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.
Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumour-related events including angiogenesis, cell invasion, and metastasis. Metalloshielding of heparan sulfate (HS) by positively charged polynuclear platinum complexes (PPCs) effectively inhibits physiologically critical HS functions. Studies using bacterial P. heparinus heparinase II showed that a library of Pt complexes varying in charge and nuclearity and the presence or absence of a dangling amine inhibits the cleavage activity of the enzyme on the synthetic pentasaccharide, Fondaparinux (FPX). Charge-dependent affinity of PPC for FPX was seen in competition assays with methylene blue and ethidium bromide. The dissociation constant (K ) of TriplatinNC for FPX was directly measured by isothermal titration calorimetry (ITC). The trend in DFT calculated interaction energies with heparin fragments is consistent with the spectroscopic studies. Competitive inhibition of TAMRA-R internalization in human carcinoma (HCT116) cells along with studies in HCT116, wildtype CHO and mutant CHO-pgsA745 (lacking HS/CS) cells confirm that HSPG-mediated interactions play an important role in the cellular accumulation of PPCs.
1H, 15N correlated NMR spectroscopy has proven to be a suitable method to investigate the reaction of the anticancer drug cisplatin cis‐[PtCl2(NH3)2] (1) with DNA. All the intermediates in reactions of 1 with complementary model oligonucleotides can be detected with this method; one of these intermediates is shown.
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