Binding to the DNA Minor Groove by Heterocyclic Dications: From AT‐Specific Monomers to GC Recognition with Dimers

Rupesh Nanjunda1, W. David Wilson1

1 Department of Chemistry, Georgia State University, Atlanta, Georgia
Publication Name:  Current Protocols in Nucleic Acid Chemistry
Unit Number:  Unit 8.8
DOI:  10.1002/0471142700.nc0808s51
Online Posting Date:  December, 2012
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Compounds that bind in the DNA minor groove have provided critical information on DNA molecular recognition, have found extensive uses in biotechnology, and are providing clinically useful drugs against diseases as diverse as cancer and sleeping sickness. This review focuses on the development of clinically useful heterocyclic diamidine minor groove binders. These compounds have shown us that the classical model for minor groove binding in AT DNA sequences must be expanded in several ways: compounds with nonstandard shapes can bind strongly to the groove, water can be directly incorporated into the minor groove complex in an interfacial interaction, and the compounds can form cooperative stacked dimers to recognize GC and mixed AT/GC base pair sequences. Curr. Protoc. Nucleic Acid Chem. 51:8.8.1‐8.8.20. © 2012 by John Wiley & Sons, Inc.

Keywords: DNA minor groove; heterocyclic amidines; DNA complex structures; surface plasmon resonance; stacked minor groove dimers

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Table of Contents

  • Introduction
  • DNA Groove Shape and Chemistry
  • Classical‐AT‐Specific Minor Groove Binders
  • Variations on the Classical Minor Groove Model
  • Extension to GC Base Pair Recognition
  • Conclusion and Prospects
  • Acknowledgments
  • Literature Cited
  • Figures
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Literature Cited

Literature Cited
   Athri, P. and Wilson, W.D. 2009. Molecular dynamics of water‐mediated interactions of a linear benzimidazole‐biphenyl diamidine with the DNA minor groove. J. Am. Chem. Soc. 131:7618‐7625.
   Bailly, C. and Waring, M.J. 1995. Transferring the purine 2‐amino group from guanines to adenines in DNA changes the sequence‐specific binding of antibiotics. Nucleic Acids Res. 23:885‐892.
   Bailly, C., Tardy, C., Wang, L., Armitage, B., Hopkins, K., Kumar, A., Schuster, G.B., Boykin, D.W., and Wilson, W.D. 2001. Recognition of ATGA sequences by the unfused aromatic dication DB293 forming stacked dimers in the DNA minor groove. Biochemistry 40:9770‐9779.
   Bajic, M., Kumar, A., and Boykin, D.W. 1996. Synthesis of 2,5‐bis‐(4‐cyanophenyl)‐furan. Heterocycl. Commun. 2:135‐140.
   Balasubramanian, S. and Neidle, S. 2009. G‐quadruplex nucleic acids as therapeutic targets. Curr. Opin. Chem. Biol. 13:345‐353.
   Balasubramanian, S., Hurley, L.H., and Neidle, S. 2011. Targeting G‐quadruplexes in gene promoters: A novel anticancer strategy. Nat. Rev. Drug Discov. 10:261‐275.
   Bishop, E.P., Rohs, R., Parker, S.C.J., West, S.M., Liu, P., Mann, R.S., Honig, B., and Tullius, T.D. 2011. A map of minor groove shape and electrostatic potential from hydroxyl radical cleavage patterns of DNA. ACS Chem. Biol. 6:1314‐1320.
   Bostock‐Smith, C.E., Harris, S.A., Laughton, C.A., and Searle, M.S. 2001. Induced fit DNA recognition by a minor groove binding analogue of Hoechst 33258: Fluctuations in DNA A tract structure investigated by NMR and molecular dynamics simulations. Nucleic Acids Res. 29:693‐702.
   Boykin, D.W., Kumar, A., Bender, B.K., Hall, J.E., and Tidwell, R.R. 1996. Anti‐pneumocystis activity of bis‐amidoximes and bis‐O‐alkylamidoximes prodrugs. Bioorg. Med. Chem. Lett. 6:3017‐3020.
