DNA G-quadruplexes (G4s) have been identified within the promoter regions of many proto-oncogenes. Thus, G4s represent attractive targets for cancer therapy, and the design and development of new drugs as G4 binders is a very active field of medicinal chemistry. Here, molecular biophysics and biology methods were employed to investigate the interaction of chiral metallohelices with a series of four DNA G4s (hTelo, c-myc, c-kit1, c-kit2) that are formed by the human telomeric sequence (hTelo) and in the promoter regions of c-MYC and c-KIT proto-oncogenes. We show that the investigated water-compatible, optically pure metallohelices, which are made by self-assembly of simple nonpeptidic organic components around FeII ions and exhibit bioactivity emulating the natural systems, bind with high affinity to G4 DNA and much lower affinity to duplex DNA. Notably, both enantiomers of a metallohelix containing a m-xylenyl bridge (5 b) were found to effectively inhibit primer elongation catalyzed by Taq DNA polymerase by stabilizing G4 structures formed in the template strands containing c-myc and c-kit2 G4-forming sequences. Moreover, both enantiomers of 5 b downregulated the expression of c-MYC and c-KIT oncogenes in human embryonic kidney cells at mRNA and protein levels. As metallohelices also bind alternative nucleic acid structures, they hold promise as potential multitargeted drugs.

Department of Chemistry University of Warwick Coventry CV4 7AL UK

Institute of Biophysics Czech Academy of Sciences Kralovopolska 135 61265 Brno Czech Republic

Zobrazit více v PubMed

J. Spiegel, S. Adhikari, S. Balasubramanian, Trends Chem. 2020, 2, 123-136.

G. Biffi, D. Tannahill, J. McCafferty, S. Balasubramanian, Nat. Chem. 2013, 5, 182;

P. A. Summers, B. W. Lewis, J. Gonzalez-Garcia, R. M. Porreca, A. H. M. Lim, P. Cadinu, N. Martin-Pintado, D. J. Mann, J. B. Edel, J. B. Vannier, M. K. Kuimova, R. Vilar, Nat. Commun. 2021, 12, 162.

V. S. Chambers, G. Marsico, J. M. Boutell, M. Di Antonio, G. P. Smith, S. Balasubramanian, Nature 2015, 33, 877-881.

E. H. Blackburn, Nature 1991, 350, 569-573;

J. L. Mergny, C. Helene, Nat. Med. 1998, 4, 1366-1367.

J. Dai, D. Chen, R. A. Jones, L. H. Hurley, D. Yang, Nucleic Acids Res. 2006, 34, 5133-5144.

X. Tong, W. Lan, X. Zhang, H. Wu, M. Liu, C. Cao, Nucleic Acids Res. 2011, 39, 6753-6763.

S. Cogoi, L. E. Xodo, Nucleic Acids Res. 2006, 34, 2536-2549.

D. Y. Sun, K. X. Guo, J. J. Rusche, L. H. Hurley, Nucleic Acids Res. 2005, 33, 6070-6080.

Y. Qin, E. M. Rezler, V. Gokhale, D. Sun, L. H. Hurley, Nucleic Acids Res. 2007, 35, 7698-7713.

A. Siddiqui-Jain, C. L. Grand, D. J. Bearss, L. H. Hurley, Proc. Natl. Acad. Sci. USA 2002, 99, 11593-11598.

S. Rankin, A. P. Reszka, J. Huppert, M. Zloh, G. N. Parkinson, A. K. Todd, S. Ladame, S. Balasubramanian, S. Neidle, J. Am. Chem. Soc. 2005, 127, 10584-10589.

C. V. Dang, Cell 2012, 149, 22-35.

W. Wang, S. Hu, Y. Gu, Y. Yan, D. B. Stovall, D. Li, G. Sui, Biochim. Biophys. Acta Rev. Cancer 2020, 1874, 188410;

B.-J. Chen, Y.-L. Wu, Y. Tanaka, W. Zhang, Int. J. Mol. Sci. 2014, 10, 1084-1096.

M. Nannini, G. Biasco, A. Astolfi, M. A. Pantaleo, J. Med. Genet. 2013, 50, 653-661.

X. Wang, C. X. Zhou, J. W. Yan, J. Q. Hou, S. B. Chen, T. M. Ou, L. Q. Gu, Z. S. Huang, J. H. Tan, ACS Med. Chem. Lett. 2013, 4, 909-914.

Q. Li, J. F. Xiang, Q. F. Yang, H. X. Sun, A. J. Guan, Y. L. Tang, Nucleic Acids Res. 2013, 41, D1115-D1123.

D. Monchaud, M. P. Teulade-Fichou, Org. Biomol. Chem. 2008, 6, 627-636.

C. L. Ruehl, A. H. M. Lim, T. Kench, D. J. Mann, R. Vilar, Chem. Eur. J. 2019, 25, 9691-9700;

O. Domarco, C. Kieler, C. Pirker, C. Dinhof, B. Englinger, J. M. Reisecker, G. Timelthaler, M. D. García, C. Peinador, B. K. Keppler, W. Berger, A. Terenzi, Angew. Chem. Int. Ed. 2019, 58, 8007-8012;

Angew. Chem. 2019, 131, 8091-8096;

M. Gillard, J. Weynand, H. Bonnet, F. Loiseau, A. Decottignies, J. Dejeu, E. Defrancq, B. Elias, Chem. Eur. J. 2020, 26, 13849-13860;

J. Rubio-Magnieto, S. Kajouj, F. Di Meo, M. Fossépré, P. Trouillas, P. Norman, M. Linares, C. Moucheron, M. Surin, Chem. Eur. J. 2018, 24, 15577-15588.

