Substitution‐Inert Trinuclear Platinum Complexes Efficiently Condense/Aggregate Nucleic Acids and Inhibit Enzymatic Activity

Malina, Jaroslav; Farrell, Nicholas; Brabec, Viktor

doi:10.1002/ange.201408012

Cited by 15 publications

(6 citation statements)

References 34 publications

(42 reference statements)

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“…Secondly, for the substitution-inert polynuclear platinum compounds, binding is accompanied by compaction of the DNA, significantly more efficient that that induced by spermine. 8,9,28 The two features combined then reinforce the description of the phosphate clamp as a distinct third mode of ligand-DNA binding. The results here also indicate that TriplatinNC binds predominantly in a selective fashion to isolated AT base-pairs of the Dickerson-Drew dodecamer.…”

Section: Discussionmentioning

confidence: 58%

“…8,9 DNA binding by these compounds also protects against minor groove alkylation, in a manner similar to minor-groove binders such as Adriamycin. 10 The most studied compound among this new series of potential platinum drugs, a sub-set of the large polynuclear platinum class, is TriplatinNC (TpNC) where the leaving groups are displaced by two diaminohexanes resulting in an 8+ charged complex.…”

Section: Introductionmentioning

confidence: 98%

“…Indeed, the phosphate clamp-DNA interactions further result in displacement of intercalated ethidium bromide, and facilitate cooperative binding of Hoechst 33258 at the minor groove. 8,9,13 …”

Section: Introductionmentioning

confidence: 99%

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Solution studies on DNA interactions of substitution-inert platinum complexes mediated via the phosphate clamp

Kipping

Farrell

2015

Dalton Trans.

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The phosphate clamp is a distinct mode of ligand-DNA binding where the molecular is manifest through (“non-covalent”) hydrogen-bonding from am(m)ines of polynuclear platinum complexes to the phosphate oxygens on the oligonucleotide backbone. This third mode of DNA is unique from the “classical” DNA intercalators and minor groove binding agents and even the closely related covalently binding mononuclear and polynuclear drugs. 2D 1H NMR studies on the Dickerson Drew Dodecamer (DDD, d(CGCGAATTCGCG)2) showed significant A-T contacts mainly on nucleotides A6, T7 and T8 implying a selective bridging from C9G10 in the 3' direction to C9G10 of the opposite strand. {1H, 15N} HSQC NMR Spectroscopy using the fully 15N-labelled compound ([{trans-Pt(NH2)3(H2N(CH2)6NH3}2μ-(H2N(CH2)6NH2)2(Pt(NH3)2]8+ (TriplatinNC) showed at pH6 significant chemical shift and 1J(195Pt-15N) coupling constants from free drug and DDD-TriplatinNC at pH 7 indicative of formation of the phosphate clamp. 31P NMR results are also reported for the hexamer d(CGTACG)2 showing changes in 31P NMR chemical shifts indicative of changes around the phosphorous center. The studies confirm the DNA binding modes by substitution-inert (non-covalent) polynuclear platinum complexes and help to further establish the chemotype as a new class of potential anti-tumor agents in their own right with a distinct profile of biological activity.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 98%

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Solution studies on DNA interactions of substitution-inert platinum complexes mediated via the phosphate clamp

Kipping

Farrell

2015

Dalton Trans.

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“…33 The DNA binding motif of the phosphate clamp “in solution” is characterized by high binding affinity, some minor-groove selectivity and highly efficient condensation of DNA. 34 The dynamics study of the substitution-inert AH44 is of further relevance because the clear residence in the minor groove supports the view from parallel biophysical experiments that the DNA condensation effects are driven by minor-groove affinity. 35 The simulations, coupled with NMR evidence, 12 further confirm that the crystallographically observed structures exist in solution and are relevant in explaining the biological activity of this series.…”

Section: Discussionmentioning

confidence: 68%

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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“…). A afinidade também é maior do que para o brometo de etídio (Figura 10d), porém observa-se que as afinidades de ligação não mudam significativamente com a variação estrutural, como por exemplo, aumento da cadeia carbônica entre os centros de platina(MALINA;BRABEC, 2014aBRABEC, , 2014b. FARRELL; BRABEC, 2019).…”

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Interações não covalentes entre SI-PPCs e biomoléculas: um estudo por simulações de dinâmica molecular

Rosa¹

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Vários estudos com complexos polinucleares de platina (II) inertes para substituição (SI-PPC) têm sido sintetizados nos últimos anos devido à forma de ligação ao DNA apresentada por esses compostos. Esse novo tipo de coordenação é obtido pelo reconhecimento molecular por meio da formação de estruturas não covalentes, comumente chamadas de grampos e garfos de fosfato, que geram pequenas alterações dos sulcos maior e menor do DNA. Esses compostos têm apresentado também, alta capacidade de inibir o processo de metástase através da interação com outras biomoléculas que contém grupos sulfatos, como os glicosaminoglicanos, estabilizando tais grupos e inibindo a atividade de enzimas que estão relacionadas com o processo de angiogênese e consequentemente, o processo de metástase. Neste trabalho, usamos simulações de dinâmica molecular (DM) para estudar a formação dessas estruturas cíclicas entre diferentes SI-PPCs e biomoléculas. Os resultados mostraram a influência do complexo através do número de grampos e garfos de fosfato formados. Com base na caracterização conformacional dos fragmentos de DNA, mostramos que os SI-PPCs estudados interagem preferencialmente no sulco menor, exceto por dois deles, monoplatinNC e AH44. Os fosfatos dos pares citosina-guanina (C-G) são os principais locais para essas interações não-covalentes. Por outro lado, este trabalho apresenta diversas análises das interações não-covalentes formadas entre uma molécula de heparina (código PDB: 1HPN) e SI-PPCs obtidas através de simulações de dinâmica molecular. Os resultados das análises de posições atômicas mostraram que os complexos diplatinNC e AH44, ambos complexos carregados com carga 6+, foram os mais rígidos. Por outro lado, uma análise de flutuação atômica mostrou que há uma redução na flutuação dos átomos na região central da molécula de heparina, assim como a análise da área de superfície acessível ao solvente (SASA) indica uma redução na área acessível da heparina pelo solvente ao interagir com SI-PPCs. A avaliação das ligações de hidrogênio confirma a formação de ligações não covalentes, o que pode sugerir uma diminuição da ação do 1HPN impedindo a ação das enzimas sobre este substrato. Pelo que sabemos, este trabalho é o primeiro relacionado a SI-PPCs que traz simulações de DM e uma análise completa das interações nãocovalentes com diferentes biomoléculas.

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Substitution‐Inert Trinuclear Platinum Complexes Efficiently Condense/Aggregate Nucleic Acids and Inhibit Enzymatic Activity

Cited by 15 publications

References 34 publications

Solution studies on DNA interactions of substitution-inert platinum complexes mediated via the phosphate clamp

Solution studies on DNA interactions of substitution-inert platinum complexes mediated via the phosphate clamp

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

Interações não covalentes entre SI-PPCs e biomoléculas: um estudo por simulações de dinâmica molecular

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