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Medicinal Chemistry Research

, Volume 23, Issue 9, pp 4042–4049 | Cite as

A benzimidazopyridoquinoxaline as promising scaffold for G-quadruplex DNA targeting

  • Asmae Zanzoul
  • Youssef Ramli
  • El Mokhtar Essassi
  • Geneviève Pratviel
Original Research

Abstract

In the search for new molecular scaffolds for G-quadruplex DNA targeting, we prepared a pentacyclic, crescent-shaped, benzimidazopyridoquinoxaline derivative, which proved to bind to G-quadruplex DNA with a modest affinity but did not bind to double-stranded DNA. The binding properties of this compound toward G-quadruplex DNA were better than those exhibited by other aromatic molecules such as ellipticine or indoloquinoxaline derivatives. Consequently, it is considered as a promising lead for optimization of selective G-quadruplex DNA recognition properties.

Keywords

Heterocyclic G4-ligand FRET-melting Quinoxaline Anticancer 

Notes

Acknowledgments

This work was partly supported by the International Associated Moroccan-French Laboratory on Molecular Chemistry (LIA, LCMMF). Thomas Marie is acknowledged for technical assistance.

Supplementary material

44_2014_985_MOESM1_ESM.pdf (775 kb)
Supplementary material 1 (PDF 774 kb)

