DOI: 10.1002/chem.201101148 Pt II Coordination to N1 of 9-Methylguanine: Why it Facilitates Binding of Additional Metal Ions to the Purine Ring Barbara Müller, [a] Wei-Zheng Shen, [a] Pablo J. Sanz Miguel, [b] Francisca M. Albertí, [a] Tushar van der Wijst, [a] Marc Noguera, [c] Luis Rodríguez-Santiago, [c] Mariona Sodupe, [c] and Bernhard Lippert* [a] Introduction In general, the N1 position of N9-blocked guanine nucleo- bases is not a kinetically preferred metal-binding site under physiological pH conditions, unlike N7, which is unprotonat- ed over a wide pH range (pK a of the guaninium cation is in the order of 2 to 3), displays a favorable orientation of the guanine dipole moment for attracting cations, and in double-stranded DNA is highly accessible in the major groove. [1] The N1 site, on the other hand, is located in the in- terior of DNA, involved in hydrogen bonding with cytosine, is protonated up to a moderately alkaline pH (pK a  9.5), and is surrounded by two exocyclic groups, O6 and N2H 2 , which can impair metal binding. Still, metal coordination to N1 of guanine has been verified in several instances, both with the corresponding nucleoside and oligonucleotides [2] as well as model nucleobases (9-alkylguanines), sometimes in combination with N7 or even N3. [3–6] In fact, we observed that twofold metal binding to the preferred N7 and the less- preferred N3 site acidifies the N1H position to such an extent that it becomes deprotonated at physiological pH. [7] Apart from understanding such basic mechanisms, we were particularly interested in the following specific aspects of metal coordination to N1 of guanine: first, the question of basicity of the guaninato ligand upon Pt II binding to N1. It relates to the propensity of metalated anionic nucleobases to bind either a proton and to thereby generate a metal-sta- bilized rare nucleobase tautomer, [8] or to bind additional metal cations to produce multinuclear complexes. With N3- platinated 1-methyluracilato (1-MeU) and 1-methylthymina- to (1-MeT) species, these points have been studied exten- sively. [9, 10] The second aspect, which likewise is related to the first one and had caught our attention, is the use of gua- Abstract: The preparation and X-ray crystal structure analysis of {trans-[Pt- ACHTUNGTRENNUNG(MeNH 2 ) 2 ACHTUNGTRENNUNG(9-MeG-N1) 2 ]}·ACHTUNGTRENNUNG{3 K 2 ACHTUNGTRENNUNG[Pt- ACHTUNGTRENNUNG(CN) 4 ]}·6H 2 O(3a) (with 9-MeG being the anion of 9-methylguanine, 9- MeGH) are reported. The title com- pound was obtained by treating [Pt- ACHTUNGTRENNUNG(dien)(9-MeGH-N7)] 2 + (1; dien = di- ethylenetriamine) with trans-[Pt- ACHTUNGTRENNUNG(MeNH 2 ) 2 ACHTUNGTRENNUNG(H 2 O) 2 ] 2 + at pH 9.6, 60 8C, and subsequent removal of the [(dien)- Pt II ] entities by treatment with an excess amount of KCN, which converts the latter to [Pt(CN) 4 ] 2 . Cocrystalliza- tion of K 2 [Pt(CN) 4 ] with trans-[Pt- ACHTUNGTRENNUNG(MeNH 2 ) 2 ACHTUNGTRENNUNG(9-MeG-N1) 2 ] is a conse- quence of the increase in basicity of the guanine ligand following its depro- tonation and Pt coordination at N1. This increase in basicity is reflected in the pK a values of trans-[PtACHTUNGTRENNUNG(MeNH 2 ) 2 (9- MeGH-N1) 2 ] 2 + (4.4  0.1 and 3.3  0.4). The crystal structure of 3a reveals rare (N7,O6 chelate) and unconventional (N2,C2,N3) binding patterns of K + to the guaninato ligands. DFT calcula- tions confirm that K + binding to the sugar edge of guanine for a N1-plati- nated guanine anion is a realistic option, thus ruling against a simple packing effect in the solid-state struc- ture of 3a. The linkage isomer of 3a, trans-[PtACHTUNGTRENNUNG(MeNH 2 ) 2 ACHTUNGTRENNUNG(9-MeG-N7) 2 ] (6a) has likewise been isolated, and its acid–base properties determined. Com- pound 6a is more basic than 3a by more than 4 log units. Binding of metal entities to the N7 positions of 9-MeG in 3a has been studied in detail for [(NH 3 ) 3 Pt II ], trans-[(NH 3 ) 2 Pt II ], and [(en)Pd II ] (en = ethylenediamine) by using 1 H NMR spectroscopy. Without exception, binding of the second metal takes place at N7, but formation of a molecular guanine square with trans- [(Me 2 NH 2 )Pt II ] cross-linking N1 posi- tions and trans-[(NH 3 ) 2 Pt II ] cross-link- ing N7 positions could not be con- firmed unambiguously, despite the fact that calculations are fully consistent with its existence. Keywords: bioinorganic chemistry · guanine · nucleobases · platinum · transition metals [a] Dr. B. Müller, Dr. W.-Z. Shen, Dr. F.M. Albertí, Dr. T. van der Wijst, Prof. B. Lippert Fakultät Chemie, Technische Unversität Dortmund Otto-Hahn-Strasse 6, 44221 Dortmund (Germany) Fax: (+ 49) 231-755-3797 E-mail : bernhard.lippert@tu-dortmund.de [b] Dr. P. J. Sanz Miguel Departamento de Química Inorgµnica Instituto de Síntesis Química y Catµlisis HomogØnea (ISQCH) Universidad de Zaragoza—CSIC, 50009 Zaragoza (Spain) [c] Dr. M. Noguera, Dr. L. Rodríguez-Santiago, Prof. M. Sodupe Department de Química, Universitat Autónoma Barcelona Bellaterra, 08193 Barcelona (Spain) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201101148.  2011 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 9970 – 9983 9970