Monosaccharides are added to the hydrophilic face of a self-assembled asymmetric FeII metallohelix, using CuAAC chemistry. The sixteen resulting architectures are water-stable and optically pure, and exhibit improved antiproliferative selectivity against colon cancer cells (HCT116 p53+/+ ) with respect to the non-cancerous ARPE-19 cell line. While the most selective compound is a glucose-appended enantiomer, its cellular entry is not mainly glucose transporter-mediated. Glucose conjugation nevertheless increases nuclear delivery ca 2.5-fold, and a non-destructive interaction with DNA is indicated. Addition of the glucose units affects the binding orientation of the metallohelix to naked DNA, but does not substantially alter the overall affinity. In a mouse model, the glucose conjugated compound was far better tolerated, and tumour growth delays for the parent compound (2.6 d) were improved to 4.3 d; performance as good as cisplatin but with the advantage of no weight loss in the subjects.

Department of Biophysics Centre of the Region Hana for Biotechnological and Agricultural Research Faculty of Science Palacký University Šlechtitelů 27 78371 Olomouc Czech Republic

Department of Chemistry University of Warwick Coventry CV4 7AL UK

School of Applied Sciences University of Huddersfield Huddersfield HD1 3DH UK

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

See more in PubMed

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

Faulkner A. D., Kaner R. A., Abdallah Q. M. A., Clarkson G., Fox D. J., Gurnani P., Howson S. E., Phillips R. M., Roper D. I., Simpson D. H., Scott P., Nat. Chem. 2014, 6, 797–803; PubMed

Kaner R. A., Allison S. J., Faulkner A. D., Phillips R. M., Roper D. I., Shepherd S. L., Simpson D. H., Waterfield N. R., Scott P., Chem. Sci. 2016, 7, 951–958; PubMed PMC

Song H., Rogers N. J., Allison S. J., Brabec V., Bridgewater H., Kostrhunova H., Markova L., Phillips R. M., Pinder E. C., Shepherd S. L., Young L. S., Zajac J., Scott P., Chem. Sci. 2019, 10, 8547–8557; PubMed PMC

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

Song H., Rogers N. J., Brabec V., Clarkson G. J., Coverdale J. P. C., Kostrhunova H., Phillips R. M., Postings M., Shepherd S. L., Scott P., Chem. Commun. 2020, 10.1039/D0CC02429E. PubMed DOI

Lehn J.-M., Rigault A., Siegel J., Harrowfield J., Chevrier B., Moras D., Proc. Natl. Acad. Sci. USA 1987, 84, 2565–2569; PubMed PMC

Hotze A. C., Kariuki B. M., Hannon M. J., Angew. Chem. Int. Ed. 2006, 45, 4839–4842; PubMed

Angew. Chem. 2006, 118, 4957–4960;

Vellas S. K., Lewis J. E., Shankar M., Sagatova A., Tyndall J. D., Monk B. C., Fitchett C. M., Hanton L. R., Crowley J. D., Molecules 2013, 18, 6383–6407; PubMed PMC

Glasson C. R., Meehan G. V., Motti C. A., Clegg J. K., Turner P., Jensen P., Lindoy L. F., Dalton Trans. 2011, 40, 10481–10490; PubMed

Gamba I., Rama G., Ortega-Carrasco E., Maréchal J.-D., Martínez-Costas J., Eugenio Vázquez M., López M. V., Chem. Commun. 2014, 50, 11097–11100. PubMed

Howson S. E., Allan L. E., Chmel N. P., Clarkson G. J., van Gorkum R., Scott P., Chem. Commun. 2009, 1727–1729. PubMed

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

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

Angew. Chem. 2018, 130, 15949–15953;

Malina J., Scott P., Brabec V., Nucleic Acids Res. 2015, 43, 5297–5306. PubMed PMC

Mitchell D. E., Clarkson G., Fox D. J., Vipond R. A., Scott P., Gibson M. I., J. Am. Chem. Soc. 2017, 139, 9835–9838. PubMed PMC

Guan Y., Du Z., Gao N., Cao Y., Wang X., Scott P., Song H., Ren J., Qu X., Sci. Adv. 2018, 4, 0. PubMed PMC

Kalafatovic D., Giralt E., Molecules 2017, 22, 1929. PubMed PMC

Stewart K. M., Horton K. L., Kelley S. O., Org. Biomol. Chem. 2008, 6, 2242–2255. PubMed

Sakai N., Matile S., J. Am. Chem. Soc. 2003, 125, 14348–14356; PubMed

Takeuchi T., Kosuge M., Tadokoro A., Sugiura Y., Nishi M., Kawata M., Sakai N., Matile S., Futaki S., ACS Chem. Biol. 2006, 1, 299–303. PubMed

Utsugi T., Schroit A. J., Connor J., Bucana C. D., Fidler I. J., Cancer Res. 1991, 51, 3062–3066; PubMed

Dathe M., Schümann M., Wieprecht T., Winkler A., Beyermann M., Krause E., Matsuzaki K., Murase O., Bienert M., Biochemistry 1996, 35, 12612–12622; PubMed

Riedl S., Zweytick D., Lohner K., Chem. Phys. Lipids 2011, 164, 766–781. PubMed PMC

Fischer P. M., Med. Res. Rev. 2007, 27, 755–795; PubMed

Guidotti G., Brambilla L., Rossi D., Trends Pharmacol. Sci. 2017, 38, 406–424; PubMed

Kauffman W. B., Fuselier T., He J., Wimley W. C., Trends Biochem. Sci. 2015, 40, 749–764. PubMed PMC

Johannssen T., Lepenies B., Trends Biotechnol. 2017, 35, 334–346. PubMed

Derivery E., Bartolami E., Matile S., Gonzalez-Gaitan M., J. Am. Chem. Soc. 2017, 139, 10172–10175; PubMed PMC

Kong L., Almond A., Bayley H., Davis B. G., Nat. Chem. 2016, 8, 461–469; PubMed

Cai L., Gu Z., Zhong J., Wen D., Chen G., He L., Wu J., Gu Z., Drug Discovery Today 2018, 23, 1126–1138; PubMed

Ardá A., Jiménez-Barbero J., Chem. Commun. 2018, 54, 4761–4769. PubMed

Taylor C. M., Tetrahedron 1998, 54, 11317–11362.

