Antitumor Agents DOI: 10.1002/anie.201303251 Robust Structure and Reactivity of Aqueous Arsenous Acid– Platinum(II) Anticancer Complexes** enana U. Miodragovic ´, Jeremy A. Quentzel, Josh W. Kurutz, Charlotte L. Stern, Richard W. Ahn, Irawati Kandela, Andrew Mazar, and Thomas V. OHalloran* Two inorganic drugs, the widely used cis-diamminedichloro- platinum(II) [1] and antileukemia agent arsenic trioxide, are highly successful agents for treatment of cancer. Cisplatin is used in combination chemotherapy to treat ovarian, testicu- lar, head, neck, and bladder cancers. [2] Unfortunately, these and other cancers frequently develop resistance to this drug and there are intensive efforts to develop new agents that overcome cisplatin resistance. [3] As 2 O 3 , discovered as a tradi- tional Chinese medicine, is now an FDA-approved front line treatment for acute promyelocytic leukemia [4] and has also shown preliminary efficacy in the treatment of blood cancers such as multiple myeloma and myelodysplastic syndromes. [4a] Both compounds induce apoptotic cell death, but through different pathways: cisplatin reacts with DNA and causes intra- and interstrand DNA cross-links, [2a,d] whereas at low concentrations arsenous acid, the principal component of aqueous solutions of As 2 O 3 at pH 7, can react with and trigger degradation of key zinc-depen- dent regulatory proteins and also inhibit angiogenesis, migra- tion, and invasion. At higher concentrations it triggers apop- tosis [5, 6] through pathways that involve elevated levels of reac- tive oxygen species (ROS) in mitochondria. [4a, 5, 7] Synergistic activity of these drugs has been reported [8] supporting the idea that compounds combining both species may have advantages as anticancer therapeutics. The only example of a platinum adduct with arsenous acid in the literature emerged in efforts to develop efficient systems for loading As 2 O 3 into liposomes with aquated forms of cisplatin: extended X-ray absorption fine structure (EXAFS) spectroscopy suggested that a new type of Pt II –As III center was stabilized in the nanocrystalline formulation. [9] Given the absence of structural precedents in the literature, it was not clear that such complexes could exist or would be stable in aqueous solution. Herein we report synthetic routes to a novel family of small-molecule com- plexes of the aqueous form of As 2 O 3 bound directly to Pt II as an As(OH) 2 moiety and demonstrate that their robust molecular structure involves an As III center that acts simulta- neously as a Lewis acid and a Lewis base. These arsenoplatins are stable in solution and exhibit chemical bonding, ligand substitution chemistry, and biological activities that are distinct from the parent compounds and show promising activity in drug-resistant cancer cell lines. Arsenoplatin 1 (Figure 1) is synthesized by heating cisplatin with As 2 O 3 in an acetonitrile/water mixture (9:1, v/v) at 90 8C for three days. The yield increases from 23% to 75% when the starting material is K 2 [PtCl 4 ] (see the Supporting Information for syntheses and characterizations of 1–3). Variations on this Pt–As core complex are accessible by varying the substituent on the nitrile. For instance, arseno- platin 2 is obtained from the reaction of K 2 [PtCl 4 ] with As 2 O 3 in the presence of propionitrile (Figure 1). Conditions for the synthesis of 2 were different from 1 owing to the different miscibility of propionitrile in water (1:9, v/v). Complex 2 is obtained at room temperature after 4 days, whereas 1 is Figure 1. Thermal ellipsoid plots of a) complex 1a (1 crystallizes in two crystal systems) and b) complex 2. Solvent molecules have been omitted for clarity. The plots are drawn at 50% probability level. [10] [*] Dr. . U. Miodragovic ´, J. A. Quentzel, Dr. J. W. Kurutz, C. L. Stern, Dr. R. W. Ahn, Dr. I. Kandela, Prof.Dr. A. Mazar, Prof.Dr. T. V. O’Halloran Chemistry of Life Processes Institute and Department of Chemistry Northwestern University 2145 Sheridan Road, Evanston, IL 60208 (USA) E-mail: t-ohalloran@northwestern.edu Homepage: http://www.chemistry.northwestern.edu/faculty/ thomas-ohalloran.html [**] We thank the NIH (NCI Cancer Nanotechnology Platform Partner- ships Grant U01CA151461 and PSOC grant U54CA143869, Center of Cancer Nanotechnology Excellence Grants U54CA119341, P50CA090386, and Core Grant P30CA060553 to the Robert H. Lurie Comprehensive Cancer Center) and the CDMRP Breast Cancer Research Program BC076723 for funding. R. W. Ahn thanks the CDMRP Breast Cancer Research Program Predoctoral Fellowship (BC073413). We thank Prof. M. Djuran, Dr. E. Que, and E. Swindell for valuable discussions. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201303251. A ngewandte Chemi e 10749 Angew. Chem. Int. Ed. 2013, 52, 10749 –10752  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim