Biological relevance of interaction of platinum drugs with O-donor ligands

Gorle, Anil K.; Berners‐Price, Susan J.; Farrell, Nicholas

doi:10.1016/j.ica.2019.118974

Cited by 10 publications

(5 citation statements)

References 44 publications

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“…We have previously suggested that the O-donor polyanionic biomolecules such as GAGs present multiple neighboring donors on a more complex polymeric, biomolecular template acting as a Lewis base "sink". 24 Both carboxylate and sulfate interactions play an important role in the overall triplatin− GAG interaction. The relative importance of both will be highly dependent on the sulfation status in longer-chain HS.…”

Section: ■ Conclusionmentioning

confidence: 99%

Probing Disaccharide Binding to Triplatin as Models for Tumor Cell Heparan Sulfate (GAG) Interactions

et al. 2023

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In this study, we have used [1H, 15N] NMR spectroscopy to investigate the interactions of the trinuclear platinum anticancer drug triplatin (1) (1,0,1/t,t,t or BBR3464) with site-specific sulfated and carboxylated disaccharides. Specifically, the disaccharides GlcNS(6S)-GlcA (I) and GlcNS(6S)-IdoA(2S) (II) are useful models of longer-chain glycosaminoglycans (GAGs) such as heparan sulfate (HS). For both the reactions of 15N-1 with I and II, equilibrium conditions were achieved more slowly (65 h) compared to the reaction with the monosaccharide GlcNS(6S) (9 h). The data suggest both carboxylate and sulfate binding of disaccharide I to the Pt with the sulfato species accounting for <1% of the total species at equilibrium. The rate constant for sulfate displacement of the aqua ligand (k L2) is 4 times higher than the analogous rate constant for carboxylate displacement (k L1). There are marked differences in the equilibrium concentrations of the chlorido, aqua, and carboxy-bound species for reactions with the two disaccharides, notably a significantly higher concentration of carboxylate-bound species for II, where sulfate-bound species were barely detectable. The trend mirrors that reported for the corresponding dinuclear platinum complex 1,1/t,t, where the rate constant for sulfate displacement of the aqua ligand was 3 times higher than that for acetate. Also similar to what we observed for the reactions of 1,1/t,t with the simple anions, aquation of the sulfato group is rapid, and the rate constant k –L2 is 3 orders of magnitude higher than that for displacement of the carboxylate (k –L1). Molecular dynamics calculations suggest that extra hydrogen-bonding interactions with the more sulfated disaccharide II may prevent or diminish sulfate binding of the triplatin moiety. The overall results suggest that Pt–O donor interactions should be considered in any full description of platinum complex cellular chemistry.

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Section: ■ Conclusionmentioning

confidence: 99%

Probing Disaccharide Binding to Triplatin as Models for Tumor Cell Heparan Sulfate (GAG) Interactions

et al. 2023

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“…[5,6] Beyond its fundamental nature, the significance of the trans effect extends to comprehending and constructing reaction mechanisms that elucidate the interaction between platinum-based anticancer compounds and biological targets within an aqueous environment. [7][8][9][10] A well-structured mechanism stands as a crucial factor in advancing the development of more efficient potential drug candidates, particularly in the realm of new anticancer agents with enhanced pharmacokinetic profiles. [10,11] In all scenarios, whether in conventional inorganic synthesis or processes occurring within biological environments, the kinetic nature of the phenomenon underscores the vital importance of a precise comprehension of the trans effect.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring Trans Effect Concept in Pt(II) Complexes through the Quantum Theory of Atoms in Molecules and Chemical Bond Overlap Model Perspectives

Santos‐Jr,

Da Silva,

Dias

et al. 2024

Advcd Theory and Sims

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This study utilizes Density Functional Theory (DFT) alongside the Chemical Bond Overlap (OP) Model and Quantum Theory of Atoms in Molecules (QTAIM) to reinterpret the well‐established trans effect in square‐planar Pt(II) complexes. Investigating ligand exchange mechanisms in trans‐[()T] (T = , , , , CO, ) via transition state localization and intrinsic reaction coordinate calculations, overlap descriptors (OP/TOP) such as density, repulsion, and polarizability are computed for Pt−T and Pt−L bonds for reactants and transition states. Through OP/TOP and QTAIM, key descriptors correlating are identified with the trans‐directing effectiveness of ligands, revealing higher electron density donation and more electron‐rich bonds in stronger trans‐directing ligands. This combined methodology offers insights into ligand trans‐directing character, enhancing understanding of their reactivity and bonding behavior.

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“…It has been suggested that, upon intracellular hydrolysis of their leaving ligands (e.g., chlorides), they interact with their main pharmacological target (DNA) via non-conventional bonds—since they allow the formation of intra- and interstrand long-range adducts (not available for the conventional mononuclear Pt-drugs (e.g., cisplatin))—leading to an enhanced and less-repairable therapeutic effect [ 9 , 15 , 17 ]. More recently, a new class of polycationic platinum chelates without hydrolysable moieties was developed by Farrell et al [ 18 , 19 , 20 , 21 , 22 ]. Instead of covalently binding to DNA, these compounds impact on the nucleic acid through electrostatic interactions with the phosphate groups, the so-called phosphate clamps.…”

Section: Introductionmentioning

confidence: 99%

A Non-Conventional Platinum Drug against a Non-Small Cell Lung Cancer Line

et al. 2023

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A dinuclear Pt(II) complex with putrescine as bridging polyamine ligand ([Pt2Put2(NH3)4]Cl4) was synthesized and assessed as to its potential anticancer activity against a human non-small cell lung cancer line (A549), as well as towards non-cancer cells (BEAS-2B). This effect was evaluated through in vitro cytotoxicity assays (MTT and SRB) coupled to microFTIR and microRaman spectroscopies, the former delivering information on growth-inhibiting and cytotoxic abilities while the latter provided very specific information on the metabolic impact of the metal agent (at the sub-cellular level). Regarding cancer cells, a major impact of [Pt2Put2(NH3)4]Cl4 was evidenced on cellular proteins and lipids, as compared to DNA, particularly via the Amide I and Amide II signals. The effect of the chelate on non-malignant cells was lower than on malignant ones, evidencing a promising low toxicity towards healthy cells.

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Biological relevance of interaction of platinum drugs with O-donor ligands

Cited by 10 publications

References 44 publications

Probing Disaccharide Binding to Triplatin as Models for Tumor Cell Heparan Sulfate (GAG) Interactions

Probing Disaccharide Binding to Triplatin as Models for Tumor Cell Heparan Sulfate (GAG) Interactions

Exploring Trans Effect Concept in Pt(II) Complexes through the Quantum Theory of Atoms in Molecules and Chemical Bond Overlap Model Perspectives

A Non-Conventional Platinum Drug against a Non-Small Cell Lung Cancer Line

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