Factors affecting DNA-DNA interstrand cross-links in the antiparallel 3'-3' sense: a comparison with the 5'-5' directional isomer
Author(s)
Ruhayel, Rasha A
Moniodis, Joseph J
Yang, Xiaohong
Kasparkova, Jana
Brabec, Viktor
Berners-Price, Susan J
Farrell, Nicholas P
Griffith University Author(s)
Year published
2009
Metadata
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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(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)]4+ (BBR3464, 1), [{trans-PtCl(NH3)2}2(μ-NH2(CH2)6NH2)]2+ (BBR3005, 2), [{trans-PtCl(NH3)2}2(μ-H2N(CH2)3NH2(CH2)4)]3+ (BBR3571, 3) and [{trans-PtCl(NH3)2}2{μ-H2N(CH2)3-N(COCF3)(CH2)4}]2+ (BBR3571-COCF3, 4) were studied. Two different molecular biology approaches were used to investigate ...
View more >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(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)]4+ (BBR3464, 1), [{trans-PtCl(NH3)2}2(μ-NH2(CH2)6NH2)]2+ (BBR3005, 2), [{trans-PtCl(NH3)2}2(μ-H2N(CH2)3NH2(CH2)4)]3+ (BBR3571, 3) and [{trans-PtCl(NH3)2}2{μ-H2N(CH2)3-N(COCF3)(CH2)4}]2+ (BBR3571-COCF3, 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 [1H, 15N] HSQC NMR spectroscopy studies of the reaction of [15N]-1 with the sequence 5′-d{TATACATGTATA}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 [15N]-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.
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View more >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(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)]4+ (BBR3464, 1), [{trans-PtCl(NH3)2}2(μ-NH2(CH2)6NH2)]2+ (BBR3005, 2), [{trans-PtCl(NH3)2}2(μ-H2N(CH2)3NH2(CH2)4)]3+ (BBR3571, 3) and [{trans-PtCl(NH3)2}2{μ-H2N(CH2)3-N(COCF3)(CH2)4}]2+ (BBR3571-COCF3, 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 [1H, 15N] HSQC NMR spectroscopy studies of the reaction of [15N]-1 with the sequence 5′-d{TATACATGTATA}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 [15N]-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.
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Journal Title
Chemistry - A European Journal
Volume
15
Issue
37
Funder(s)
ARC
Grant identifier(s)
DP0662817
Subject
Chemical sciences
Bioinorganic chemistry