Anticancer metallohelices: nanomolar potency and high selectivity† †Electronic supplementary information (ESI) available: Experimental details, syntheses, biophysical analyses, antimicrobial, anticancer, toxicity, and mechanistic studies. See DOI: 10.1039/c5sc03677a Click here for additional data fi

New optically pure helicate-like architectures are extremely active against cancer cell lines, with IC50 values as low as 40 nM, but nearly three orders of magnitude less active against healthy cells. There is also low toxicity to microbes and amoeba.

[1]  V. Brabec,et al.  Recognition of DNA/RNA bulges by antimicrobial and antitumor metallohelices. , 2015, Dalton transactions.

[2]  V. Brabec,et al.  Shape-selective recognition of DNA abasic sites by metallohelices: inhibition of human AP endonuclease 1 , 2015, Nucleic acids research.

[3]  Rebecca A. Kaner,et al.  Metallohelices: potential mimetics of α-helical peptides in cancer treatment? , 2015, Future medicinal chemistry.

[4]  Rebecca A. Kaner,et al.  Asymmetric triplex metallohelices with high and selective activity against cancer cells. , 2014, Nature chemistry.

[5]  X. Qu,et al.  Chiral metallohelical complexes enantioselectively target amyloid β for treating Alzheimer's disease. , 2014, Journal of the American Chemical Society.

[6]  John G. Moffat,et al.  Phenotypic screening in cancer drug discovery — past, present and future , 2014, Nature Reviews Drug Discovery.

[7]  D. Green,et al.  Die another way – non-apoptotic mechanisms of cell death , 2014, Journal of Cell Science.

[8]  J. Milner,et al.  Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53-independent pathways , 2014, Oncogenesis.

[9]  Rebecca A. Kaner,et al.  Metallohelices with activity against cisplatin-resistant cancer cells; does the mechanism involve DNA binding? , 2013 .

[10]  Corbin E. Meacham,et al.  Tumour heterogeneity and cancer cell plasticity , 2013, Nature.

[11]  U. Eggert.  The why and how of phenotypic small-molecule screens. , 2013, Nature chemical biology.

[12]  F. Sams-Dodd,et al.  Is poor research the cause of the declining productivity of the pharmaceutical industry? An industry in need of a paradigm shift. , 2013, Drug discovery today.

[13]  M. Li,et al.  Metallosupramolecular complex targeting an α/β discordant stretch of amyloid β peptide , 2012 .

[14]  D. Sall,et al.  Modern phenotypic drug discovery is a viable, neoclassic pharma strategy. , 2012, Journal of medicinal chemistry.

[15]  S. Howson,et al.  Approaches to the synthesis of optically pure helicates. , 2011, Dalton transactions.

[16]  G. Clarkson,et al.  Origins of stereoselectivity in optically pure phenylethaniminopyridine tris-chelates M(NN')3(n+) (M = Mn, Fe, Co, Ni and Zn). , 2011, Dalton transactions.

[17]  Matthias Ernst,et al.  Cancer research: past, present and future , 2011, Nature Reviews Cancer.

[18]  D. Swinney,et al.  How were new medicines discovered? , 2011, Nature Reviews Drug Discovery.

[19]  N. Hodges,et al.  Arginine conjugates of metallo-supramolecular cylinders prescribe helicity and enhance DNA junction binding and cellular activity. , 2011, Chemical communications.

[20]  Stefan Grimme,et al.  Effect of the damping function in dispersion corrected density functional theory , 2011, J. Comput. Chem..

[21]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[22]  Adeline R. Whitney,et al.  Complete Nucleotide Sequence Analysis of Plasmids in Strains of Staphylococcus aureus Clone USA300 Reveals a High Level of Identity among Isolates with Closely Related Core Genome Sequences , 2010, Journal of Clinical Microbiology.

[23]  A. Rodger,et al.  Antimicrobial activity of an iron triple helicate. , 2009, International journal of antimicrobial agents.

[24]  G. Clarkson,et al.  Self-assembling optically pure Fe(A-B)3 chelates. , 2009, Chemical communications.

[25]  Robert J. Deeth,et al.  Molecular modelling for transition metal complexes: Dealing with d-electron effects , 2009 .

[26]  V. Brabec,et al.  DNA binding of dinuclear iron(II) metallosupramolecular cylinders. DNA unwinding and sequence preference , 2008, Nucleic acids research.

[27]  Liang Chen,et al.  Epidemic community-associated methicillin-resistant Staphylococcus aureus: Recent clonal expansion and diversification , 2008, Proceedings of the National Academy of Sciences.

[28]  P. Gütlich,et al.  Does the solid-liquid crystal phase transition provoke the spin-state change in spin-crossover metallomesogens? , 2008, Journal of the American Chemical Society.

[29]  J. Milner,et al.  SIRT3 is Pro-Apoptotic and Participates in Distinct Basal Apoptotic Pathways , 2007, Cell cycle.

[30]  H. Verheul,et al.  Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition , 2007, Nature Reviews Cancer.

[31]  S. Khalid,et al.  Enantiomeric resolution of supramolecular helicates with different surface topographies. , 2007, Dalton transactions.

[32]  Benjamin Williams-Hubbard,et al.  DommiMOE: An implementation of ligand field molecular mechanics in the molecular operating environment , 2005, J. Comput. Chem..

[33]  R. ffrench-Constant,et al.  A single Photorhabdus gene, makes caterpillars floppy (mcf), allows Escherichia coli to persist within and kill insects , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Thierry Soussi,et al.  Assessing TP53 status in human tumours to evaluate clinical outcome , 2001, Nature Reviews Cancer.

[35]  K. Kinzler,et al.  Disruption of p53 in human cancer cells alters the responses to therapeutic agents. , 1999, The Journal of clinical investigation.

[36]  L. Hjelmeland,et al.  ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. , 1996, Experimental eye research.

[37]  A. Klamt.  Conductor-like Screening Model for Real Solvents: A New Approach to the Quantitative Calculation of Solvation Phenomena , 1995 .

[38]  Mark S. Gordon,et al.  General atomic and molecular electronic structure system , 1993, J. Comput. Chem..

[39]  J. Siegel,et al.  Spontaneous assembly of double-stranded helicates from oligobipyridine ligands and copper(I) cations: structure of an inorganic double helix. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[40]  T. Hsu,et al.  A human breast adenocarcinoma with chromosome and isoenzyme markers similar to those of the HeLa line. , 1979, Journal of the National Cancer Institute.

[41]  R. Stephenson.  A and V , 1962, The British journal of ophthalmology.

[42]  W. Marsden.  I and J , 2012 .

[43]  Frank Neese,et al.  The ORCA program system , 2012 .

[44]  V. Brabec,et al.  Optically pure, water-stable metallo-helical 'flexicate' assemblies with antibiotic activity. , 2011, Nature chemistry.

[45]  J. Andrews.  Determination of minimum inhibitory concentrations. , 2001, The Journal of antimicrobial chemotherapy.

[46]  Aris Persidis,et al.  Cancer multidrug resistance , 1999, Nature Biotechnology.

[47]  S. Reynolds,et al.  Food and water economy and its relation to growth in fifth-instar larvae of the tobacco hornworm, Manduca sexta , 1985 .