FULL PAPER DOI: 10.1002/ejic.200900038 New Insights into the Chemistry of the Antineoplastic Lanthanum Complex Tris(1,10-phenanthroline)tris(thiocyanato-κN)lanthanum(III) (KP772) and Its Interaction with Biomolecules Florian Biba, [a] Michael Groessl,* [a] Alexander Egger, [a] Alexander Roller, [a] Christian G. Hartinger, [a] and Bernhard K. Keppler [a] Keywords: Antitumor agents / Lanthanum / N ligands / Heterocycles The lanthanide complex tris(1,10-phenanthroline)tris(thio- cyanato-κN)lanthanum(III) [La(phen) 3 (NCS) 3 ] (KP772) is a promising anticancer drug candidate, capable of overcoming resistance of tumors to established chemotherapeutics. The compound was characterized by elemental analysis, IR, 1 H NMR spectroscopy, TG/DTA measurements, mass spectrom- etry and X-ray diffraction analysis. The results indicate that Introduction Lanthanide compounds, for example with cerium as metal center, have been used for the treatment of cancer (a Gd compound is in clinical development for the treatment of non-small-cell lung cancer), and as anti-emetics due to favorable pharmacological properties. [1,2] In addition, they found application in the treatment of burns and as phos- phate binders against hyperphosphatemia. [2] The mode of action of anticancer-active lanthanides is related to their similarity to calcium: Ln 3+ ions exhibit high affinity to Ca 2+ binding sites in biomolecules because of their similar ionic radii, but are higher charged (HSAB principle). [2,3] There- fore, such compounds are able to inhibit calcium fluxes, re- quired for cell cycle regulation, but they cannot only substi- tute for calcium but also for other metal ions such as Mg 2+ , Fe 3+ and Mn 2+ in proteins, leading to the inhibition of their functions. [4,5] The tumor-inhibiting activity of lanthanum is considerably enhanced by complexation with various li- gands such as phenanthroline derivatives. [6] Phenanthroline induces a cell cycle arrest in G 0 /G 1 , most likely based on its metal-chelating ability. [7,8] The La complex tris(1,10-phenanthroline)tris(thiocyan- ato-κN)lanthanum(III) (KP772; Figure 1) exerts potent ac- tivity against a wide range of tumor cell lines in vitro and a colon carcinoma xenograft model in vivo with properties comparable to cisplatin and methotrexate. [9] Notably, long- [a] University of Vienna, Institute of Inorganic Chemistry, Waehringer Str. 42, 1090 Vienna, Austria Fax: +43-1-4277-52680 E-mail: michael.groessl@univie.ac.at Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejic.200900038. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Inorg. Chem. 2009, 4282–4287 4282 KP772 is a neutral, nine-coordinate complex. In addition the behavior in water, important for the application as a chemo- therapeutic drug, and the binding to biomolecules was inves- tigated by capillary electrophoresis and ICP-MS. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) term treatment of KBC-1 cells with KP772 leads to a com- plete loss of drug resistance, and complementary studies showed that exposition of cells to subtoxic, stepwise in- creasing KP772 concentrations does not lead to acquired resistance. [10] KP772 is expected to be active against multi- drug-resistant tumors, rendering it very interesting for fur- ther (pre)clinical development. [11] Figure 1. Structure of tris(1,10-phenanthroline)tris(thiocyanato- κN)lanthanum(III) (KP772). Herein, the characterization of KP772 with regard to chemical structure, stability in water and reactivity to bio- molecules is described. Binding towards DNA is considered the most important step in the mode of action of successful metal-based anticancer compounds such as cisplatin. [12] Binding studies to nucleotides by capillary electrophoresis (CE) have been shown to be a suitable method to monitor the reaction of metal complexes to DNA model com- pounds. [13–15] Consequently, CE has emerged as a standard analytical procedure in anticancer research, especially due to its compatibility with physiological conditions. These features have made CE also interesting for the analysis of interactions of transition-metal complexes with proteins, es- pecially when coupled to inductively coupled plasma mass