Reactivity of an extremenly sterically crowded monofunctional Pt complex, [Pt(1-MeC-N3)3(H2O)]2+ (1-MeC=1-methylcytosine), toward model nucleobases and selectivity toward guanine in single- and double-stranded deoxyoligonucleotides

Abstract

Reactions of [Pt(1-MeC-N3)3Cl]NO3 (1-MeC-N3 = 1-methylcytosine, bound to Pt via N3) and the respective aqua species [Pt(1-MeC-N3)3(H2O)]2+ with the model nucleobases 9-ethylguanine (9-EtGH), 9-methyladenine (9-MeA), single-stranded 5'd(T3GT3), and double-stranded [5'd(GA-GA2GCT2CTC)]2 have been studied in solution by means of 1H NMR spectroscopy, HPLC, and electrospray ionization mass spectrometry. Reactions are generally slow, in particular with the chloro species, and guanine is the only reactive base in the oligonucleotides. However, unlike (dien)PtII, which binds randomly to the guanines in the ds dodecamer, (1-MeC-N3)3PtII binds selectively to the terminal guanine only, probably because base fraying takes place at the duplex ends. The X-ray crystal structures of [Pt(1-MeC-N3)3(9-EtG-N7)]ClO4.8H2O (1b) and of [Pt(1-MeC-N3)3(9-MeA-N7)](ClO4)2.0.5H2O as well as NMR spectroscopic studies of [Pt(1-MeC-N3)3(9-EtGH-N7)] (NO3)2.H2O (1a) are reported. The tetrakis(nucleobase) complexes adopt a head-tail-head orientation of the three 1-MeC bases and an orientation of the fourth base (purine) that permits a maximum of intracomplex H bonds between exocyclic groups. As far as the guanine adduct (1a, 1b) is concerned, relative orientations of the four bases are identical in the model and in the oligonucleotide adduct.

Electrospray ionization mass spectrometry of oligonucleotide complexes with drugs, metals, and proteins

“…It is not surprising, given the importance of Pt-based complexes in chemotherapy, that there have been a number of reports of the use of ESI-MS to examine the covalent attachment of platinum complexes to oligonucleotides (Wickham et al, 1995b;Gonnet et al, 1996b;Lowe et al, 1996;Troujman & Chottard, 1997;Janik et al, 1999;Kloster et al, 1999;Xu et al, 1999;Iannitti-Tito et al, 2000;). In one of our early studies, the binding of cisplatin to three self-complementary 6-mer oligonucleotides was examined (Wickham et al, 1995b).…”

Pt as Mediator of Strong Antiferromagnetic Coupling between Two CuII Ions in a Heteronuclear CuIIPtIICuII Complex of the Model Nucleobase 1-Methylcytosinate

“…There are, in principle, two more configurations of heterometal binding sets possible with 1: two cis-N' 2 O 2 as well as N' 3 (with pu 9-methyladenine and 9-ethylguanine) have in fact been prepared, yet with a different aim from the one raised herein. [36] Experimental Section Materials: [Pt(1-MeC-N3) 4 ](NO 3 ) 2 (1) [8] (from K 2 PtCl 4 and 1-MeC [37] ) was synthesized according to the literature. For the synthesis of the other complexes, see below.…”

Antiproliferative activity of Pt(II) and Pd(II) phosphine complexes with thymine and thymidine

“…In addition it is reported that hindered complexes are used for circumventing resistance by sterically inhibiting cellular detoxification by glutathione and other cellular thiols [36]. The presence of at least one leaving group in the synthesized complexes should allow the reaction with DNA, either for the cis and the trans complexes, as demonstrated in the literature [35].…”

“…The presence of thymine should help the binding between the metal complex and the nucleic acids, introducing an additional binding site and directing the complex also toward adenine containing sequences. The steric hindrance of the ligands should slow down the reaction rate with the DNA and probably affect the reaction mechanism and the selectivity for the binding sites [35]. In addition it is reported that hindered complexes are used for circumventing resistance by sterically inhibiting cellular detoxification by glutathione and other cellular thiols [36].…”

“…Monofunctional adduct, either cis and trans, are also able to bind DNA [32,33] and to terminate in vitro DNA and RNA synthesis [34]. Sterically hindered Pt complexes, such as [Pt(amine) 2 hetCl] + (het: N-heterocyclic ligand) bind to DNA after one amine ligand, trans to the chloride has been lost [35].…”