   Brooks, T.A., Kendrick, S., and Hurley, L. 2010. Making sense of G‐quadruplex and i‐motif functions in oncogene promoters. FEBS J. 277:3459‐3469.
   Burge, S., Parkinson, G.N., Hazel, P., Todd, A.K., and Neidle, S. 2006. Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res. 34:5402‐5415.
   Cai, X., Gray, P.J. Jr., and Von Hoff, D.D. 2009. DNA minor groove binders: Back in the groove. Cancer Treat. Rev. 35:437‐450.
   Chaires, J.B. 2008. Allostery: DNA does it, too. ACS Chem. Biol. 3:207‐209.
   Dervan, P.B., Doss, R.M., and Marques, M.A. 2005. Programmable DNA binding oligomers for control of transcription. Curr. Med. Chem. Anticancer Agents 5:373‐387.
   Edwards, T.G., Koeller, K.J., Slomczynska, U., Fok, K., Helmus, M., Bashkin, J.K., and Fisher, C. 2011. HPV episome levels are potently decreased by pyrrole‐imidazole polyamides. Antiviral Res. 91:177‐186.
   Finlay, A.C., Hochstein, F.A., Sobin, B.A., and Murphy, F.X. 1951. Netropsin, a new antibiotic produced by a Streptomyces. J. Am. Chem. Soc. 73:341‐343.
   Franks, A., Tronrud, C., Kiakos, K., Kluza, J., Munde, M., Brown, T., Mackay, H., Wilson, W.D., Hochhauser, D., Hartley, J.A., and Lee, M. 2010. Targeting the ICB2 site of the topoisomerase IIalpha promoter with a formamido‐pyrrole‐imidazole‐pyrrole H‐pin polyamide. Bioorg. Med. Chem. 18:5553‐5561.
   Gardiner‐Garden, M. and Frommer, M. 1987. CpG islands in vertebrate genomes. J. Mol. Biol. 196:261‐282.
   Goodsell, D. and Dickerson, R.E. 1986. Isohelical analysis of DNA groove‐binding drugs. J. Med. Chem. 29:727‐733.
   Greenbaum, J.A., Pang, B., and Tullius, T.D. 2007. Construction of a genome‐scale structural map at single‐nucleotide resolution. Genome Res. 17:947‐953.
   Gruss, A., Moretto, V., Ehrlich, S.D., Duwat, P., and Dabert, P. 1991. GC‐rich DNA sequences block homologous recombination in vitro. J. Biol. Chem. 266:6667‐6669.
   Hamilton, P.L. and Arya, D.P. 2012. Natural product DNA major groove binders. Nat. Prod. Rep. 29:134‐143.
   Karlsson, H.J., Eriksson, M., Perzon, E., Akerman, B., Lincoln, P., and Westman, G. 2003. Groove‐binding unsymmetrical cyanine dyes for staining of DNA: Syntheses and characterization of the DNA‐binding. Nucleic Acids Res. 31:6227‐6234.
   Khuu, P., Sandor, M., DeYoung, J., and Ho, P.S. 2007. Phylogenomic analysis of the emergence of GC‐rich transcription elements. Proc. Natl. Acad. Sci. U.S.A. 104:16528‐16533.
   Kielkopf, C.L., Baird, E.E., Dervan, P.B., and Rees, D.C. 1998. Structural basis for G.C recognition in the DNA minor groove. Nat. Struct. Biol. 5:104‐109.
   Kim, C‐H. and Tinoco, I. 2000. A retroviral RNA kissing complex containing only two G⋅C base pairs. Proc. Natl. Acad. Sci. U.S.A. 97:9396‐9401.
   Kopka, M.L., Yoon, C., Goodsell, D., Pjura, P., and Dickerson, R.E. 1985. Binding of an antitumor drug to DNA. Netropsin and C‐G‐C‐G‐A‐A‐T‐T‐BrC‐G‐C‐G. J. Mol. Biol. 183:553‐563.
   Kumar, A., Stephens, C.E., and Boykin, D.W. 1999. Palladium catalyzed cross‐coupling reactions for the synthesis of 2,5‐disubstituted furans. Heterocycl. Commun. 5:301‐304.
