具有增强溶解度的8-羟基喹啉衍生曼尼希碱的有机金属半夹心配合物：靶向多药耐药癌症

IF 4.7 2区化学 Q1 CHEMISTRY, INORGANIC & NUCLEAR

Inorganic Chemistry Pub Date : 2024-12-05 DOI:10.1021/acs.inorgchem.4c04398

Tamás Pivarcsik, Szilárd Tóth, Szonja P. Pósa, Nóra V. May, Éva Kováts, Gabriella Spengler, Izolda Kántor, Alexandra Rolya, Tivadar Feczkó, István Szatmári, Gergely Szakács, Éva A. Enyedy

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引用次数: 0

摘要

耐药性是癌症治疗的主要障碍。本文开发了四种新型有机金属配合物，其分子式为[Ru(η - 6-p-cymene)(HL)Cl]Cl和[Rh(η - 5- c5me5)(HL)Cl]Cl，用于靶向多药耐药（MDR）癌细胞，其中HL表示8-羟基喹啉衍生的曼尼希碱（HQCl-pyr和HQCl-pip）。络合的目的是获得具有改进的类药物性质的化合物。用各种光谱方法对这些配合物的结构、溶液形态和与人血清白蛋白的相互作用进行了全面的表征。用x射线晶体学分析了[Rh(η5-C5Me5)(HQCl-pip)Cl]Cl的结构。该配合物在溶液和各种生物基质中具有高度稳定性，与配体相比具有更高的溶解度，并通过配位与白蛋白结合。Rh（η5-C5Me5）配合物对MDR MES-SA/Dx5细胞株具有较强的细胞毒性（IC50分别为0.19和0.22 μM），具有较高的MDR选择性。以最有前途的配体HQCl-pip及其Rh（η - 5- c5me5）配合物为配体制备了神经节苷类功能化纳米颗粒，以提高生物利用度。在酸性条件下，纳米载体的药物释放速度比在pH 7.4条件下快，并能保持所载化合物的细胞毒性和选择性。HQCl-pip包封的Rh（η5-C5Me5）配合物已被确定为耐多药选择性化合物药理学开发的最佳候选物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Organometallic Half-Sandwich Complexes of 8-Hydroxyquinoline-Derived Mannich Bases with Enhanced Solubility: Targeting Multidrug Resistant Cancer

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Organometallic Half-Sandwich Complexes of 8-Hydroxyquinoline-Derived Mannich Bases with Enhanced Solubility: Targeting Multidrug Resistant Cancer

Drug resistance is a major obstacle in cancer treatment. Herein, four novel organometallic complexes, with the general formula [Ru(η⁶-p-cymene)(HL)Cl]Cl and [Rh(η⁵-C₅Me₅)(HL)Cl]Cl, were developed to target multidrug-resistant (MDR) cancer cells, where HL denotes 8-hydroxyquinoline-derived Mannich bases (HQCl-pyr and HQCl-pip). The aim of the complexation was to obtain compounds with improved drug-like properties. The complexes were comprehensively characterized by various spectroscopic methods in terms of their structure, solution speciation and interaction with human serum albumin. The structure of [Rh(η⁵-C₅Me₅)(HQCl-pip)Cl]Cl was analyzed by X-ray crystallography. The complexes were found to be highly stable in solution and in various biological matrices, showing enhanced solubility compared with the ligands and significant binding ability to albumin via coordination. The Rh(η⁵-C₅Me₅) complexes exhibited strong cytotoxicity against MDR MES-SA/Dx5 cell lines (IC₅₀ = 0.19 and 0.22 μM), demonstrating high MDR-selectivity. Ganglioside-functionalized nanoparticles with the most promising ligand HQCl-pip and its Rh(η⁵-C₅Me₅) complex were prepared to enhance the bioavailability. The nanocarriers showed faster drug release at acidic pH than at pH 7.4, and could retain the cytotoxicity and selectivity of the loaded compounds. The encapsulated Rh(η⁵-C₅Me₅) complex of HQCl-pip has been identified as an optimal candidate for the pharmacological development of MDR-selective compounds.

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来源期刊

Inorganic Chemistry 化学-无机化学与核化学

CiteScore

7.60

自引率

13.00%

发文量

1960

审稿时长

1.9 months

期刊介绍： Inorganic Chemistry publishes fundamental studies in all phases of inorganic chemistry. Coverage includes experimental and theoretical reports on quantitative studies of structure and thermodynamics, kinetics, mechanisms of inorganic reactions, bioinorganic chemistry, and relevant aspects of organometallic chemistry, solid-state phenomena, and chemical bonding theory. Emphasis is placed on the synthesis, structure, thermodynamics, reactivity, spectroscopy, and bonding properties of significant new and known compounds.