Biophysical analysis of natural, double-helical DNA modified by anticancer heterocyclic complexes of ruthenium(lll) in cell-free media

被引：84

作者：

Malina, J

Novakova, O

Keppler, BK

Alessio, E

Brabec, V

机构：

[1] Acad Sci Czech Republ, Inst Biophys, CS-61265 Brno, Czech Republic

[2] Univ Vienna, Inst Inorgan Chem, A-1090 Vienna, Austria

[3] Univ Trieste, Dipartimento Sci Chim, I-34127 Trieste, Italy

来源：

JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY | 2001年 / 6卷 / 04期

关键词：

DNA; ruthenium; cisplatin; cross link; anticancer drug;

D O I：

10.1007/s007750100223

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Modifications of natural DNA by three anticancer heterocyclic ruthenium(III) compounds were studied by methods of molecular biophysics. These methods included DNA binding studies using atomic absorption spectrophotometry, inhibition of restriction endonucleases, mapping of DNA adducts by transcription assay, interstrand cross-linking employing gel electrophoresis under denaturing conditions, DNA unwinding studied by gel electrophoresis, circular dichroism analysis of the B-->Z transition in DNA, and DNA melting curves measured by absorption spectrophotometry. The results indicate that the complexes HIm[trans-C1(4)Im(2)Ru(III)], HInd[trans-C1(4)Ind(2)Ru(III)], and Na [trans-C1(4)Im(Me2SO)Ru-III] (Im and Ind stand for imidazole and indazole, respectively) coordinate irreversibly to DNA. Their DNA binding mode is, however, different from that of cisplatin. Interestingly, Na [trans-C1(4)Im(Me2SO)Ru-III] binds to DNA considerably faster than the other two ruthenium compounds and cisplatin. In addition, when Na[trans C1(4)Im(Me2SO)Ru-III] binds to DNA it exhibits an enhanced base sequence specificity in comparison with the other two ruthenium complexes. Na[transCl(4)Im(Me2SO)Ru-III] also forms bifunctional intrastrand adducts on double-helical DNA which are capable of terminating RNA synthesis in vitro, while the capability of the other two ruthenium compounds to form such adducts is markedly lower. This observation has been interpreted to mean that the bifunctional adducts of HInd[trans-Cl(4)Ind(2)Ru(III)] and Na[transCl(4)Im(2)Ru(III)] formed on rigid double-helical DNA are sterically; more crowded by their octahedral geometry than those of Na[trans-Cl(4)Im(Me2SO)Ru-III]. In addition, the adducts of all three ruthenium compounds affect the conformation of DNA, Na[transCl(4)Im(Me2SO)Ru-III] being most effective. It has been suggested that the altered DNA binding mode of ruthenium compounds in comparison with cisplatin might bt an important factor responsible for the altered cytostatic activity of this class of ruthenium compounds in tumor cells.

引用

页码：435 / 445

页数：11

共 46 条

[1] SYNTHESIS AND CHARACTERIZATION OF 2 NEW CLASSES OF RUTHENIUM(III)-SULFOXIDE COMPLEXES WITH NITROGEN DONOR LIGANDS (L) - NA[TRANS-RUCL4(R2SO)(L)] AND MER,CIS-RUCL3(R2SO)(R2SO)(L) - THE CRYSTAL-STRUCTURE OF NA[TRANS-RUCL4(DMSO)(NH3)].2DMSO, NA[TRANS-RUCL4(DMSO)(IM)].H2O,ME2CO (IM=IMIDAZOLE) AND MER,CIS-RUCL3(DMSO)(DMSO)(NH3) [J].