   Lacy, E.R., Madsen, E.R., Lee, M., and Wilson, W.D. 2002. Dicationic DNA minor groove binders as antimicrobial agents. In DNA and RNA Binders, Vol. 1: From Small Molecules to Drugs (M. Demeunynck, C. Bailly, and W.D. Wilson, eds.) pp. 414‐460. WILEY‐VCH; Weinheim, Germany.
   Laughton, C.A., Tanious, F., Nunn, C.M., Boykin, D.W., Wilson, W.D., and Neidle, S. 1996. A crystallographic and spectroscopic study of the complex between d(CGCGAATTCGCG)2 and 2,5‐bis(4‐guanylphenyl)furan, an analogue of berenil. Structural origins of enhanced DNA‐binding affinity. Biochemistry 35:5655‐5661.
   Lee, M., Hartley, J.A., Pon, R.T., Krowicki, K., and Lown, J.W. 1988. Sequence specific molecular recognition by a monocationic lexitropsin of the decadeoxyribonucleotide d‐[CATGGCCATG]2: Structural and dynamic aspects deduced from high field 1H‐NMR studies. Nucleic Acids Res. 16:665‐684.
   Lee, M., Krowicki, K., Shea, R.G., Lown, J.W., and Pon, R.T. 1989. Molecular recognition between oligopeptides and nucleic acids. Specificity of binding of a monocationic bis‐furan lexitropsin to DNA deduced from footprinting and 1H NMR studies. J. Mol. Recognit. 2:84‐93.
   Liu, B., Liu, Y., Motyka, S.A., Agbo, E.E., and Englund, P.T. 2005. Fellowship of the rings: The replication of kinetoplast DNA. Trends Parasitol. 21:363‐369.
   Liu, Y., Kumar, A., DePauw, S., Nhili, R., David‐Cordonnier, M.H., Lee, M.P., Ismail, M.A., Farahat, A.A., Say, M., Chackal‐Catoen, S., Batista‐Parra, A., Neidle, S., Boykin, D.W., and Wilson, W.D. 2011. Water‐me diated binding of agents that target the DNA minor groove. J. Am. Chem. Soc. 133:10171‐10183.
   Liu, Y., Chai, Y., Kumar, A., Tidwell, R.R., Boykin, D.W., and Wilson, W.D. 2012. Designed compounds for recognition of 10 base pairs of DNA with two at binding sites. J. Am. Chem. Soc. 134:5290‐5299.
   Mallena, S., Lee, M.P., Bailly, C., Neidle, S., Kumar, A., Boykin, D.W., and Wilson, W.D. 2004. Thiophene‐based diamidine forms a “super” at binding minor groove agent. J. Am. Chem. Soc. 126:13659‐13669.
   Mdachi, R.E., Thuita, J.K., Kagira, J.M., Ngotho, J.M., Murilla, G.A., Ndung'u, J.M., Tidwell, R.R., Hall, J.E., and Brun, R. 2009. Efficacy of the novel diamidine compound 2,5‐bis(4‐amidinophenyl)‐ furan‐fis‐O‐methlylamidoxime (pafuramidine, DB289) against Trypanosoma brucei rhodesiense infection in Vervet Monkeys after oral administration. Antimicrob. Agents Chemother. 53:953‐957.
   Miao, Y., Lee, M.P., Parkinson, G.N., Batista‐Parra, A., Ismail, M.A., Neidle, S., Boykin, D.W., and Wilson, W.D. 2005. Out‐of‐shape DNA minor groove binders: Induced fit interactions of heterocyclic dications with the DNA minor groove. Biochemistry 44:14701‐14708.
   Moretti, R., Donato, L.J., Brezinski, M.L., Stafford, R.L., Hoff, H., Thorson, J.S., Dervan, P.B., and Ansari, A.Z. 2008. Targeted chemical wedges reveal the role of allosteric DNA modulation in protein‐DNA assembly. ACS Chem. Biol. 3:220‐229.
