Factors Affecting DNA–DNA Interstrand Cross‐Links in the Antiparallel 3′–3′ Sense: A Comparison with the 5′–5′ Directional Isomer

Abstract

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.

Competitive formation of DNA linkage isomers by a trinuclear platinum complex and the influence of pre-association

“…7, 8, 14 To allow for direct comparison with previous studies (and particularly the reaction of 1,1/ t,t with duplex I ) 13 similar conditions were chosen (pH 5.4, 298 K). The 1 H NMR spectra recorded immediately after addition of 1 to duplex I showed splitting in the G7, G18 and G25 imino proton resonances (Fig.…”

“…7 In contrast, studies with 5′ – d{TATACTA G TATA} 2 ( III ) (now 3′ –3′ ) showed that the pre-association and aquation steps were similar but the reaction did not yield a single distinct 1,4-GG IXL, and numerous cross-linked adducts formed. 8 Molecular dynamics simulations showed a highly distorted structure with fraying of the end base pairs and considerable widening of the minor groove. 8 The results suggest that the multiple DNA cross-links available to BB3464 may all contribute substantially to its cytotoxicity, so that the overall drug cytotoxicity could be the sum of the contributions of different interstrand and intrastrand adducts.…”

Combining aspects of the platinum anticancer drugs picoplatin and BBR3464 to synthesize a new family of sterically hindered dinuclear complexes; their synthesis, binding kinetics and cytotoxicity

“…For multinuclear platinum complexes it has been shown that hydrogen bonding and electrostatic binding between the bridging ligand and the DNA helix is important in stabilising and directing the type of DNA adducts formed. 19,[26][27][28] The ligands synthesised in this work are therefore capable of acting as both hydrogen bond acceptors/donors and when pre-associated in the DNA minor groove, can potentially form hydrogen bonds to the bases as well as ion-dipole interactions with the anionic DNA backbone.…”

A cubane-like [Ni4O4] cluster and a chloro-bridged dinuclear copper complex incorporating a hydroxyl-rich ligand: syntheses and crystal structures

“…Molecular 3d-metal clusters continue to attract attention [1] due to potential applications as catalysts for organic synthesis [2][3][4][5], models of metal-containing sites in biology [6][7][8], and single molecular magnets [9][10][11][12] or single chain magnets [13,14]. A synthetic challenge involves discovering simple and suitable ligands, which possess arrays of coordination pockets organized to create high-nuclearity molecules.…”