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Titolo:
Titanium(IV) targets phosphoesters on nucleotides: implications for the mechanism of action of the anticancer drug titanocene dichloride
Autore:
Guo, ML; Guo, ZJ; Sadler, PJ;
Indirizzi:
Univ Edinburgh, Dept Chem, Edinburgh EH9 3JJ, Midlothian, Scotland Univ Edinburgh Edinburgh Midlothian Scotland EH9 3JJ Midlothian, Scotland Nanjing Univ, Inst Coordinat Chem, Nanjing 210093, Peoples R China NanjingUniv Nanjing Peoples R China 210093 jing 210093, Peoples R China
Titolo Testata:
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
fascicolo: 7, volume: 6, anno: 2001,
pagine: 698 - 707
SICI:
0949-8257(200109)6:7<698:TTPONI>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
NUCLEIC-ACID CONSTITUENTS; TI-IV UPTAKE; METAL-IONS; ANTITUMOR AGENT; COORDINATION CHEMISTRY; ORGANOMETALLIC COMPLEX; MACROCHELATE FORMATION; AQUEOUS CHEMISTRY; SELF-ASSOCIATION; NUDE-MICE;
Keywords:
titanocene dichloride; nucleotides; DNA; anticancer agents; NMR;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
50
Recensione:
Indirizzi per estratti:
Indirizzo: Sadler, PJ Univ Edinburgh, Dept Chem, W Mains Rd, Edinburgh EH9 3JJ, Midlothian, Scotland Univ Edinburgh W Mains Rd Edinburgh Midlothian Scotland EH93JJ
Citazione:
M.L. Guo et al., "Titanium(IV) targets phosphoesters on nucleotides: implications for the mechanism of action of the anticancer drug titanocene dichloride", J BIOL I CH, 6(7), 2001, pp. 698-707

Abstract

Reactions between the anticancer drug titanocene dichloride (Cp2TiCl2) andvarious nucleotides and their constituents in aqueous solution or N,N-dimethylformamide (DMF) have been investigated by H-1 and P-31 NMR spectroscopyand in the solid state by IR spectroscopy. In aqueous solution over the pH* (PH meter reading in D2O) range 2.3-6.5, CMP forms one new species with Ti(IV) bound only to the phosphate group. In acidic media at PH* < 4.6, three species containing titanocene bound to the phosphate group of dGMP, AMP, dTMP and UMP are formed rapidly. The bases also appear to influence titanocene binding. Only one of these Ti(IV)-bound species can be detected in the PH* range of 4.6-6.5 in each case. The order of reactivity towards Cp2TiCl2(aq) at PH* ca. 3 is GMP > TMP approximate to AMP > CMP. At PH* > 7.0, hydrolysis of Cp2TiCl2 predominated and little reaction with the nucleotides was observed. Binding of deoxyribose 5'-phosphate and 4-nitrophenyl phosphateto CpTiCl2(aq) via their phosphate groups was detected by P-31 NMR spectroscopy, but no reaction between Cp2TiCl2(aq) and deoxyguanosine, 9-ethylguanine or deoxy-D-ribose was observed in aqueous solution. The nucleoside phosphodiesters 3',5'-cyclic GMP and 2',3'-cyclic CMP did not react with Cp2TiCl2(aq) in aqueous solution; however, in the less polar solvent DMF, 3',5'-cyclic GMP coordination to {Cp2Ti}(2+) via its phosphodiester group was readily observed. Binding of titanocene to the phosphodiester group of the dinucleotide GpC was also observed in DMF by P-31 NMR. The nucleoside triphosphates ATP and GTP reacted more extensively with Cp2TiCl2(aq) than their monophosphates, complexes with bound phosphate groups were formed in acidic media and to a lesser extent at neutral PH. Cleavage of phosphate bonds in ATP(and GTP) by Cp2TiCl2(aq) to form inorganic phosphate, AMP (or GMP) and ADP (or GDP) was observed in aqueous solutions. In addition, titanocene binding to ATP was not inhibited by Mg(II), but the ternary complex titanocene-ATP-Mg appeared to form. These reactions contrast markedly with those of thedrug cisplatin, which binds predominantly to the base nitrogen atoms of nucleotides and only weakly to the phosphate groups. The high affinity of Ti(IV) for phosphate groups may be important for its biological activity.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/09/20 alle ore 17:53:15