   Mrksich, M., Wade, W.S., Dwyer, T.J., Geierstanger, B.H., Wemmer, D.E., and Dervan, P.B. 1992. Antiparallel side‐by‐side dimeric motif for sequence‐specific recognition in the minor groove of DNA by the designed peptide 1‐methylimidazole‐2‐carboxamide netropsin. Proc. Natl. Acad. Sci. U.S.A. 89:7586‐7590.
   Mukherjee, A., Padmanabhan, P.K., Sahani, M.H., Barrett, M.P., and Madhubala, R. 2006. Roles for mitochondria in pentamidine susceptibility and resistance in Leishmania donovani. Mol. Biochem. Parasitol. 145:1‐10.
   Munde, M., Ismail, M.A., Arafa, R., Peixoto, P., Collar, C.J., Liu, Y., Hu, L., David‐Cordonnier, M.H., Lansiaux, A., Bailly, C., Boykin, D.W., and Wilson, W.D. 2007. Design of DNA minor groove binding diamidines that recognize GC base pair sequences: A dimeric‐hinge interaction motif. J. Am. Chem. Soc. 129:13732‐13743.
   Nanjunda, R., Munde, M., Liu, Y., and Wilson, W.D. 2012. Real‐time monitoring of nucleic acid interactions with biosensor‐surface plasmon resonance. In Methods for Studying Nucleic Acid/Drug Interactions, (M. Wanunu and Y. Tor, eds.) pp. 91‐122. CRC Press, Boca Raton, Fla.
   Neidle, S. 2001. DNA minor‐groove recognition by small molecules. Nat. Prod. Rep. 18:291‐309.
   Nguyen, B., Boykin, D.W., and Wilson, W.D. 2007. DNA minor groove interactions of antiparasitic diamidines: Re‐evaluation of the crescent‐shape concept in groove‐binding. In Synthentic and Biophysical Studies of DNA Binding Compounds (M. Lee and L. Strekowski, eds.) pp. 39‐66. Transworld Research Network, Kerala, India.
   Nguyen, B., Neidle, S., and Wilson, W.D. 2009. A role for water molecules in DNA‐ligand minor groove recognition. Acc. Chem. Res. 42:11‐21.
   Paine, M.F., Wang, M.Z., Generaux, C.N., Boykin, D.W., Wilson, W.D., De Koning, H.P., Olson, C.A., Pohlig, G., Burri, C., Brun, R., Murilla, G.A., Thuita, J.K., Barrett, M.P., and Tidwell, R.R. 2010. Diamidines for human African trypanosomiasis. Curr. Opin. Invest. Drugs 11:876‐883.
   Pandian, G.N., Shinohara, K., Ohtsuki, A., Nakano, Y., Masafumi, M., Bando, T., Nagase, H., Yamada, Y., Watanabe, A., Terada, N., Sato, S., Morinaga, H., and Sugiyama, H. 2011. Synthetic small molecules for epigenetic activation of pluripotency genes in mouse embryonic fibroblasts. ChemBioChem 12:2822‐2828.
   Parker, S.C.J. and Tullius, T.D. 2011. DNA shape, genetic codes, and evolution. Curr. Opin. Struct. Biol. 21:342‐347.
   Patel, D.J., Phan, A.T., and Kuryavyi, V. 2007. Human telomere, oncogenic promoter and 5′‐UTR G‐quadruplexes: Diverse higher order DNA and RNA targets for cancer therapeutics. Nucleic Acids Res. 35:7429‐7455.
   Peixoto, P., Liu, Y., Depauw, S., Hildebrand, M.P., Boykin, D.W., Bailly, C., Wilson, W.D, and David‐Cordonnier, M.H. 2008. Direct inhibition of the DNA‐binding activity of POU transcription factors Pit‐1 and Brn‐3 by selective binding of a phenyl‐furan‐benzimidazole dication. Nucleic Acids Res. 36:3341‐3353.
   Petraccone, L., Spink, C., Trent, J.O., Garbett, N.C., Mekmaysy, C.S., Giancola, C., and Chaires, J.B. 2011. Structure and stability of higher‐order human telomeric quadruplexes. J. Am. Chem. Soc. 133:20951‐20961.