References

  1. Balasubramanian S, Neidle S (2009) G-quadruplex nucleic acids as therapeutic targets. Curr Opin Chem Biol 13:345–353PubMedCentralCrossRefPubMedGoogle Scholar
  2. Balasubramanian S, Hurley LH, Neidle S (2011) Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat Rev Drug Discov 10:261–275PubMedCentralCrossRefPubMedGoogle Scholar
  3. Bazzicalupi C, Ferraroni M, Bilia AR, Scheggi F, Gratteri P (2013) The crystal structure of human telomeric DNA complexed with berberine: an interesting case of stacked ligand to G-tetrad ratio higher than 1:1. Nucleic Acids Res 41:632–638PubMedCentralCrossRefPubMedGoogle Scholar
  4. Bessi I, Bazzicalupi C, Richter C, Jonker HR, Saxena K, Sissi C, Chioccioli M, Bianco S, Bilia AR, Schwalbe H, Gratteri P (2012) Spectroscopic, molecular modeling, and NMR-spectroscopic investigation of the binding mode of the natural alkaloids berberine and sanguinarine to human telomeric G-quadruplex DNA. ACS Chem Biol 7:1109–1119CrossRefPubMedGoogle Scholar
  5. Burger AM, Dai F, Schultes CM, Reszka AP, Moore MJ, Double JA, Neidle S (2005) The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. Cancer Res 65:1489–1496CrossRefPubMedGoogle Scholar
  6. Collie GW, Parkinson GN (2011) The application of DNA and RNA G-quadruplexes to therapeutic medicines. Chem Soc Rev 40:5867–5892CrossRefPubMedGoogle Scholar
  7. Dai J, Carver M, Hurley LH, Yang D (2011) Solution structure of a 2:1 quindoline-c-MYC G-quadruplex: insights into G-quadruplex-interactive small molecule drug design. J Am Chem Soc 133:17673–17680PubMedCentralCrossRefPubMedGoogle Scholar
  8. De Cian A, Guittat L, Kaiser M, Sacca B, Amrane S, Bourdoncle A, Alberti P, Teulade-Fichou MP, Lacroix L, Mergny JL (2007) Fluorescence-based melting assays for studying quadruplex ligands. Methods 42:183–195CrossRefPubMedGoogle Scholar
  9. Dixon IM, Lopez F, Esteve JP, Tejera AM, Blasco MA, Pratviel G, Meunier B (2005) Porphyrin derivatives for telomere binding and telomerase inhibition. ChemBioChem 6:123–132CrossRefPubMedGoogle Scholar
  10. Drygin D, Siddiqui-Jain A, O’Brien S, Schwaebe M, Lin A, Bliesath J, Ho CB, Proffitt C, Trent K, Whitten JP, Lim JK, Von Hoff D, Anderes K, Rice WG (2009) Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. Cancer Res 69:7653–7661CrossRefPubMedGoogle Scholar
  11. Gavathiotis E, Heald RA, Stevens MF, Searle MS (2003) Drug recognition and stabilisation of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat. J Mol Biol 334:25–36CrossRefPubMedGoogle Scholar
  12. Georgiades SN, Abd Karim NH, Suntharalingam K, Vilar R (2010) Interaction of metal complexes with G-quadruplex DNA. Angew Chem Int Ed 49:4020–4034CrossRefGoogle Scholar
  13. Gowan SM, Heald R, Stevens MF, Kelland LR (2001) Potent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes. Mol Pharmacol 60:981–988PubMedGoogle Scholar
  14. Grand CL, Han H, Munoz RM, Weitman S, Von Hoff DD, Hurley LH, Bearss DJ (2002) The cationic porphyrin TMPyP4 down-regulates c-MYC and human telomerase reverse transcriptase expression and inhibits tumor growth in vivo. Mol Cancer Ther 1:565–573PubMedGoogle Scholar
  15. Granzhan A, Monchaud D, Saettel N, Guedin A, Mergny JL, Teulade-Fichou MP (2010) “One ring to bind them all”-part II: identification of promising G-quadruplex ligands by screening of cyclophane-type macrocycles. J Nucleic Acids. doi: 10.4061/2010/460561
  16. Gudkov A (2008). Aminoacridines and other heterocyclic compounds for NF-κB inhibition and modulation of cell growth or apoptosis. In PCT Int Appl. WO 2008090417 Google Scholar
  17. Haider SM, Neidle S, Parkinson GN (2011) A structural analysis of G-quadruplex/ligand interactions. Biochimie 93:1239–1251CrossRefPubMedGoogle Scholar
  18. Hounsou C, Guittat L, Monchaud D, Jourdan M, Saettel N, Mergny JL, Teulade-Fichou MP (2007) G-quadruplex recognition by quinacridines: a SAR, NMR, and biological study. ChemMedChem 2:655–666CrossRefPubMedGoogle Scholar
