Antitumor Trans Platinum DNA Adducts: NMR and HPLC Study of the Interaction Between a trans-Pt Iminoether Complex and the Deoxy Decamer d(CCTCGCTCTC).d(GAGAGCGAGG).
The single-stranded oligonucleotide 5'-d(CCTCGCTCTC) (I) was reacted with the antitumor trans platinum iminoderivative trans-[PtCl(2){E-HN = C(OMe)Me}(2)] (trans-EE) and subsequently annealed with its complementary strand 5'-d(GAGAGCGAGG) (II). The platinated duplex was characterized by 1D and 2D proton NMR spectroscopy at 600 MHz. In agreement with previous studies by different techniques trans-EE was found to form a monofunctional adduct with the duplex involving the guanine residue. The modification by trans-EE has been found to induce only minor local distortion in the duplex geometry. Two key crosspeaks observed in the NOESY map corresponding to a close contact between G5-H8 and the methoxy and the methyl group, respectively, enabled us to dock the trans-EE complex with the duplex by geometry optimization. The results support the idea that the antitumor activity of trans-EE is related to lesion of DNA fundamentally different from that of cisplatin. Unexpectedly, the NOESY spectra indicated that at the high NaCl concentration used (0.2 M) the duplex was found to undergo slow deplatination. This was subsequently proved by HPLC. In a separate experiment on platination of the single strand in a salt free environment the HPLC analysis showed that the monofunctional adduct was not deplatinated, however, after 24 hours, additidnal minor isomers were detected.
Andersen
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B
Department of Chemistry University of Bergen Allegt.41 Bergen N-5007 Norway.
Margiotta
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N
Coluccia
M
M
Natile
G
G
Sletten
E
E