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Amino Acids as Chelating Ligands for Platinum: Enhanced Stability in an Aqueous Environment Promoted by Biocompatible Molecules.

ABSTRACT: Platinum-based chemotherapeutics are a cornerstone in the treatment of many malignancies. However, their dose-limiting side effects have rooted efforts to develop new drug candidates with higher selectivity for tumor tissues and less problematic side effects. Here, we developed a cytotoxic platinum(II) complex based on Zeise's salt, containing the nonsteroidal anti-inflammatory drug acetylsalicylic acid and alanine as ligands (4). The previously developed complex (5) displayed high reactivity against sulfur-containing biomolecules; therefore, we put the focus on the optimization of the structure regarding its stability. Different amino acids were used as biocompatible chelating ligands to achieve this aim. Differences in the coordination sphere caused pronounced changes in the stability of Zeise-type precursors 1-3. Coordination with l-Ala through N in the trans position to ethylene showed the most promising results and was employed to stabilize 5. As a result, complex 4 showed improved stability and cytotoxicity, outperforming both 5 and 1.

SUBMITTER: Cucchiaro A

PROVIDER: S-EPMC10683014 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Amino Acids as Chelating Ligands for Platinum: Enhanced Stability in an Aqueous Environment Promoted by Biocompatible Molecules.

Cucchiaro Andrea A Scherfler Amelie A Corinti Davide D Berden Giel G Oomens Jos J Wurst Klaus K Gust Ronald R Crestoni Maria Elisa ME Kircher Brigitte B Cziferszky Monika M

Journal of medicinal chemistry 20231108 22

Platinum-based chemotherapeutics are a cornerstone in the treatment of many malignancies. However, their dose-limiting side effects have rooted efforts to develop new drug candidates with higher selectivity for tumor tissues and less problematic side effects. Here, we developed a cytotoxic platinum(II) complex based on Zeise's salt, containing the nonsteroidal anti-inflammatory drug acetylsalicylic acid and alanine as ligands (<b>4</b>). The previously developed complex (<b>5</b>) displayed high ...[more]

PMID: 37937969

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Project description:We have investigated the phase behavior of self-assembled lyotropic liquid crystals (LC) formed by ternary mixtures of oleoylethanolamide (OEA), water and arginine. OEA, a natural analog of the endogenous cannabinoid anandamide involved in the peripheral regulation of feeding, was selected as a main component due to its capacity to induce efficient decreases in food intake and gains in body mass. Arginine was selected as representative hydrophilic amino acid and added to the OEA-water mixture at different concentrations. The phase diagrams were determined by combining cross-polarized optical microscopy and small angle x-ray scattering. First, the phase diagram for the OEA-water system was determined. It was shown that these two compounds give rise to reverse Ia3d double gyroid and reverse Pn3m double diamond cubic phases existing in bulk over a large window of temperature and composition, and that for water content beyond 25% Pn3m coexisted with excess water. Successively, the influence of arginine as guest molecule in the water channels of the reverse LC was investigated. For the sake of comparison, results for the OEA-water-arginine system were compared with analog series of OEA-water-glucose. The results showed that, at a fixed water content and temperature, the phase behavior of the liquid crystalline phases is strongly dependent on arginine concentration. In more detail, arginine could be encapsulated in the bulk OEA-water LC up to 2.0% wt, whereas transitions from Ia3d to Pn3m cubic phase were observed with increasing arginine concentration. Interestingly, upon an increase of water concentration beyond 20-25%, Pn3m phase started to coexist with excess water releasing the arginine in external water solution. Quantitative measurements of arginine content inside the LC water channels and in the excess external water solution revealed a complete release of the amino acid, demonstrating that the investigated lyotropic liquid crystalline systems can be used as ideal vehicles for the delivery of functional hydrophilic active molecules in aqueous environment.

Project description:Many microorganisms secrete molecules that interact with resources outside of the cell. This includes, for example, enzymes that degrade polymers like chitin, and chelators that bind trace metals like iron. In contrast to direct uptake via the cell surface, such release strategies entail the risk of losing the secreted molecules to environmental sinks, including 'cheating' genotypes. Nevertheless, such secretion strategies are widespread, even in the well-mixed marine environment. Here, we investigate the benefits of a release strategy whose efficiency has frequently been questioned: iron uptake in the ocean by secretion of iron chelators called siderophores. We asked the question whether the release itself is essential for the function of siderophores, which could explain why this risky release strategy is widespread. We developed a reaction-diffusion model to determine the impact of siderophore release on iron uptake from the predominant iron sources in marine environments, colloidal or particulate iron, formed due to poor iron solubility. We found that release of siderophores is essential to accelerate iron uptake, as secreted siderophores transform slowly diffusing large iron particles to small, quickly diffusing iron-siderophore complexes. In addition, we found that cells can synergistically share their siderophores, depending on their distance and the size of the iron sources. Our study helps understand why release of siderophores is so widespread: even though a large fraction of siderophores is lost, the solubilization of iron through secreted siderophores can efficiently increase iron uptake, especially if siderophores are produced cooperatively by several cells. Overall, resource uptake mediated via release of molecules transforming their substrate could be essential to overcome diffusion limitation specifically in the cases of large, aggregated resources. In addition, we find that including the reaction of the released molecule with the substrate can impact the result of cooperative and competitive interactions, making our model also relevant for release-based uptake of other substrates.

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Amino Acids as Chelating Ligands for Platinum: Enhanced Stability in an Aqueous Environment Promoted by Biocompatible Molecules.

Publications

Amino Acids as Chelating Ligands for Platinum: Enhanced Stability in an Aqueous Environment Promoted by Biocompatible Molecules.

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