  19. Jain SC, Bhandary KK, Sobell HM (1979) Visualization of drug–nucleic acid interactions at atomic resolution. VI. Structure of two drug–dinucleoside monophosphate crystalline complexes, ellipticine-5-iodocytidylyy (3′–5′) guanosine and 3,5,6,8-tetramethyl-N-methyl phenanthrolinium-5-iodocytidylyl (3′–5′) guanosine. J Mol Biol 135:813–840CrossRefPubMedGoogle Scholar
  20. Jaumot J, Gargallo R (2012) Experimental methods for studying the interactions between G-quadruplex structures and ligands. Curr Pharm Des 18:1900–1916CrossRefPubMedGoogle Scholar
  21. Koeppel F, Riou JF, Laoui A, Mailliet P, Arimondo PB, Labit D, Petitgenet O, Helene C, Mergny JL (2001) Ethidium derivatives bind to G-quartets, inhibit telomerase and act as fluorescent probes for quadruplexes. Nucleic Acids Res 29:1087–1096PubMedCentralCrossRefPubMedGoogle Scholar
  22. Kohn KW, Waring MJ, Glaubiger D, Friedman CA (1975) Intercalative binding of ellipticine to DNA. Cancer Res 35:71–76PubMedGoogle Scholar
  23. Largy E, Granzhan A, Hamon F, Verga D, Teulade-Fichou MP (2013) Visualizing the quadruplex: from fluorescent ligands to light-up probes. Top Curr Chem 330:111–177CrossRefPubMedGoogle Scholar
  24. Le Pecq JB, Nguyen Dat X, Gosse C, Paoletti C (1974) A new antitumoral agent: 9-hydroxyellipticine. Possibility of a rational design of anticancerous drugs in the series of DNA intercalating drugs. Proc Natl Acad Sci USA 71:5078–5082PubMedCentralCrossRefPubMedGoogle Scholar
  25. Leonetti C, Scarsella M, Riggio G, Rizzo A, Salvati E, D’Incalci M, Staszewsky L, Frapolli R, Stevens MF, Stoppacciaro A, Mottolese M, Antoniani B, Gilson E, Zupi G, Biroccio A (2008) G-quadruplex ligand RHPS4 potentiates the antitumor activity of camptothecins in preclinical models of solid tumors. Clin Cancer Res 14:7284–7291CrossRefPubMedGoogle Scholar
  26. Ma Y, Ou TM, Tan JH, Hou JQ, Huang SL, Gu LQ, Huang ZS (2009) Synthesis and evaluation of 9-O-substituted berberine derivatives containing aza-aromatic terminal group as highly selective telomeric G-quadruplex stabilizing ligands. Bioorg Med Chem Lett 19: 3414–3417Google Scholar
  27. Ma Y, Ou TM, Tan JH, Hou JQ, Huang SL, Gu LQ, Huang ZS (2011) Quinolino-benzo-[5,6]-dihydroisoquindolium compounds derived from berberine: a new class of highly selective ligands for G-quadruplex DNA in c-myc oncogene. Eur J Med Chem 46:1906–1913CrossRefPubMedGoogle Scholar
  28. Ma DL, He HZ, Leung KH, Zhong HJ, Chan DS, Leung CH (2013) Label-free luminescent oligonucleotide-based probes. Chem Soc Rev 42:3427–3440CrossRefPubMedGoogle Scholar
  29. Mergny JL, Maurizot JC (2001) Fluorescence resonance energy transfer as a probe for G-quartet formation by a telomeric repeat. Chembiochem 2:124–132CrossRefPubMedGoogle Scholar
  30. Mergny JL, Lacroix L, Teulade-Fichou MP, Hounsou C, Guittat L, Hoarau M, Arimondo PB, Vigneron JP, Lehn JM, Riou JF, Garestier T, Hélène C (2001) Telomerase inhibitors based on quadruplex ligands selected by a fluorescence assay. Proc Natl Acad Sci USA 98:3062–3067PubMedCentralCrossRefPubMedGoogle Scholar
  31. Miller KM, Rodriguez R (2011) G-quadruplexes: selective DNA targeting for cancer therapeutics? Expert Rev Clin Pharmacol 4:139–142CrossRefPubMedGoogle Scholar
  32. Monchaud D, Teulade-Fichou MP (2008) A Hitchhiker’s guide to G-quadruplex ligands. Org Biomol Chem 6:627–636CrossRefPubMedGoogle Scholar
  33. Monchaud D, Allain C, Bertrand H, Smargiasso N, Rosu F, Gabelica V, De Cian A, Mergny JL, Teulade-Fichou MP (2008) Ligands playing musical chairs with G-quadruplex DNA: a rapid and simple displacement assay for identifying selective G-quadruplex binders. Biochimie 90:1207–1223CrossRefPubMedGoogle Scholar
  34. Monchaud D, Granzhan A, Saettel N, Guedin A, Mergny JL, Teulade-Fichou MP (2010) “One ring to bind them all”-part I: the efficiency of the macrocyclic scaffold for G-quadruplex DNA recognition. J Nucleic Acids. doi: 10.4061/2010/525862
