Control of size in losartan/copper(II) coordination complex hydrophobic precipitate

Denadai, Ângelo Márcio Leite; Silva, Jéferson G. Da; Guimarães, Pedro Pires Goulart; Gomes, Leonardo Bertolini S.; Mangrich, Antônio S.; Rezende, Edivaltrys Inayve Pissinati de; Daniel, Izabela M.P.; Beraldo, Heloísa; Sinisterra, Rubén D.

doi:10.1016/j.msec.2013.05.033

Cited by 11 publications

(3 citation statements)

References 54 publications

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“…Figures S3 and S4 present the solubility curves of IVER, IVER/βCD, EPRI, and EPRI/βCD. The great advantage of these materials is the possibility to produce simple formulations without the need to use costly additives or surfactants, acting as a controlled release system driven by dissolution of the solid phase. − …”

Section: Results and Discussionmentioning

confidence: 99%

Hydrophobic Nanoprecipitates of β-Cyclodextrin/Avermectins Inclusion Compounds Reveal Insecticide Activity against Aedes aegypti Larvae and Low Toxicity against Fibroblasts

Moreira

Bittencourt

Costa

et al. 2018

J. Agric. Food Chem.

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In the present work, hydrophobic nanoprecipitates (HNPs) of inclusion complexes formed between β-cyclodextrin (βCD) and the avermectins (AVMs) named eprinomectin (EPRI) and ivermectin (IVER) were synthesized and characterized, and their larvicidal activity against Aedes aegypti and human safety against fibroblasts were evaluated. Initially, thermogravimetric analysis/differential thermal analysis data revealed that inclusion increased the thermal stability of AVMs in the presence of βCD. Nuclear magnetic resonance experiments and density functional theory calculations pointed out the inclusion of the benzofuran ring of the two AVMs in the βCD cavity. Isothermal titration calorimetry experiments allowed identification of different binding constants for EPRI/βCD ( K = 1060) and βCD/IVER ( K = 1700) systems, despite the structural similarity. Dynamic light scattering titrations of AVMs' dimethyl sulfoxide solution in βCD aqueous solution demonstrated that the formed HNPs have lower sizes in the presence of βCD. Finally, the inclusion of EPRI in βCD increased its larval toxicity and reduced its human cytotoxicity, while for IVER/βCD no beneficial effect was observed upon inclusion. These results were rationalized in terms of structural differences between the two molecules. Finally, the EPRI/βCD complex has great potential as an insecticide against A. aegypti larvae with high human safety.

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Section: Results and Discussionmentioning

confidence: 99%

Hydrophobic Nanoprecipitates of β-Cyclodextrin/Avermectins Inclusion Compounds Reveal Insecticide Activity against Aedes aegypti Larvae and Low Toxicity against Fibroblasts

Moreira

Bittencourt

Costa

et al. 2018

J. Agric. Food Chem.

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“…However, Losartan has been described to spontaneously form an insoluble complex with Cu 81, and ARB-Cu complexes have been reported to display anti-oxidant activity 828384, pointing to the possibility of Cu-chelation by ARBs. Whether the underlying mechanistic event that governs the ARB-mediated protection against Cu-induced toxicity is attributed to Cu complexation by ARBs has yet to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin

Spincemaille

Chandhok

Zibert

et al. 2014

MIC

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The human pathology Wilson disease (WD) is characterized by toxic copper (Cu) accumulation in brain and liver, resulting in, among other indications, mitochondrial dysfunction and apoptosis of hepatocytes. In an effort to identify novel compounds that can alleviate Cu-induced toxicity, we screened the Pharmakon 1600 repositioning library using a Cu-toxicity yeast screen. We identified 2 members of the drug class of Angiotensin II Type 1 receptor blockers (ARBs) that could increase yeast tolerance to Cu, namely Candesartan and Losartan. Subsequently, we show that specific ARBs can increase yeast tolerance to Cu and/or the chemotherapeutic agent cisplatin (Cp). The latter also induces mitochondrial dysfunction and apoptosis in mammalian cells. We further demonstrate that specific ARBs can prevent the prevalence of Cu-induced apoptotic markers in yeast, with Candesartan Cilexetil being the ARB which demonstrated most pronounced reduction of apoptosis-related markers. Next, we tested the sensitivity of a selection of yeast knockout mutants affected in detoxification of reactive oxygen species (ROS) and Cu for Candesartan Cilexetil rescue in presence of Cu. These data indicate that Candesartan Cilexetil increases yeast tolerance to Cu irrespectively of major ROS-detoxifying proteins. Finally, we show that specific ARBs can increase mammalian cell tolerance to Cu, as well as decrease the prevalence of Cu-induced apoptotic markers. All the above point to the potential of ARBs in preventing Cu-induced toxicity in yeast and mammalian cells.

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“…1:1 copper: Losartan complex forms at low molar ratio, and a 1:2 species is formed at molar ratios > 1 [52]. This last 1:2 complex is enthalpically favored, due to the metal-ligand bond strengthened by Ligand Field Stabilization Energy.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Complex formation equilibria of Cu2+ and Zn2+ with Irbesartan and Losartan

Lachowicz

Nurchi

Crisponi

et al. 2017

European Journal of Pharmaceutical Sciences

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We conducted a thorough study of Cu 2+ complex formation equilibria with Irbesartan and Losartan, the two primary drugs for the cure of cardiovascular diseases, with the aim of recognising if these drugs could exert a chelating action toward Cu 2+. We used different complementary techniques to gain a clear picture of the involved protonation and complexation equilibria. The low solubility in water of the ligands and of the formed metal complexes prevented the use of water as solvent, so we had to perform the measurements in mixed methanol-water solvents. Further, we studied the related equilibria with Zn 2+ for evaluating a potential interference of this essential metal ion, largely present in biological fluids. Our study provided a strong evaluation of the formed complexes and of the relative stability constants. The binding of both metal ions takes place through the tetrazole moiety except for the Zn 2+ -Irbesartan system. In this last case, NMR measurements gave evidence of a tautomeric equilibrium involving the imidazole ring and the aliphatic chain. The estimated complexation model, and the related stability constants, allowed a speciation study in human plasma, based on a number of simplifying assumptions, which remarked that both drugs, Losartan and Irbesartan, could exert a chelating action, scavenging non-negligible amounts of Cu 2+ from the organism.

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Control of size in losartan/copper(II) coordination complex hydrophobic precipitate

Cited by 11 publications

References 54 publications

Hydrophobic Nanoprecipitates of β-Cyclodextrin/Avermectins Inclusion Compounds Reveal Insecticide Activity against Aedes aegypti Larvae and Low Toxicity against Fibroblasts

Hydrophobic Nanoprecipitates of β-Cyclodextrin/Avermectins Inclusion Compounds Reveal Insecticide Activity against Aedes aegypti Larvae and Low Toxicity against Fibroblasts

Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin

Complex formation equilibria of Cu2+ and Zn2+ with Irbesartan and Losartan

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