The Human Telomeric Sequence (T 2 AG 3 ) n is Efficiently Cross‐Linked by AN1 Binding to the Platinum of a trans ‐Pt(NH 3 ) 2 Chelate of an Antisense Oligo‐2′‐ O ‐Methylribonucleotide

In order to irreversibly cross‐link an antisense oligonucleotide to the human telomeric sequence (T 2 AG 3 ) n , the inter‐strand bridging rearrangement described by Leng et al. was investigated on (21‐mer antisense) (20‐mer target) duplexes: (G*NG*)(TA) ⇄ (G*NG)(TA*), G*NG* being a trans ‐[Pt(NH 3 ) 2 {1,3‐(GNG)‐ N7 ‐G, N7 ‐G}] chelate with N = U or T. Three different duplexes were studied, confirming first that for a DNA target strand the rearrangement was faster with a platinated oligo‐2′‐ O ‐methylribonucleotide than with a deoxy oligonucleotide as antisense strand. Second, a telomeric DNA target strand was cross‐linked faster than an all‐purine oligonucleotide containing a single TA doublet. Accordingly, the half time of formation of the cross‐linked hybrid duplex [2′‐OMe‐r(CCCUAACCCG*UGACCCUAACCC)]·[d(T 2 AG 3 ) 2 (TTA*G 3 )(T 2 AG 3 )] is one minute, compared with the nine days required for the complete formation of the bridged d(CTCCTG*TGTCTC)·d(GAGATA*AGGAG) duplex. The NMR analysis of the latter showed that the platinum cross‐link involves the A*N1 moiety as ligand. The timescale difference between the two reactions raised the question of an eventual kinetic cross‐link which might isomerize to the final one observed. This question was addressed using 1‐deazaadenine in the TA doublet of the three target strands of this work. No cross‐linking reaction was observed, proving that AN1 is the bridging atom in all the cases studied so far. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)