  35. Moore MJ, Schultes CM, Cuesta J, Cuenca F, Gunaratnam M, Tanious FA, Wilson WD, Neidle S (2006) Trisubstituted acridines as G-quadruplex telomere targeting agents. Effects of extensions of the 3,6- and 9-side chains on quadruplex binding, telomerase activity, and cell proliferation. J Med Chem 49:582–599CrossRefPubMedGoogle Scholar
  36. Murat P, Singh Y, Defrancq E (2011) Methods for investigating G-quadruplex DNA/ligand interactions. Chem Soc Rev 40:5293–5307CrossRefPubMedGoogle Scholar
  37. Neidle S (2010) Human telomeric G-quadruplex: the current status of telomeric G-quadruplexes as therapeutic targets in human cancer. FEBS J 277:1118–1125CrossRefPubMedGoogle Scholar
  38. Ou TM, Lu YJ, Zhang C, Huang ZS, Wang XD, Tan JH, Chen Y, Ma DL, Wong KY, Tang JC, Chan AS, Gu LQ (2007) Stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc by quindoline derivatives. J Med Chem 50:1465–1474CrossRefPubMedGoogle Scholar
  39. Ou TM, Lu YJ, Tan JH, Huang ZS, Wong KY, Gu LQ (2008) G-quadruplexes: targets in anticancer drug design. ChemMedChem 3:690–713CrossRefPubMedGoogle Scholar
  40. Paoletti C, Le Pecq JB, Dat-Xuong N, Juret P, Garnier H, Amiel JL, Rouesse J (1980) Antitumor activity, pharmacology, and toxicity of ellipticines, ellipticinium, and 9-hydroxy derivatives: preliminary clinical trials of 2-methyl-9-hydroxy ellipticinium (NSC 264-137). Recent Results Cancer Res 74:107–123CrossRefPubMedGoogle Scholar
  41. Pennarun G, Granotier C, Gauthier LR, Gomez D, Hoffschir F, Mandine E, Riou JF, Mergny JL, Mailliet P, Boussin FD (2005) Apoptosis related to telomere instability and cell cycle alterations in human glioma cells treated by new highly selective G-quadruplex ligands. Oncogene 24:2917–2928CrossRefPubMedGoogle Scholar
  42. Qin Y, Hurley LH (2008) Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regions. Biochimie 90:1149–1171PubMedCentralCrossRefPubMedGoogle Scholar
  43. Romera C, Bombarde O, Bonnet R, Gomez D, Dumy P, Calsou P, Gwan JF, Lin JH, Defrancq E, Pratviel G (2011) Improvement of porphyrins for G-quadruplex DNA targeting. Biochimie 93:1310–1317CrossRefPubMedGoogle Scholar
  44. Shibinskaya MO, Lyakhov SA, Mazepa AV, Andronati SA, Turov AV, Zholobak NM, Spivak NY (2010) Synthesis, cytotoxicity, antiviral activity and interferon inducing ability of 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines. Eur J Med Chem 45:1237–1243CrossRefPubMedGoogle Scholar
  45. Tauchi T, Shin-ya K, Sashida G, Sumi M, Okabe S, Ohyashiki JH, Ohyashiki K (2006) Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia. Oncogene 25:5719–5725CrossRefPubMedGoogle Scholar
  46. Wheelhouse RT, Sun D, Han H, Xiaoguang Han F, Hurley LH (1998) Cationic porphyrins as telomerase inhibitors: the interaction of tetra-(N-methyl-4-pyridyl)porphine with quadruplex DNA. J Am Chem Soc 120:3261–3262CrossRefGoogle Scholar
  47. Xu Y (2011) Chemistry in human telomere biology: structure, function and targeting of telomere DNA/RNA. Chem Soc Rev 40:2719–2740CrossRefPubMedGoogle Scholar
  48. Zniber R, El Hajji AJ, Achour R, Cherkaoui MZ, Harrata A (2000) Synthèse et charactérisation de nouveaux composés benzimidazoliques et quinoxaliniques à propriétés pharmacologiques potentielles. J Soc Chim Tunisie IV:783–787Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Asmae Zanzoul
    • 1
    • 2
    • 3
  • Youssef Ramli
    • 3
  • El Mokhtar Essassi
    • 3
  • Geneviève Pratviel
    • 1
    • 2
  1. 1.Laboratoire de Chimie de CoordinationCNRS, UPR 8241Toulouse Cedex 4France
  2. 2.Université de Toulouse, UPS, INPT, LCCToulouseFrance
  3. 3.Laboratoire de Chimie Organique Hétérocyclique, pôle de compétences pharmacochimie, Faculté des SciencesUniversité Mohammed V-AgdalRabatMorroco

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