Lucía Otero

Bio: Lucía Otero is an academic researcher from University of the Republic. The author has contributed to research in topics: Trypanosoma cruzi & Ruthenium. The author has an hindex of 24, co-authored 46 publications receiving 1542 citations. Previous affiliations of Lucía Otero include Pasteur Institute.

Novel antitrypanosomal agents based on palladium nitrofurylthiosemicarbazone complexes: DNA and redox metabolism as potential therapeutic targets.

Abstract: In the search for new therapeutic tools against American Trypanosomiasis palladium complexes with bioactive nitrofuran-containing thiosemicarbazones as ligands were obtained. Sixteen novel palladium (II) complexes with the formulas [PdCl2(HL)] and [Pd(L)2] were synthesized, and the crystal structure of [Pd(5-nitrofuryl-3-acroleine thiosemicarbazone)2] x 3DMSO was solved by X-ray diffraction methods. Most complexes showed higher in vitro growth inhibition activity against Trypanosoma cruzi than the standard drug Nifurtimox. In most cases, the activity of the ligand was maintained or even increased as a result of palladium complexation. In addition, the complexes' mode of antitrypanosomal action was investigated. Although the complexes showed strong DNA binding, all data strongly suggest that the main trypanocidal mechanism of action is the production of oxidative stress as a result of their bioreduction and extensive redox cycling. Moreover, the complexes were found to be irreversible inhibitors of trypanothione reductase.

New organoruthenium complexes with bioactive thiosemicarbazones as co-ligands: potential anti-trypanosomal agents

Abstract: In the search for new therapeutic tools against neglected diseases produced by trypanosomatid parasites, and particularly against African Trypanosomiasis, whose etiological agent is Trypanosoma brucei, organoruthenium compounds with bioactive nitrofuran containing thiosemicarbazones (L) as co-ligands were obtained. Four ruthenium(II) complexes with the formula [Ru2(p-cymene)2(L)2]X2, where X = Cl or PF6, were synthesized and the crystal structures of two of them were solved by X-ray diffraction methods. Two of the complexes show significant in vitro growth inhibition activity against Trypanosoma brucei brucei and are highly selective towards trypanosomal cells with respect to mammalian cells (J774 murine macrophages). These promising results make the title organoruthenium compounds good lead candidates for further developments towards potential antitrypanosomal organometallic drugs.

Screening organometallic binuclear thiosemicarbazone ruthenium complexes as potential anti-tumour agents: cytotoxic activity and human serum albumin binding mechanism

Abstract: Four complexes combining the {Ru(p-cym)} moiety (p-cym = para-cymene) with thiosemicarbazone (TSC) ligands containing the 5-nitrofuryl pharmacophore were investigated in vitro for their properties as prospective anti-tumour agents. The compounds are dimeric structures of general formula [Ru2(p-cym)2(L)2]X2 where X = Cl−, PF6− and L = deprotonated 5-nitrofuraldehyde TSC (L1), and the N-methyl (L2), N-ethyl (L3) and N-phenyl (L4) derivatives. The precursor [RuCl2(p-cym)]2, all TSC ligands L1–L4 and their corresponding complexes 1–4 were screened in vitro for their cytotoxicity against a range of human cancer cell lines (HL-60 acute promyelocytic leukemia, A2780 ovarian adenocarcinoma, MCF7 breast adenocarcinoma and PC3 grade IV prostate carcinoma). While the precursor complex was found to be inactive and L4 exhibited moderate activity only in the MCF7 cell line, the coordination of L4 to the {Ru(p-cym)} moiety remarkably enhanced the activity of the whole complex. In fact, complex 4 [Ru2(p-cym)2(L4)2]Cl2 was found to be the most active agent of the whole series, and was studied further (as well as complex 1 for comparison). Concerning the mode of action, the mechanism of cell death for both 1 and 4 seemed to be related to apoptotic processes, and they strongly interacted with tubulin (involved in the cell cycle) and with integrin (involved in the cytoskeleton formation). As an approach to their pharmacokinetics, the interaction of 1 and 4 with human serum albumin (HSA) was assessed. A quantitative model for the binding of 4 to HSA is proposed from Circular Dichroism data, and validated by fluorescence results. Models of Forster resonance energy transfer and fluorescence quenching afforded the distance of 4 to the lone Trp214 residue. Importantly, HSA binding enhanced the cytotoxicity of 4 and correlated well with the HSA binding data. Our results consistently indicate that [Ru2(p-cymene)2(L4)2]Cl2 is quite promising as a prospective metallodrug for cancer chemotherapy.

Principles Of Fluorescence Spectroscopy

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Drug Discovery Today

Abstract: In recent years, tools for the development of new drugs have been dramatically improved. These include genomic and proteomic research, numerous biophysical methods, combinatorial chemistry and screening technologies. In addition, early ADMET studies are employed in order to significantly reduce the failure rate in the development of drug candidates. As a consequence, the lead finding, lead optimization and development process has gained marked enhancement in speed and efficiency. In parallel to this development, major pharma companies are increasingly outsourcing many components of drug discovery research to biotech companies. All these measures are designed to address the need for a faster time to market. New screening methodologies have contributed significantly to the efficiency of the drug discovery process. The conventional screening of single compounds or compound libraries has been dramatically accelerated by high throughput screening methods. In addition, in silico screening methods allow the evaluation of virtual compounds. A wide range of new lead finding and lead optimization opportunities result from novel screening methods by NMR, which are the topic of this review article.

Antitumour metal compounds: more than theme and variations

Abstract: Triggered by the resounding success of cisplatin, the past decades have seen tremendous efforts to produce clinically beneficial analogues. The recent achievement of oxaliplatin for the treatment of colon cancer should, however, not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs. Strategies opening up new avenues are increasingly being sought using complexes of metals other than platinum such as ruthenium or gallium. Based on the chemical differences between these metals, the spectrum of molecular mechanisms of action and potential indications can be broadened substantially. Other approaches focus on complexes with tumour-targeting properties, thereby maximizing the impact on cancer cells and minimizing the problem of adverse side effects, and complexes with biologically active ligands.

Classical and Non-Classical Ruthenium-Based Anticancer Drugs: Towards Targeted Chemotherapy

Abstract: Ruthenium-based anticancer chemotherapies are making significant advances in clinical trials. Until recently, the focus has been on coordination complexes, and mechanisms such as "activation by reduction" and "transferrin-targeted delivery" have been proposed to account for the excellent cytotoxicity and low general toxicity of these complexes. More recently organoruthenium compounds, which to some extent appear not to follow the established rules, have started to be investigated. Despite such differences, similar activities between certain coordination and organometallic compounds suggest similar modes of action are present. DNA, the classic target, is believed to be the dominant mechanism for cytotoxicity with certain ruthenium drugs, while with others, non-classical targets are thought to be more important. In this article we describe these features and show how both ruthenium coordination complexes and organoruthenium compounds represent an ideal scaffold for further drug design and optimisation.