title: Unique DNA binding mode of antitumor trinuclear tridentate platinum(II) compound.
abstract: The new trinuclear tridentate Pt(II) complex [Pt(3)Cl(3)(hptab)](3+) (1; hptab = N,N,N',N',N'',N''-hexakis(2-pyridylmethyl)-1,3,5-tris(aminomethyl)benzene) exhibits promising cytotoxic effects in human and mouse tumor cells including those resistant to conventional cisplatin (Dalton Trans. 2006, 2617; Chem. Eur. J. 2009, 15, 5245). The present study is focused on the molecular pharmacology of 1, in particular on its interactions with DNA (which is the major pharmacological target of platinum antitumor drugs), to elucidate more deeply the mechanism underlying its antitumor effects. Results obtained with the aid of methods of molecular biophysics and pharmacology reveal new details of DNA modifications by 1. Complex 1 binds to DNA forming in the absence of proteins and molecular crowding agents mainly trifunctional intrastrand cross-links. In these DNA adducts all three Pt(II) centers of 1 are coordinated to DNA base residues, which leads to extensive conformational alterations in DNA. An intriguing aspect of the DNA-binding mode of this trinuclear Pt(II) complex 1 is that it can cross-link proteins to DNA. Even more interestingly, 1 can cross-link in the presence of molecular crowding agent, which mimics environmental conditions in cell nucleus, two DNA duplexes in a high yield--a feature observed for the first time for antitumor trinuclear platinum complexes. Thus, the concept for the design of agents capable of forming intramolecular tridentate DNA adducts, DNA-protein and interduplex DNA-DNA cross-links based on trinuclear tridentate Pt(II) complexes with semirigid aromatic linkers may result in new compounds which exhibit a variety of biological effects and can be also useful in nucleic acids research.
authors: Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic.
authors: Radana
authors: R
authors: Olivova
authors: Jana
authors: J
authors: Kasparkova
authors: Oldrich
authors: O
authors: Vrana
authors: Marie
authors: M
authors: Vojtiskova
authors: Tereza
authors: T
authors: Suchankova
authors: Olga
authors: O
authors: Novakova
authors: Weijiang
authors: W
authors: He
authors: Zijian
authors: Z
authors: Guo
authors: Viktor
authors: V
authors: Brabec
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D009944:Organoplatinum Compounds; C542128:Pt(3)Cl(3)-(N,N,N',N',N'',N''-hexakis(2-pyridylmethyl)-1,3,5-tris(aminomethyl)benzene)(perchlorate); D004247:DNA