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Unique DNA binding mode of antitumor trinuclear tridentate platinum(II) compound.
Olivova, Radana; Kasparkova, Jana; Vrana, Oldrich; Vojtiskova, Marie; Suchankova, Tereza; Novakova, Olga; He, Weijiang; Guo, Zijian; Brabec, Viktor.
Afiliação
  • Olivova R; Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic.
Mol Pharm ; 8(6): 2368-78, 2011 Dec 05.
Article em En | MEDLINE | ID: mdl-22050363
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Compostos Organoplatínicos / DNA / Antineoplásicos Limite: Animals / Humans Idioma: En Ano de publicação: 2011 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Compostos Organoplatínicos / DNA / Antineoplásicos Limite: Animals / Humans Idioma: En Ano de publicação: 2011 Tipo de documento: Article