   Raskatov, J.A., Meier, J.L., Puckett, J.W., Yang, F., Ramakrishnan, P. and Dervan, P.B. 2012a. Modulation of NF‐κB‐dependent gene transcription using programmable DNA minor groove binders. Proc. Natl. Acad. Sci. U.S.A. 109:1023‐1028.
   Raskatov, J.A., Hargrove, A.E., So, A.Y., and Dervan, P.B. 2012b. Pharmacokinetics of Py‐Im polyamides depend on architecture: Cyclic versus linear. J. Am. Chem. Soc. 134:7995‐7999.
   Reddy, B.S., Sondhi, S.M., and Lown, J.W. 1999. Synthetic DNA minor groove‐binding drugs. Pharmacol. Ther. 84:1‐111.
   Rohs, R., West, S.M., Sosinsky, A., Liu, P., Mann, R.S., and Honig, B. 2009. The role of DNA shape in protein‐DNA recognition. Nature 461:1248‐1253.
   Shapiro, T.A. and Englund, P.T. 1995. The structure and replication of kinetoplast DNA. Ann. Rev. Microbiol. 49:117‐143.
   Shinohara, K., Bando, T., and Sugiyama, H. 2010. Anticancer activities of alkylating pyrrole‐imidazole polyamides with specific sequence recognition. Anticancer Drugs 21:228‐242.
   Simpson, I.J., Lee, M., Kumar, A., Boykin, D.W., and Neidle, S. 2000. DNA minor groove interactions and the biological activity of 2,5‐bis. Bioorg. Med. Chem. Lett. 10:2593‐2597.
   Soeiro, M.N., de Castro, S.L., de Souza, E.M., Batista, D.G., Silva, C.F., and Boykin, D.W. 2008. Diamidine activity against trypanosomes: the state of the art. Curr. Mol. Pharmacol. 1:151‐161.
   Stewart, M.L., Krishna, S., Burchmore, R.J., Brun, R., de Koning, H.P., Boykin, D.W., Tidwell, R.R., Hall, J.E., and Barrett, M.P. 2005. Detection of arsenical drug resistance in Trypanosoma brucei with a simple fluorescence test. Lancet 366:486‐487.
   Tanious, F.A., Spychala, J., Kumar, A., Greene, K., Boykin, D.W., and Wilson, W.D. 1994. Different binding mode in AT and GC sequences for unfused‐aromatic dications. J. Biomol. Struct. Dyn. 11:1063‐1083.
   Tanious, F., Wilson, W.D., Wang, L., Kumar, A., Boykin, D.W., Marty, C., Baldeyrou, B., and Bailly, C. 2003. Cooperative dimerization of a heterocyclic diamidine determines sequence‐specific DNA recognition. Biochemistry 42:13576‐13586.
   Tanious, F.A., Laine, W., Peixoto, P., Bailly, C., Goodwin, K.D., Lewis, M.A., Long, E.C., Georgiadis, M.M., Tidwell, R.R., and Wilson, W.D. 2007. Unusually strong binding to the DNA minor groove by a highly twisted benzimidazole diphenylether: Induced fit and bound water. Biochemistry 46:6944‐6956.
   Tidwell, R.R. and Boykin, D.W. 2004. Dicationic DNA minor groove binders as antimicrobial agents. In DNA and RNA Binders, Vol. 2: From Small Molecules to Drugs (M. Demeunynck, C. Bailly, and W.D. Wilson, eds.) pp. 414‐460. Wiley‐VCH; Verlag GmbH, Weinheim, Germany.
   Trent, J.O., Clark, G.R., Kumar, A., Wilson, W.D., Boykin, D.W., Hall, J.E., Tidwell, R.R., Blagburn, B.L., and Neidle, S. 1996. Targeting the minor groove of DNA: Crystal structures of two complexes between furan derivatives of berenil and the DNA dodecamer d(CGCGAATTCGCG)2. J. Med. Chem. 39:4554‐4562.
   Walker, W.L., Kopka, M.L., and Goodsell, D.S. 1997. Progress in the design of DNA sequence‐specific lexitropsins. Biopolymers 44:323‐334.
