Trans-(NH3)(2)Pt(II)-modified deoxyoligonucleotides as potential antisense agents: cross-linking reactions between two 12-mers.

Abstract

An approach is presented which probes the possible use of trans-[(NH3)(2)PtCl](+)-modified deoxyoligonucleotides in the antisense strategy. It consists of (1) the selective platination of an oligonucleotide containing 11 pyrimidine (T, C) bases as well as a single guanine (G) as a Pt-anchoring group at the 5'-end to give trans-[(NH3)(2)Pt¿5'-d(G(N7)T(2)C(2)T(2)C(2)T(2)C¿Cl](10-) 1 ("antisense strand") and (2) subsequent hybridization with the purine 12-mer 5'-d(GA(2)G(2)A(2)G(2)A(2)G)(11-) ("sense strand"). According to HPLC, three major species 2-4 are formed during reaction (2), all of which are cross-linking adducts between 1 and the sense strand, as confirmed by ESI MS and melting temperature measurements. Only for the major product 3 can a structure be proposed on the basis of 1D and 2D NMR spectra. According to these, G(1) of the antisense strand is cross-linked with G(20) via trans-(NH3)(2)Pt(II). The complementary overhangs of the duplex represent "sticky ends" and are, in principle, capable of associating into multimers of the duplex.