel P. Role of 6-Mercaptopurine in the potential therapeutic targets DNA base pairs and G-quadruplex DNA: insights from quantum chemical and molecular dynamics simulations. J Biomol Struct Dyn. 2018;36(6):1369-1401.
[56] Hohenstein EG, Chill ST, Sherrill CD. Assessment of the performance of the M05-2X and M06-2X exchange-correlation functionals for noncovalent interactions in biomolecules. J Chem Theor Comput. 2008; 4(12):1996-2000.