Bond M. R., Hanover J. A., J. Cell Biol. 2015, 208, 869–880; PubMed PMC

Yang X., Qian K., Nat. Rev. Mol. Cell Biol. 2017, 18, 452–465. PubMed PMC

Rudd P. M., Elliott T., Cresswell P., Wilson I. A., Dwek R. A., Science 2001, 291, 2370–2376. PubMed

Doores K. J., Gamblin D. P., Davis B. G., Chem. Eur. J. 2006, 12, 656–665; PubMed

Calvaresi E. C., Hergenrother P. J., Chem. Sci. 2013, 4, 2319–2333. PubMed PMC

Jones E., Polt R., Front. Chem. 2015, 3, 40; PubMed PMC

Mulder G. J., Trends Pharmacol. Sci. 1992, 13, 302–304. PubMed

Warburg O., Science 1956, 123, 309–314; PubMed

Warburg O., Wind F., Negelein E., J. Gen. Physiol. 1927, 8, 519. PubMed PMC

Nomoto M., Yamada K., Haga M., Hayashi M., J. Pharm. Sci. 1998, 87, 326–332; PubMed

Poduslo J. F., Curran G. L., Mol. Brain Res. 1994, 23, 157–162; PubMed

Muthu D., Robin P., Curr. Drug Delivery 2005, 2, 59–73. PubMed

Gallego I., Rioboo A., Reina J. J., Díaz B., Canales Á., Cañada F. J., Guerra-Varela J., Sánchez L., Montenegro J., ChemBioChem 2019, 20, 1400–1409. PubMed

Percec V., Leowanawat P., Sun H.-J., Kulikov O., Nusbaum C. D., Tran T. M., Bertin A., Wilson D. A., Peterca M., Zhang S., J. Am. Chem. Soc. 2013, 135, 9055–9077; PubMed

Tanaka J., Gleinich A. S., Zhang Q., Whitfield R., Kempe K., Haddleton D. M., Davis T. P., Perrier S., Mitchell D. A., Wilson P., Biomacromolecules 2017, 18, 1624–1633; PubMed

Adesoye O. G., Mills I. N., Temelkoff D. P., Jackson J. A., Norris P., J. Chem. Educ. 2012, 89, 943–945.

Lipshutz B. H., Taft B. R., Angew. Chem. Int. Ed. 2006, 45, 8235–8238; PubMed

Angew. Chem. 2006, 118, 8415–8418.

Jewett J. C., Bertozzi C. R., Chem. Soc. Rev. 2010, 39, 1272–1279. PubMed PMC

Liu P., Lu Y., Gao X., Liu R., Zhang-Negrerie D., Shi Y., Wang Y., Wang S., Gao Q., Chem. Commun. 2013, 49, 2421–2423. PubMed

Moradi S. V., Hussein W. M., Varamini P., Simerska P., Toth I., Chem. Sci. 2016, 7, 2492–2500. PubMed PMC

Polt R., Dhanasekaran M., Keyari C. M., Med. Res. Rev. 2005, 25, 557–585. PubMed

Varamini P., Mansfeld F. M., Blanchfield J. T., Wyse B. D., Smith M. T., Toth I., J. Med. Chem. 2012, 55, 5859–5867. PubMed

Bapst J.-P., Calame M., Tanner H., Eberle A. N., Bioconjugate Chem. 2009, 20, 984–993. PubMed

Duverger E., Carpentier V., Roche A.-C., Monsigny M., Exp. Cell Res. 1993, 207, 197–201; PubMed

Lefebvre T., Ferreira S., Dupont-Wallois L., Bussière T., Dupire M.-J., Delacourte A., Michalski J.-C., Caillet-Boudin M.-L., Biochim. Biophys. Acta Gen. Subj. 2003, 1619, 167–176; PubMed

Monsigny M., Rondanino C., Duverger E., Fajac I., Roche A.-C., Biochim. Biophys. Acta Gen. Subj. 2004, 1673, 94–103. PubMed

Jamieson E. R., Lippard S. J., Chem. Rev. 1999, 99, 2467–2498. PubMed

Hall H., Gurský J., Nicodemou A., Rybanská I., Kimlíčková E., Piršel M., Mutat. Res. 2006, 593, 177–186. PubMed

Malina J., Hannon M. J., Brabec V., Nucleic Acids Res. 2008, 36, 3630–3638. PubMed PMC

Wolfe S. A., Nekludova L., Pabo C. O., Annu. Rev. Biophys. Biomol. Struct. 2000, 29, 183–212. PubMed

Pavletich N. P., Pabo C. O., Science 1991, 252, 809–817. PubMed

Dicobalt(ii) helices kill colon cancer cells via enantiomer-specific mechanisms; DNA damage or microtubule disruption