Palladium(II) and Platinum(II) Organometallic Complexes with the Model Nucleobase Anions of Thymine, Uracil, and Cytosine: Antitumor Activity and Interactions with DNA of the Platinum Compounds O Jose ´ Ruiz,* ,† Julia Lorenzo, ‡ Laura Sanglas, ‡ Natalia Cutillas, † Consuelo Vicente, † Marı ´a Dolores Villa, † Francesc X. Avile ´s, ‡ Gregorio Lo ´ pez, † Virtudes Moreno, § Jose ´ Pe ´ rez, | and Delia Bautista ⊥ Departamento de Quı ´mica Inorga ´ nica, UniVersidad de Murcia, 30071-Murcia, Spain, Institut de Biotecnologı ´a i Biomedicina, Department de Bioquı ´mica i de Biologı ´a Molecular, UniVersitat Auto ` noma de Barcelona, 08193 Barcelona, Spain, Department de Quı ´mica Inorga ` nica, UniVersitat de Barcelona, Martı ´ i Franque ` s 1-11, 08028 Barcelona, Spain, Departamento de Ingenierı ´a Minera, Geolo ´ gica y Cartogra ´ fica, A Ä rea de Quı ´mica Inorga ´ nica, UniVersidad Polite ´ cnica de Cartagena, 30203-Cartagena, Spain, and SUIC, Edificio SACE, UniVersidad de Murcia, 30071-Murcia, Spain Received March 7, 2006 Pd(II) and Pt(II) complexes with the anions of the model nucleobases 1-methylthymine (1-MethyH), 1-methyluracil (1-MeuraH), and 1-methylcytosine (1-MecytH) of the types [Pd(dmba)(µ-L)] 2 [dmba ) N,C-chelating 2-((dimethyl- amino)methyl)phenyl; L ) 1-Methy, 1-Meura or 1-Mecyt] and [M(dmba)(L)(L′)] [L ) 1-Methy or 1-Meura; L′ ) PPh 3 (M ) Pd or Pt), DMSO (M ) Pt)] have been obtained. Palladium complexes of the types [Pd(C 6 F 5 )(N-N)(L)] [L ) 1-Methy or 1-Meura; N-N ) N,N,N′,N′-tetramethylethylenediamine (tmeda), 2,2′-bipyridine (bpy), or 4,4′- dimethyl-2,2′-bipyridine (Me 2 bpy)] and [NBu 4 ][Pd(C 6 F 5 )(1-Methy) 2 (H 2 O)] have also been prepared. The crystal structures of [Pd(dmba)(µ-1-Methy)] 2 , [Pd(dmba)(µ-1-Mecyt)] 2 ‚2CHCl 3 , [Pd(dmba)(1-Methy)(PPh 3 )]‚3CHCl 3 , [Pt(dmba)- (1-Methy)(PPh 3 )], [Pd(tmeda)(C 6 F 5 )(1-Methy)], and [NBu 4 ][Pd(C 6 F 5 )(1-Methy) 2 (H 2 O)]‚H 2 O have been established by X-ray diffraction. The DNA adduct formation of the new platinum complexes synthesized was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by the platinum complexes on plasmid DNA pBR322 were also obtained. Values of IC 50 were also calculated for the new platinum complexes against the tumor cell line HL-60. All the new platinum complexes were more active than cisplatin (up to 20-fold in some cases). Introduction The faster reaction kinetics of Pd(II) electrophiles as compared to the corresponding Pt(II) compounds (ca. 10 5 times) yet otherwise similar chemistry of the two metals make the former convenient analogues for studies of Pt- nucleobase interactions. 1-4 Studies of this kind are of interest with respect to the mode of action of Pt antitumor drugs. 5 Pyrimidine nucleobases (Scheme 1), particularly in their anionic forms, are versatile ligands. In fact, their several potential donor sites enable them to form homo- and heteropolynuclear complexes. These compounds can exhibit metal-metal interactions which nature have been examined. 6-8 Few studies have been directed toward organometallic * To whom correspondence should be addressed. E-mail: jruiz@um.es. Fax: (+34) 968 36 41 48. † Departamento de Quı ´mica Inorga ´nica, Universidad de Murcia. ‡ Institut de Biotecnologı ´a i Biomedicina, Universitat Auto `noma de Barcelona. § Department de Quı ´mica Inorga `nica, Universitat de Barcelona. | A Ä rea de Quı ´mica Inorga ´nica, Universidad Polite ´cnica de Cartagena. ⊥ Edificio SACE, Universidad de Murcia. O Dedicated to Dr. Jose ´-Antonio Abad on the occasion of his retirement. (1) Micklitz, W.; Sheldrick, W. S.; Lippert, B. Inorg. Chem. 1990, 29, 211. (2) Barnham, K. J.; Bauer, C. J.; Djuran, M. I.; Mazid, M. A.; Rau, T.; Sadler, P. J. Inorg. Chem. 1995, 34, 2826. (3) Shen, W.-Z.; Gupta, D.; Lippert, B. Inorg. Chem. 2005, 44, 8249. (4) Cisplatin. Chemistry and Biochemistry of a leading Anticancer Drug; Lippert, B., Ed.; Wiley-VCH: Weinheim, Germany, 1999. (5) Jamieson, E. R.; Lippard, S. J. Chem. Rev. 1999, 99, 2467. (6) Mealli, C.; Pichierri, F.; Randaccio, L.; Zangrando, E.; Krumm, M.; Holthenrich, D.; Lippert, B. Inorg. Chem. 1995, 34, 3418. (7) Kampf, G.; Willermann, M.; Freisinger, E.; Lippert, B. Inorg. Chim. Acta 2002, 330, 179. Inorg. Chem. 2006, 45, 6347-6360 10.1021/ic060374e CCC: $33.50 © 2006 American Chemical Society Inorganic Chemistry, Vol. 45, No. 16, 2006 6347 Published on Web 07/15/2006