|
|||||
|
|
Mechanistic insights into antitumor effects of new dinuclear cis Pt complexes containing aromatic linkers |
|
| Authors: | Lenka Zerzankova Marie Vojtiskova Tereza Suchankova Zijian Guo Viktor Brabec |
| Affiliation: | a Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic b Department of Experimental Physics, Faculty of Sciences, Palacky University, tr. Svobody 26, 77146 Olomouc, Czech Republic c State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, PR China |
| Abstract: | The primary objective was to understand more deeply the molecular mechanism underlying different antitumor effects of dinuclear PtII complexes containing aromatic linkers of different length, {[cis-Pt(NH3)2Cl]2(4,4′-methylenedianiline)}2+ (1) and {[cis-Pt(NH3)2Cl]2(α,α′-diamino-p-xylene)}2+ (2). These complexes belong to a new generation of promising polynuclear platinum drugs resistant to decomposition by sulfur nucleophiles which hampers clinical use of bifunctional polynuclear trans PtII complexes hitherto tested. Results obtained with the aid of methods of molecular biophysics and pharmacology reveal differences and new details of DNA modifications by 1 and 2 and recognition of these modifications by cellular components. The results indicate that the unique properties of DNA interstrand cross-links of this class of polynuclear platinum complexes and recognition of these cross-links may play a prevalent role in antitumor effects of these metallodrugs. Moreover, the results show for the first time a strong specific recognition and binding of high-mobility-group-domain proteins, which are known to modulate antitumor effects of clinically used platinum drugs, to DNA modified by a polynuclear platinum complex. |
| Keywords: | BBR3464, [{trans-PtCl(NH3)2}2-μ-trans-Pt(NH3)2(NH2(CH2)6NH2)2]4+ BBR3610, [{trans-PtCl(NH3)2}2-μ-{trans-H2N(CH2)6NH2(CH2)2NH2(CH2)6NH2}]4+ bp, base pair Cisplatin, cis-diamminedichloridoplatinum(II) CFE, cell-free extract CL, cross-link Complex boldFont" >1, {[cis-Pt(NH3)2Cl]2(4,4&prime -methylenedianiline)}2+ Complex 2, {[cis-Pt(NH3)2Cl]2(α,α&prime -diamino-p-xylene)}2+ CT, calf-thymus DPP, differential pulse polarography EtBr, ethidium bromide FAAS, flameless atomic absorption spectrophotometry HMG, high-mobility-group IC50, concentration inhibiting cell growth by 50% MTT, [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] PAGE, polyacrylamide gel electrophoresis rb, the number of molecules of the metal complex bound per nucleotide residue ri, the molar ratio of free metal complex to nucleotide-phosphates at the onset of incubation with DNA |
| 本文献已被 ScienceDirect 等数据库收录！ | |