   Wang, L., Bailly, C., Kumar, A., Ding, D., Bajic, M., Boykin, D.W., and Wilson, W.D. 2000. Specific molecular recognition of mixed nucleic acid sequences: an aromatic dication that binds in the DNA minor groove as a dimer. Proc. Natl. Acad. Sci. U.S.A. 97:12‐16.
   Wang, L., Carrasco, C., Kumar, A., Stephens, C.E., Bailly, C., Boykin, D.W., and Wilson, W.D. 2001. Evaluation of the influence of compound structure on stacked‐dimer formation in the DNA minor groove. Biochemistry 40:2511‐2521.
   Wang, L., Kumar, A., Boykin, D.W., Bailly, C., and Wilson, W.D. 2002. Comparative thermodynamics for monomer and dimer sequence‐dependent binding of a heterocyclic dication in the DNA minor groove. J. Mol. Biol. 317:361‐374.
   Waring, M.J. and Bailly, C. 1994. The purine 2‐amino group as a critical recognition element for binding of small molecules to DNA. Gene 149:69‐79.
   Wartell, R.M., Larson, J.E., and Wells, R.D. 1974. Netropsin. Specific probe for A‐T regions of duplex deoxyribonucleic acid. J. Biol. Chem. 249:6719‐6731.
   Werbovetz, K. 2006. Diamidines as antitrypanosomal, antileishmanial and antimalarial agents. Curr. Opin. Investig. Drugs 7:147‐157.
   Wheeler, R.J., Gull, K., and Gluenz, E. 2012. Detailed interrogation of trypanosome cell biology via differential organelle staining and automated image analysis. BMC Biol. 10:1‐17.
   Wilson, W.D. 1996. Reversible Interactions of nucleic acids with small molecules. In Nucleic Acids in Chemistry and Biology, 2nd Edition (G.M. Blackburn and M.J. Gait, eds.) pp. 331‐374. Oxford University Press, New York.
   Wilson, W.D., Tanious, F.A., Buczak, H., Venkatramanan, M.K., Das, B.P., and Boykin, D.W. 1990. The effects of ligand structure on binding mode and specificity in the interaction of unfused aromatic cations with DNA. In Molecular Basis of Specificity in Nucleic Acid‐Drug Interactions (B. Pullman and J. Jortner, eds.) pp. 331‐353. Academic Press, New York.
   Wilson, W.D., Ratmeyer, L., Zhao, M., Strekowski, L., and Boykin, D. 1993. The search for structure‐specific nucleic acid‐interactive drugs: effects of compound structure on RNA versus DNA interaction strength. Biochemistry 32:4098‐4104.
   Wilson, W.D., Nguyen, B., Tanious, F.A., Mathis, A., Hall, J.E., Stephens, C.E., and Boykin, D.W. 2005. Dications that target the DNA minor groove: Compound design and preparation, DNA interactions, cellular distribution and biological activity. Curr. Med. Chem. Anticancer Agents 5:389‐408.
   Wilson, W.D, Tanious, F.A., Mathis, A., Tevis, D., Hall, J.E., and Boykin, D.W. 2008. Antiparasitic compounds that target DNA. Biochimie 90:999‐1014.
   Xi, H., Davis, E., Ranjan, N., Xue, L., Hyde‐Volpe, D., and Arya, D.P. 2011. Thermodynamics of nucleic acid “shape readout” by an aminosugar. Biochemistry 50:9088‐9113.
   Zerial, M., Salinas, J., Filipski, J., and Bernardi, G. 1986. Genomic localization of hepatitis B virus in a human hepatoma cell line. Nucleic Acids Res. 14:8373‐8386.
   Zhang, L., Kasif, S., Cantor, C.R., and Broude, N.E. 2004. GC/AT‐content spikes as genomic punctuation marks. Proc. Natl. Acad. Sci. U.S.A. 101:16855‐16860.
   Zimmer, C. 1975. Effects of the antibiotics netropsin and distamycin A on the structure and function of nucleic acids. Prog. Nucleic Acid Res. Mol. Biol. 15:285‐318.
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