DOI: 10.1002/cmdc.201402066 Cellular Accumulation, Lipophilicity and Photocytotoxicity of Diazido Platinum(IV) Anticancer Complexes Ana M. Pizarro, [a, b] Ruth J. McQuitty, [a] Fiona S. Mackay, [c] Yao Zhao, [a] Julie A. Woods, [d] and Peter J. Sadler* [a] Introduction Cisplatin, cis-[PtCl 2 (NH 3 ) 2 ] or cis-dia- mminedichloridoplatinum(II), is a well-established potent anticancer drug. [1] The mechanism of cisplatin anticancer activity involves platina- tion of two adjacent guanine resi- dues of nuclear DNA—a deadly lesion that results in the de- struction of cancer cells. [2] The persistent problem of severe adverse side effects caused by platinum(II) drugs such as cisplatin, carboplatin and oxali- platin has stimulated exploration of using a less-toxic prodrug. Platinum(IV) complexes can act as prodrugs that undergo re- duction to cytotoxic platinum(II) in vivo. [3] While decreasing ad- verse side effects, reliance upon intracellular reduction does not necessarily improve targeting. Single-wavelength light as a method of activation via photoreduction of photoactivatable platinum(IV) prodrugs offers spatial and temporal resolution, increasing the targeting ability of the platinum pharmaco- phore. [4] We have previously shown that photoactivation of nontoxic platinum(IV) complexes such as trans,trans,trans-[Pt(N 3 ) 2 (OH) 2 - (NH 3 )(py)] (complex 4 in this work), can generate potent cyto- toxic species, up to 80-times more active than cisplatin follow- ing irradiation. Such photoactivated platinum(IV) complexes are capable of causing cell death in a number of cell lines by a mechanism distinct from that of cisplatin. [5] The lipophilicity of a drug is critical to its pharmacological properties. It is thought to be crucial for its absorption, distri- bution, metabolism and excretion in patients. [6] A measure of lipophilicity, and an integral part of Lipinski’s rules, [7] is the par- tition coefficient of a compound, which is usually determined as its partitioning between octanol and water. [8] Lipophilicity can also be related to the retention time of a compound on a reversed-phase column by high-performance liquid chroma- tography (HPLC). [9] Not only can lipophilicity be useful in the pharmacokinetic studies of a drug candidate, but it can also be related to other features, such as cell penetration and accu- mulation, and even cytotoxic potency, which in turn can again provide useful information in an iterative approach to drug design. Lipophilicity is thought to play a key role in the passive influx of drug molecules into cells. [10] Platinum drugs are be- lieved to undergo both passive and active uptake into cells. [11] In addition, although the mechanisms of cisplatin intracellular accumulation are still not fully understood, [12] active efflux and the resulting loss of drug accumulation has been linked to cis- platin resistance in tumour cells. [10b] Complexes with increased lipophilicity may increase passage across the lipid bilayer with- out relying on active/facilitated transport, potentially circum- venting resistance. The mechanisms of transmembrane traffick- ing are currently of much interest, [13] since knowledge of mem- brane transporters implicated in drug accumulation can be The lipophilicity of ten photoactivatable platinum(IV) diazido prodrugs of formula trans,trans,trans-[Pt(N 3 ) 2 (OH) 2 (R)(R’)] (where R and R’ are NH 3 , methylamine, ethylamine, pyridine, 2-pico- line, 3-picoline or thiazole) has been determined by their reten- tion times on reversed-phase HPLC. The lipophilicity of the complexes shows a linear dependence on the lipophilicity (par- tition coefficient) of the ligands. Accumulation of platinum in A2780 human ovarian cancer cells after one hour drug expo- sure in the dark is compared with their cytotoxic potency on activation with UVA (365 nm) and to their lipophilicity. No cor- relation between lipophilicity and intracellular accumulation of platinum was observed, perhaps suggesting involvement of active transport and favoured influx of selected structures. Fur- thermore, no correlation between platinum accumulation and photocytotoxicity was observed in A2780 cancer cells, implying that the type of intracellular damage induced by these com- plexes plays a key role in their cytotoxic effects. [a] Dr. A. M. Pizarro, Dr. R. J. McQuitty, Dr. Y. Zhao, Prof. P.J. Sadler Department of Chemistry, University of Warwick Gibbet Hill Road, Coventry CV4 7AL (UK) E-mail: P.J.Sadler@warwick.ac.uk [b] Dr. A. M. Pizarro IMDEA Nanoscience C/ Faraday 9, Cantoblanco, 28049 Madrid (Spain) [c] Dr. F. S. Mackay Department of Chemistry, University of Edinburgh West Mains Road, Edinburgh EH9 3JJ (UK) [d] Dr. J. A. Woods Photobiology Unit, Department of Dermatology, University of Dundee Ninewells Hospital and Medical School, Dundee DD1 9SY (UK) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201402066.  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemMedChem 2014, 9, 1169 – 1175 1169 CHEMMEDCHEM FULL PAPERS