Chimeric Platinum-Polyamines and DNA Binding. Kinetics of DNA Interstrand Cross-Link Formation by Dinuclear Platinum Complexes with Polyamine Linkers

Ruhayel, Rasha A.; Langner, Janina S.; Oke, Matilda-Jane; Berners‐Price, Susan J.; Zgani, Ibrahim; Farrell, Nicholas

doi:10.1021/ja301397h

Cited by 27 publications

(24 citation statements)

References 64 publications

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“…Surprisingly, the rate constant for conversion of the combined monofunctional species to the combined bifunctional adducts is two fold higher than that observed for the reaction of 1,1/ t,t with duplex I , when analysed by the same kinetic model. 13 In most other kinetic studies of interstrand cross-linking by multinuclear platinum complexes performed to date, 7, 13, 18 similar rate constants have been observed for the aquation step and for bifunctional adduct formation, consistent with aquation of the monofunctional adduct occuring prior to fixation of the cross-link and this step being rate limiting. A possible explanation for the higher value of k BF is that, at least for some environments of the combined monofunctional adducts, the {PtN 3 Cl} end group is pointing away from the DNA so that restricted access of the solvent to the Pt coordination sphere is less significant than in the pre-associated states.…”

Section: Discussionsupporting

confidence: 60%

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

et al. 2015

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2D [1H, 15N] HSQC NMR spectroscopy has been used to monitor the reaction of fully 15N-labelled [{trans-PtCl(NH3)2}2(μ-trans-Pt(NH3)2 {NH2(CH2)6NH2}2)]4+ (BBR3464 (15N-1)) with the 14-mer duplex (5’-{d(ATACATG(7)G(8)TACATA)}-3’. 5’-{d(TATG(18)TACCATG(25)TAT)}-3’ or I) at pH 5.4 and 298 K, to examine the possible formation of 1,4 and 1,5-GG adducts in both 5′ –5′ and 3′ –3′ directions. In a previous study, the binding of the dinuclear 1,1/t,t to I showed specific formation of the 5′ –5′ 1,4 G(8)G(18) cross-link, whereas in this case a mixture of adducts were formed. Initial 1H NMR spectra suggested the presence of two pre-associated states aligned in both directions along the DNA. The pre-association was studied in the absence of covalent binding, by use of the “non-covalent” analog [{trans-Pt(NH3)3}2(μ-trans-Pt(NH3)2 {NH2(CH2)6NH2}2)]6+ (AH44, 0). Chemical shift changes of DNA protons combined with NOE connectivities between CH2 and NH3 protons of 0 and the adenine H2 protons on I show that that two different molecules of 0 are bound in the minor groove. Molecular dynamic simulations were performed to study the interaction of 0 at the two pre-association sites using charges derived from density functional theory (DFT) calculations. Structures where the central platinum is located in the minor groove and the aliphatic linkers extend into the major groove, in opposite directions, often represent the lowest energy structures of the snapshots selected. In the reaction of 15N-1 and I, following the pre-association step, aquation occurs to give the mono aqua monochloro species 2, with a rate constant of 3.43 ± 0.03 × 10−5s−1. There was evidence for two monofunctional adducts (3, 4) bound to the 3′ (G8) and 5′ (G7) residues and the asymmetry of the 1H,15N peak for 3 suggested two conformers of the 3′ adduct, aligned in different directions along the DNA. The rate constant for combined monofunctional adduct formation (0.6 ± 0.1 M−1) is ca. 2-fold lower for 1 compared to 1,1/t,t, whereas the rate constant for conversion of the combined monofunctional species to combined bifunctional adducts (5) (8.0 ± 0.2 × 10−5s−1) is two-fold higher.

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Section: Discussionsupporting

confidence: 60%

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

et al. 2015

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“…In our work, we are defining the mechanism of action of a second distinct class of platinum‐based anticancer agents based on the polynuclear platinum structure (PPCs). The original intent and design was to produce a series of discrete DNA adducts structurally distinct from those formed by the { cis ‐Pt(am(m)ine) 2 } class, thereby circumventing DNA repair mechanisms associated with resistance to the clinically used drugs . More recently, we have demonstrated that heparan sulfate proteoglycans (HSPGs) act as very efficient receptors for PPC cellular accumulation .…”

Section: Introductionmentioning

confidence: 99%

Structural Factors Affecting Binding of Platinum Anticancer Agents with Phospholipids: Influence of Charge and Phosphate Clamp Formation

