Factors Affecting DNA–DNA Interstrand Cross‐Links in the Antiparallel 3′–3′ Sense: A Comparison with the 5′–5′ Directional Isomer |
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| Authors: | Rasha A Ruhayel Joseph J Moniodis Dr Xiaohong Yang Dr Jana Kasparkova Dr Viktor Brabec Prof Susan J Berners‐Price Prof Nicholas P Farrell Prof |
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| Institution: | 1. Chemistry M313, School of Biomedical, Biomolecular & Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley WA 6009 (Australia);2. Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia, 23284‐2006 (USA), Fax: (+1)?804‐828‐8599;3. Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., 612 65 Brno (Czech Republic), Fax: (+420)541‐240‐499;4. Department of Experimental Physics, Faculty of Sciences, Palacky University, 77146 Olomouc (Czech Republic);5. Current address: Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland 4222 (Australia), Fax: (+617)?5552 8220 |
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| 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(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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| Keywords: | antitumor agents bioinorganic chemistry DNA kinetics platinum |
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