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Evaluating Ligand Modifications of the Titanocene and Auranofin Moieties for the Development of More Potent Anticancer Drugs.

ABSTRACT: Over time platinum-based anticancer drugs have dominated the market, but their side effects significantly impact the quality of life of patients. Alternative treatments are being developed all over the world. The titanocene and auranofin families of compounds, discovered through an empirical search for other metal-based therapeutics, hold tremendous promise to improve the outcomes of cancer treatment. Herein we present a historical perspective of these compounds and review current efforts focused on the evolution of their ligands to improve their physiological solution stability, cancer selectivity, and antiproliferative performance, guided by a clear understanding of the coordination chemistry and aqueous speciation of the metal ions, of the cytotoxic mechanism of action of the compounds, and the external factors that limit their therapeutic potential. Newer members of these families of compounds and their combination in novel bimetallic complexes are the result of years of scientific research. We believe that this review can have a positive impact in the development and understanding of the metal-based drugs of gold, titanium, and beyond.

SUBMITTER: Fernandez-Vega L

PROVIDER: S-EPMC8152503 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Evaluating Ligand Modifications of the Titanocene and Auranofin Moieties for the Development of More Potent Anticancer Drugs.

Fernandez-Vega Lauren L Ruiz Silva Valeria A VA Domínguez-González Tania M TM Claudio-Betancourt Sebastián S Toro-Maldonado Rafael E RE Capre Maso Luisa C LC Ortiz Karina Sanabria KS Pérez-Verdejo Jean A JA González Janeishly Román JR Rosado-Fraticelli Grecia T GT Meléndez Fabiola Pagán FP Betancourt Santiago Fabiola M FM Rivera-Rivera Daniel A DA Navarro Carlos Martínez CM Bruno Chardón Andrea C AC Vera Axel O AO Tinoco Arthur D AD

Inorganics 20200126 2

Over time platinum-based anticancer drugs have dominated the market, but their side effects significantly impact the quality of life of patients. Alternative treatments are being developed all over the world. The titanocene and auranofin families of compounds, discovered through an empirical search for other metal-based therapeutics, hold tremendous promise to improve the outcomes of cancer treatment. Herein we present a historical perspective of these compounds and review current efforts focuse ...[more]

PMID: 34046448

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Project description:IntroductionCancer is a big challenge of the 21 century, whose defeat requires efficient antitumor drugs.ObjectivesThe paper aims to investigate the synergistic effect of two structural building blocks, phenothiazine and poly(ethylene glycol), towards efficient antitumor drugs.MethodsTwo PEGylated phenothiazine derivatives were synthetized by attaching poly(ethylene glycol) of 550 Da to the nitrogen atom of phenothiazine by ether or ester linkage. Their antitumor activity has been investigated on five human tumour lines and a mouse tumor line as well, by determination of IC50. The in vivo toxicity was determined by measuring the LD50 in BALB/c mice by the sequential method and the in vivo antitumor potential was measured by the tumours growth test. The antitumor mechanism was investigated by complexation studies of zinc and magnesium ions characteristic to the farnesyltransferase enzyme, by studies of self-aggregation in the cells proximity and by investigation of the antitumor properties of the acid species resulted by enzymatic cleavage of the PEGylated derivatives.ResultsThe two compounds showed antitumor activity, with IC50 against mouse colon carcinoma cell line comparable with that of the traditional antitumor drugs 5-Fluorouracil and doxorubicin. The phenothiazine PEGylation resulted in a significant toxicity diminishing, the LD50 in BALB/c mice increasing from 952.38 up to 1450 mg/kg, in phenothiazine equivalents. Both compounds inflicted a 92% inhibition of the tumour growth for doses much smaller than LD50. The investigation of the possible tumour inhibition mechanism suggested the nanoaggregate formation and the cleavage of ester bonds as key factors for the inhibition of cancer cell proliferation and biocompatibility improvement.ConclusionPhenothiazine and PEG building blocks have a synergetic effect working for both tumour growth inhibition and biocompatibility improvement. All these findings recommend the PEGylated phenothiazine derivatives as a valuable workbench for a next generation of antitumor drugs.

Dataset Information

Evaluating Ligand Modifications of the Titanocene and Auranofin Moieties for the Development of More Potent Anticancer Drugs.

Publications

Evaluating Ligand Modifications of the Titanocene and Auranofin Moieties for the Development of More Potent Anticancer Drugs.

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