DOI: 10.1002/chem.200601581 Design and Non-Covalent DNA Binding of Platinum(II) Metallacalix[4]arenes Miguel A. Galindo, [d] David Olea, [c] M. Angustias Romero, [d] Julio Gómez, [c] Pedro del Castillo, [c] Michael J. Hannon,* [a] Alison Rodger,* [b] FØlix Zamora,* [c] and Jorge A. R. Navarro* [d] Dedicated to Professor Bernhard Lippert on the occasion of his 60th birthday Introduction The mechanism of interaction of classical DNA-targeting metal-based drugs generally involves covalent binding to nu- cleobase moieties and a low degree of selectivity. [1] There- fore, there is a considerable interest in the design of new DNA-binding metal-based drugs that exhibit enhanced se- lectivity and novel interaction modes, for instance non-cova- lent interactions that mimic the interaction mode of pro- teins. [2,3] Recently, a hexacationic ammonium-functionalised bis-calixarene has been observed to bind DNA and has been proposed to do so through binding in the major groove. [4] Metallacalix[n]arenes are a class of container molecules that are structurally and functionally related to classical organic calixarenes in which the methylene and phenol rings have been respectively replaced by a metal fragment and a bent nitrogen heterocycle. Like their organic analogues, these systems are able to give a rich variety of host–guest interac- tions, which include metal-ion, anion and ion-pair recogni- tion. [5] In this regard, we and others have shown that their cationic nature leads to a concomitant high affinity for Abstract: A set of cyclic tetranuclear complexes of the metallacalix[4]arene type with formula [{Pt(en)(L)} 4 ] 4 + (en = ethylenediamine; 2 : LH = 5- chloro-2-hydroxypyrimidine (5-Cl- Hpymo); 3 : LH = 5-bromo-2-hydroxy- pyrimidine (5-Br-Hpymo); 4 : LH = 5- iodo-2-hydroxypyrimidine (5-I- Hpymo)) have been obtained from the reaction between cis-protected square- planar [Pt(en)ACHTUNGTRENNUNG(H 2 O) 2 ] 2 + metal entities and LH in aqueous media. Additional- ly, the binding properties of 2, 3, 4 and their congener [{Pt(en)(L)} 4 ] 4 + (1: LH = 2-hydroxypyrimidine (Hpymo)) with calf thymus-DNA (ct-DNA) have been studied by using different tech- niques including circular and linear di- chroism (CD and LD, respectively) and UV-visible absorbance spectroscopies, gel electrophoresis, fluorescence com- petitive-binding studies and atomic force microscopy (AFM). The results are consistent with significant non-co- valent interactions taking place be- tween the polynuclear cyclic species and ct-DNA. Moreover, gel electro- phoresis, linear dichroism titrations and AFM images of ct-DNA with metalla- calixarenes show ct-DNA coiling at low metallacalixarene concentrations and upon subsequent increments in metallacalixarene concentration ct- DNA can be seen to uncoil with con- comitant formation of long and inflexi- ble ct-DNA structures. Keywords: atomic force microsco- py · binding studies · DNA · metal- lacalixarenes · platinum [a] Prof. M. J. Hannon School of Chemistry, The University of Birmingham Edgbaston, Birmingham, B15 2TT (UK) Fax: (+ 44)1214-147-871 E-mail: m.j.hannon@bham.ac.uk [b] Prof. A. Rodger Department of Chemistry, University of Warwick Gibbet Hill Road, Coventry, CV4 7AL (UK) Fax: (+ 44)1203-524-112 E-mail: A.Rodger@warwick.ac.uk [c] Dr. D. Olea, Dr. J. Gómez, Dr. P. delCastillo, Dr. F. Zamora Facultad de Ciencias, Universidad Autónoma de Madrid 28049 Madrid (Spain) Fax: (+ 34)91-497-4833 E-mail: felix.zamora@uam.es [d] Dr. M. A. Galindo, Dr. M. A. Romero, Dr. J. A. R. Navarro Departamento de Química Inorgµnica Universidad de Granada Av. Fuentenueva S/N, 18071 Granada (Spain) Fax: (+ 34)95-824-8526 E-mail: jarn@ugr.es Supporting information for this article is available on the WWW under http://www.chemistry.org or from the author. Chem.Eur.J. 2007, 13, 5075–5081 # 2007 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 5075 FULL PAPER