Multifaceted Studies of the DNA Interactions and In Vitro Cytotoxicity of Anticancer Polyaromatic Platinum(II) Complexes

Abstract

(2016) Multifaceted studies of the DNA interactions and in vitro cytotoxicity of anticancer polyaromatic platinum(II) complexes. Chemistry -A European Journal, 22 (26). pp. 8943-8954. Permanent WRAP URL: http://wrap.warwick.ac.uk/80972 Copyright and reuse:The Warwick Research Archive Portal (WRAP) makes this work by researchers of the University of Warwick available open access under the following conditions. Copyright © and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable the material made available in WRAP has been checked for eligibility before being made available.Copies of full items can be used for personal research or study, educational, or not-for profit purposes without prior permission or charge. Provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. Publisher's statement:"This is the peer reviewed version of the following article: Pages, Benjamin J., Sakoff, Jennette, Gilbert, Jayne, Rodger, Alison, Chmel, Nikola P., Jones, Nykola C., Kelly, Sharon M., Ang, Dale L. and Aldrich-Wright, Janice R.. (2016) Multifaceted studies of the DNA interactions and in vitro cytotoxicity of anticancer polyaromatic platinum(II) complexes. Chemistry -A European Journal, 22 (26). pp. 8943-8954.which has been published in final form at http://dx.doi.org/10.1002/chem.201601221 This article may be used for noncommercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving." A note on versions:The version presented here may differ from the published version or, version of record, if you wish to cite this item you are advised to consult the publisher's version. Please see the 'permanent WRAP URL' above for details on accessing the published version and note that access may require a subscription.For more information, please contact the WRAP Team at: wrap@warwick.ac.uk FULL PAPER Multifaceted studies of the DNA interactions and in vitro cytotoxicity of anticancer polyaromatic platinum(II) complexesBenjamin J. Pages, [a] Jennette Sakoff, [b] Jayne Gilbert, [b] Alison Rodger, [c] Nikola P. Chmel, [c] Nykola C. Jones, [d] Sharon M. Kelly, [e] Dale L. Ang, [a] Janice R. Aldrich-Wright.* [a] Abstract: This paper reports a detailed biophysical analysis of the DNA binding and cytotoxicity of six platinum complexes (PCs). They are of the type [Pt(PL)(SS-dach)]Cl2, where PL is a polyaromatic ligand and SS-dach is 1S,2S-diaminocyclohexane. The DNA binding of these complexes was investigated using six techniques including ultraviolet and fluorescence spectroscopy, linear dichroism, synchrotron radiation circular dichroism, isothermal titration calorimetry and mass spectrometry. This portfolio of techniques has not been extensively used to study the interactions of such complexes previously; each assay provided unique insight. The in vitro cytotoxicity of these ...

Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines

“…To decrease the reaction with diverse metabolic biomolecules, such as the thiol-containing metallothionein proteins and GSH, and facilitate DNA binding, new designs for covalently binding platinum drugs are desirable. Therefore, 9-aminoacridine Pt-complexes [ 45 ], hybrid compounds combining biologically active nitroxyl radicals and platinum pharmacophores [ 46 ], or other platinum intercalators with high anti-cancer activity, such as multinuclear complexes with active ligands were developed to increase cellular cisplatin uptake, lower the reactivity with the aforementioned metabolic biomolecules, and elevate interstrand crosslinking [ 47 , 48 ]. Further in vitro and in vivo studies are necessary to validate their efficiency in the future.…”

Transition Metal Intercalators as Anticancer Agents—Recent Advances

“…Interactions of these platinum complexes (PCs) with DNA have been studied using various spectroscopic techniques as well as mass spectrometry and isothermal titration calorimetry, which provided evidence for a GC-selective intercalative binding mode and DNA affinity in the range of ~10 4 –10 6 M −1 [27]. In vitro cytotoxicity assays showed greater activity than cisplatin and its analogues against a range of cell lines with a number of complexes demonstrating low-nanomolar activity (Table 1) [27].…”

“…In vitro cytotoxicity assays showed greater activity than cisplatin and its analogues against a range of cell lines with a number of complexes demonstrating low-nanomolar activity (Table 1) [27]. For complexes consisting of bpy (i.e., Pt5 ), phen (i.e., Pt1 ) or their derivatives thereof, a correlation was apparent between DNA binding affinity and cytotoxicity where a higher DNA binding affinity was directly proportional to increased cytotoxicity, indicating DNA binding influences the apoptotic activity of these PCs.…”

Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

“…These PCs are active against cisplatin-resistant cell lines, 18 induce cell death in cancerous cells by a caspaseindependent mechanism, [18][19][20] and bind to DNA through non-covalent intercalation. 21 In particular, the lead complex [Pt(5,6-dimethyl-phen)(SS-dach)]Cl 2 (56MESS, Figure 1) is up to 100 times more active than cisplatin in several cell lines, with nanomolar activity against L1210 murine leukaemia and Du145 prostate cancer cells. 21 These polyaromatic PCs and kiteplatin each have demonstrated great potential as platinum drug candidates, due to their different cellular mechanisms and enhanced DNA repair inhibition, respectively, and due to their outperformance of cisplatin in several cell lines.…”

“…21 In particular, the lead complex [Pt(5,6-dimethyl-phen)(SS-dach)]Cl 2 (56MESS, Figure 1) is up to 100 times more active than cisplatin in several cell lines, with nanomolar activity against L1210 murine leukaemia and Du145 prostate cancer cells. 21 These polyaromatic PCs and kiteplatin each have demonstrated great potential as platinum drug candidates, due to their different cellular mechanisms and enhanced DNA repair inhibition, respectively, and due to their outperformance of cisplatin in several cell lines. These factors, in addition to kiteplatin's higher activity than that of [Pt(1R,2R-dach)Cl 2 ], 8 prompted the development of polyaromatic PCs incorporating 1,4-dach as an A L and phen, 5methyl-phen (5Mephen) and 5,6-dimethyl-phen (56Me 2 phen) as a P L (to produce complexes 1, 2 and 3 respectively, Figure 1).…”