S. K. Mishra, A. Tawani, A. Mishra, A. Kumar, Sci. Rep. 2016, 6, 38144.

A. Minard, D. Morgan, F. Raguseo, A. Di Porzio, D. Liano, A. G. Jamieson, M. Di Antonio, Chem. Commun. 2020, 56, 8940-8943.

H. Song, M. Postings, P. Scott, N. J. Rogers, Chem. Sci. 2021, 12, 1620-1631;

M. J. Hannon, V. Moreno, M. J. Prieto, E. Moldrheim, E. Sletten, I. Meistermann, C. J. Isaac, K. J. Sanders, A. Rodger, Angew. Chem. Int. Ed. 2001, 40, 879-884;

Angew. Chem. 2001, 113, 903-908.

H. Yu, X. Wang, M. Fu, J. Ren, X. Qu, Nucleic Acids Res. 2008, 36, 5695-5703;

J. S. Wang, Y. Chen, J. S. Ren, C. Q. Zhao, X. G. Qu, Nucleic Acids Res. 2014, 42, 3792-3802.

A. Zhao, S. E. Howson, C. Zhao, J. Ren, P. Scott, C. Wang, X. Qu, Nucleic Acids Res. 2017, 45, 5026-5035;

C. Zhao, H. Song, P. Scott, A. Zhao, H. Tateishi-Karimata, N. Sugimoto, J. Ren, X. Qu, Angew. Chem. Int. Ed. 2018, 57, 15723-15727;

Angew. Chem. 2018, 130, 15949-15953727.

S. E. Howson, A. Bolhuis, V. Brabec, G. J. Clarkson, J. Malina, A. Rodger, P. Scott, Nat. Chem. 2012, 4, 31-36.

J. Malina, P. Scott, V. Brabec, Dalton Trans. 2015, 44, 14656-14665;

V. Brabec, S. E. Howson, R. A. Kaner, R. M. Lord, J. Malina, R. M. Phillips, Q. M. A. Abdallah, P. C. McGowan, A. Rodger, P. Scott, Chem. Sci. 2013, 4, 4407-4416.

D. H. Simpson, A. Hapeshi, N. J. Rogers, V. Brabec, G. J. Clarkson, D. J. Fox, O. Hrabina, G. L. Kay, A. K. King, J. Malina, A. D. Millard, J. Moat, D. I. Roper, H. Song, N. R. Waterfield, P. Scott, Chem. Sci. 2019, 10, 9708-9720.

O. Hrabina, J. Malina, H. Kostrhunova, V. Novohradsky, J. Pracharova, N. Rogers, D. H. Simpson, P. Scott, V. Brabec, Inorg. Chem. 2020, 59, 3304-3311.

D. Monchaud, C. Allain, M. P. Teulade-Fichou, Bioorg. Med. Chem. Lett. 2006, 16, 4842-4845.

D. Renciuk, I. Kejnovska, P. Skolakova, K. Bednarova, J. Motlova, M. Vorlickova, Nucleic Acids Res. 2009, 37, 6625-6634.

J. Kypr, I. Kejnovska, D. Renciuk, M. Vorlickova, Nucleic Acids Res. 2009, 37, 1713-1725.

D. Monchaud, C. Allain, H. Bertrand, N. Smargiasso, F. Rosu, V. Gabelica, A. De Cian, J.-L. Mergny, M.-P. Teulade-Fichou, Biochimie 2008, 90, 1207-1223.

J. L. Mergny, J. C. Maurizot, ChemBioChem 2001, 2, 124-132.

T. Kimura, K. Kawai, M. Fujitsuka, T. Majima, Tetrahedron 2007, 63, 3585-3590.

B. Holz, S. Klimasauskas, S. Serva, E. Weinhold, Nucleic Acids Res. 1998, 26, 1076-1083;

E. L. Rachofsky, R. Osman, J. B. A. Ross, Biochemistry 2001, 40, 946-956.

F. X. G. Han, R. T. Wheelhouse, L. H. Hurley, J. Am. Chem. Soc. 1999, 121, 3561-3570.

H. Y. Han, L. H. Hurley, M. Salazar, Nucleic Acids Res. 1999, 27, 537-542;

P. Wang, L. Ren, H. P. He, F. Liang, X. Zhou, Z. Tan, ChemBioChem 2006, 7, 1155-1159.

O. Hrabina, J. Malina, P. Scott, V. Brabec, Chem. Eur. J. 2020, 26, 16554-16562.

J. Malina, P. Scott, V. Brabec, Chem. Eur. J. 2020, 26, 8435-8442.

J. Malina, P. Scott, V. Brabec, Sci. Rep. 2020, 10, 14543.

K. J. Livak, T. D. Schmittgen, Methods 2001, 25, 402-408.

Asymmetric triplex metallohelices stabilise DNA G-quadruplexes in promoter oncogene sequences and efficiently reduce their expression in cancer cells

Metallohelices stabilize DNA three-way junctions and induce DNA damage in cancer cells

Metallohelix vectors for efficient gene delivery via cationic DNA nanoparticles