DOI: 10.1002/asia.201100883 Preparation of Organometallic Ruthenium–Arene–Diaminotriazine Complexes as Binding Agents to DNA Natalia Busto, [a] Jesffls Valladolid, [a] Cristina Aliende, [a] FØlix A. Jalón, [b] Blanca R. Manzano, [b] Ana M. Rodríguez, [b] Jorge F. Gaspar, [c] Celia Martins, [c] Tarita Biver, [d] Gustavo Espino,* [a] JosØ María Leal, [a] and BegoÇa García* [a] Introduction The breakthrough synthesis of cisplatin in 1965 revolution- ized cancer chemotherapy and opened new horizons in the search for new metal-based drugs. [1–3] Decades later, it is still one of the most-efficient treatments in clinical use despite its side-effects. [4] Since then, a lot of metallic compounds have been investigated, and a few of them have been suc- cessfully used as anticancer drugs. Moreover, we have learnt that both the pharmacological targets and the modes of action are not universal. Consequently, open-minded strat- egies must be conceived not only in the design but also in the evaluation of these metallodrugs. More recently, organometallic compounds have emerged as a very interesting alternative resource in medicinal chemistry for several reasons. First of all, these hybrids com- bine features of both, the metallic center and one or more organic fragments. On the one hand, these compounds are endowed with the versatile stereochemistry and redox prop- erties of the corresponding metal cation, together with its ability to bind to biological targets. On the other hand, or- ganometallic species can exhibit a huge variety of function- alized organic ligands with very specific reactivities. In par- ticular, it is possible to prepare sturdy Ru II –arene complexes of the general formula [(h 6 -arene)RuCl 2 (L)] or [(h 6 - arene)RuClACHTUNGTRENNUNG(L-L)]Y, where the characteristic p-bonded arene is relatively inert to displacement under physiological conditions [4] and provides redox stability by withdrawing electronic density from the metal ion. [5] These arenes may [a] Dr. N. Busto, J. Valladolid, C. Aliende, Dr. G. Espino, Prof. J.M. Leal, Prof. B. García Departamento de Química Facultad de Ciencias. Universidad de Burgos Plaza Misael BaÇuelos s.n., 09001, Burgos (Spain) Fax: (+ 34) 947-258831 E-mail : gespino@ubu.es begar@ubu.es [b] Prof. F. A. Jalón, Prof. B. R. Manzano, Dr. A. M. Rodríguez Departamento de Química Inorgµnica, Orgµnica y Bioquímica Facultad de Químicas-IRICA. Universidad de Castilla-La Mancha Avda. Camilo JosØ Cela, 10, 13071, Ciudad Real (Spain) [c] Prof. J.F. Gaspar, C. Martins Departamento de GenØtica Universidade Nova de Lisboa Faculdade de Ciencias MØdicas, CIGMH 1349-008, Lisboa (Portugal) [d] Dr. T. Biver Chemistry and Industrial Chemistry Department University of Pisa 56126 Pisa (Italy) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201100883. Abstract: The reactions of two diami- notriazine ligands 2,4-diamino-6-(2-pyr- idyl)-1,3,5-triazine (2-pydaT) and 6- phenyl-2,4-diamino-1,3,5-triazine (PhdaT) with ruthenium–arene precur- sors led to a new family of rutheniu- m(II) compounds that were spectro- scopically characterized. Four of the complexes were cationic, with the gen- eral formula [(h 6 -arene)Ru(k 2 -N,N-2- pydaT)Cl]X (X = BF 4 , TsO; arene = p- cymene: 1·BF 4 , 1·TsO; arene = ben- zene: 2·BF 4 , 2·TsO). The neutral cyclo- metalated complex [(h 6 -p-cymene)R- u(k 2 -C,N-PhdaT*)Cl] (3) was also iso- lated. The structures of complexes 2·BF 4 and 3·H 2 O were determined by X-ray diffraction. Complex 1·BF 4 un- derwent a partial reversible-aquation process in water. UV/Vis and NMR spectroscopic measurements showed that the reaction was hindered by the addition of NaCl and was pH-con- trolled in acidic solution. At pH 7.0 (sodium cacodylate) Ru–Cl complex 1·BF 4 was the only species present in solution, even at low ionic strength. However, in alkaline medium (KOH), complex 1·BF 4 underwent basic hydrol- ysis to afford a Ru–OH complex (5). Fluorimetric studies revealed that the interaction of complex 1·BF 4 with DNA was not straightforward; instead, its main features were closely linked to ionic strength and to the [DNA]/com- plex ratio. The bifunctional complex 1·BF 4 was capable of interacting con- currently through both its p-cymene and 2-pydaT groups. Cytotoxicity and genotoxicity studies showed that, con- trary to the expected behavior, the complex species was biologically inac- tive; the formation of a Ru–OH com- plex could be responsible for such be- havior. Keywords: arenes · DNA · organo- metallic complexes · ruthenium · triazines 788  2012 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Asian J. 2012, 7, 788 – 801 FULL PAPERS