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Reported herein is a study of the unusual 3′-3′ 1,4-GG interstrand cross-link (IXL) formation in duplex DNA by a series of polynuclear platinum anticancer complexes. To examine the effect of possible preassociation through charge and hydrogen-bonding effects the closely related compounds [{trans-PtCl(NH 3 ) 2 } 2 (μ-trans-Pt(NH 3 ) 2 -{NH 2 (CH 2 ) 6 NH 2 } 2 )] 4+ (BBR3464, 1), [{trans-PtCl (NH 3 ) 2 } 2 (μ-NH 2 (CH 2 ) 6 -NH 2 )] 2+ (BBR3005, 2), [{trans-PtCl-(NH 3 ) 2 } 2 (μ-H 2 N (CH 2 ) 3 NH 2 (CH 2 ) 4 )] 3+ (BBR3571, 3) and [{trans-PtCl(NH 3 ) 2 } 2 -{μ-H 2 N(CH 2 ) 3 -N(COCF 3 ) (CH 2 ) 4 }] 2+ (BBR3571-COCF 3 , 4) were studied. Two different molecular biology approaches were used to investigate the effect of DNA template upon IXL formation in synthetic 20-base-pair duplexes. In the "hybridisation directed" method the monofunctionally adducted top strands were hybridised with their complementary 5′-end labelled strands; after 24 h the efficiency of interstrand cross-linking in the 5′-5′ direction was slightly higher than in the 3′-3′ direction. The second method involved "postsynthetic modification" of the intact duplex; significantly less cross-linking was observed, but again a slight preference for the 5′-5′ duplex was present. 2D [ 1 H, 15 N] HSQC NMR spectroscopy studies of the reaction of [ 15 N]-1 with the sequence 5′-d{TATAC-ATGTATA} 2 allowed direct comparison of the stepwise formation of the 3′-3′ IXL with the previously studied 5′-5′ IXL on the analogous sequence 5′-d(ATATGTACATAT) 2 . Whereas the preassociation and aquation steps were similar, differences were evident at the monofunctional binding step. The reaction did not yield a single distinct 3′-3′ 1,4-GG IXL, but numerous cross-linked adducts formed. Similar results were found for the reaction with the dinuclear [ 15 N]-2. Molecular dynamics simulations for the 3′-3′ IXLs formed by both 1 and 2 showed a highly distorted structure with evident fraying of the end base pairs and considerable widening of the minor groove.