Gorle

Zhang

Liu

et al. 2018

Chemistry A European J

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We report a detailed NMR and DFT study of the interaction of polynuclear platinum anticancer agents (PPCs) with negatively charged phospholipids as a mechanism for their cellular uptake. The reactions of fully N-labelled [{trans-PtCl(NH ) } (μ-trans-Pt(NH ) {NH (CH ) NH } )] ( N-1, 1,0,1/t,t,t) and the dinuclear [{trans-PtCl(NH ) } {μ-H N(CH ) NH }] ( N-2, 1,1/t,t) with the sodium salt of 1,2-dihexanoyl-sn-glycero-3-phosphate (DHPA) were studied at 298 K, pH ≈5.4, by [ H, N] HSQC 2D NMR spectroscopy. Both N-1 and N-2 form an initial mono-adduct in which the DHPA is coordinated via the phosphate O atom. For the dinuclear N-2, coordination of a second DHPA, in two different orientations, leads to two conformers of the bifunctional adduct. For N-1, coordination of the second DHPA allows the central {PtN } coordination unit to bind electrostatically to two additional DHPA molecules via phosphate clamp interactions, in an extended network. For both 1,0,1/t,t,t (1) and 1,1/t,t (2), equilibrium conditions are obtained more slowly (>35 h) than in the presence of phosphate (12 h) and in each case the rate constant for the first step of DHPA binding (k ) is about 8 times higher than that for phosphate, whereas the rate constants for the reverse reactions are quite similar. Reaction of N-1 with the sodium salt of 1,2-dihexanoyl-sn-glycero-3-[phosphatidyl-l-serine] (DHPS) showed only minor adduct formation via coordination to the N-donor atom of the phosphoserine group.

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“…31 In that study the role of the central NH 2 groups in the spermine-like linker of 1′ was also probed, by comparison with the spermidine-like derivative 1 . Reported in this paper is a study of the solution behavior of both 1 and 1′ , including measurement of the p K a values of the coordinated water ligands in their aquated derivatives.…”

Section: Introductionmentioning

confidence: 99%

Solution studies of dinuclear polyamine-linked platinum-based antitumour complexes

et al. 2011

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The aquation profiles of two novel dinuclear polyamine-linked, platinum-based antitumour complexes [{trans-PtCl(15NH3)2}2{μ-(15NH2(CH2)615NH2(CH2)615NH2)}]3+ (BBR3007, 1,1/t,t-6,6, 1) and [{trans-PtCl(15NH3)2}2{μ-(15NH2(CH2)615NH2(CH2)215NH2(CH2)615NH2)}]4+ (BBR3610, 1,1/t,t-6,2,6, 1′) have been probed using 2D [1H, 15N] HSQC NMR spectroscopy. Reported herein are the rate constants for the hydrolysis of 1 and 1′, as well as the acid dissociation constants of the coordinated aqua ligands in their aquated derivatives. The aquation and anation rate constants for the single step aquation model in 15 mM NaClO4 (pH 5.4) at 298 K are, for 1, k1 = 7.2 ± 0.1 ×10−5 s−1, k−1 = 0.096 ± 0.002 M−1 s−1 and, for 1′, k1 = 4.0 ± 0.2 × 10−5 s−1, k−1 = 1.4 ± 0.1 M−1 s−1. The effect of the linker backbone (Pt(tetra(m)mine vs. polyamine) was evaluated by comparison with previous data for the trinuclear complex [{trans-PtCl(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)]4+ (1,0,1/t,t,tor BBR3464). The pK1 for 1,0,1/t,t,t(3.44) is closest to that of 1 (3.12), while the pronounced difference for 1′ (4.54), means that 1′ is the least aquated of the three complexes at equilibrium. pKa values of 5.92 were calculated for the aquated forms of both 1 and 1′, which are 0.3 pKunits higher than for either 1,0,1/t,t,t, or the dinuclear 1,1/t,t. The higher pKa values for both polyamine-linked compounds may be attributed to the formation of macrochelates between the central NH2 groups and the {PtN3O}coordination sphere of the aquated species.

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Chimeric Platinum-Polyamines and DNA Binding. Kinetics of DNA Interstrand Cross-Link Formation by Dinuclear Platinum Complexes with Polyamine Linkers

Cited by 27 publications

References 64 publications

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

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

Structural Factors Affecting Binding of Platinum Anticancer Agents with Phospholipids: Influence of Charge and Phosphate Clamp Formation

Solution studies of dinuclear polyamine-linked platinum-based antitumour complexes

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