RESUMEN
Invited for this month's cover are the collaborating groups of Esteban Rodríguez-Arce from the University of Chile and María Contel from The City University of New York Brooklyn College. The cover picture shows "Supergold" a very powerful gender neutral warrior with superpowers who fights against cancer! The warrior's golden armor and sword represent the pharmacological power of the gold atom. Engraved on the shield, the gold-thiosemicarbazone molecules are the warrior's coat of arms. Supergold selectively destroys different cancer cells. More information can be found in the Research Article by Esteban Rodríguez-Arce, María Contel, and co-workers.
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Oro , Tiosemicarbazonas , Humanos , Oro/farmacología , Tiosemicarbazonas/farmacología , Masculino , Femenino , Antineoplásicos/farmacologíaRESUMEN
This work describes the synthesis of four gold(I) [AuClL] compounds containing chloro and biologically active protonated thiosemicarbazones based on 5-nitrofuryl (L=HSTC). The stability of the compounds in dichloromethane, DMSO, and DMSO/culture media solutions was investigated by spectroscopy, cyclic voltammetry, and conductimetry, indicating the formation overtime of cationic monometallic [Au(HTSC)(DMSO)]± or [Au(HTSC)2 ]± , and/or dimeric species. Neutral [{Au(TSC)}2 ] species were obtained from one of the compounds in dichlomethane/n-hexane solution and characterized by X-ray crystallography revealing a Au-Au bond, and deprotonated thiosemicarbazone (TSC). The cytotoxicity of the gold compounds and thiosemicarbazone ligands was evaluated against selected cancer cell lines and compared to that of Auranofin. Studies of the most stable, cytotoxic, and selective compound on a renal cancer cell line (Caki-1) demonstrated its relevant antimigratory and anti-angiogenic properties, and preferential accumulation in the cell nuclei. Its mode of action seems to involve interaction with DNA, and subsequent cell death via apoptosis.
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Antineoplásicos , Tiosemicarbazonas , Oro , Línea Celular Tumoral , Dimetilsulfóxido , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/químicaRESUMEN
A green analytical method for the determination of Cu and Zn in rice samples was developed. This method was based on an ozone-assisted extraction (OAE) in diluted acid media. A novel closed system was designed for this purpose that allowed four simultaneous sample treatments being safe for the laboratory environment. The method consisted in 0.5 g of the sample, 15 minutes of ozonation, and 3 minutes of centrifugation. The obtained supernatant was ready for Cu and Zn determinations by flame atomic absorption spectrometry. Detection limits were 0.20 and 0.08 mg kg-1 for Cu and Zn, respectively, with a precision (RSD) better than 5% for both elements. A certified reference material of rice flour was analyzed for trueness evaluation, and the mean recoveries (%) were 100.4 (Cu) and 95.9 (Zn). Several commercial rice samples were analyzed using this method, and the results were compared with those obtained using traditional microwave-assisted digestion (MAE). Both methods yielded comparable results. Cu and Zn levels were in accordance with reported values in other regions. The OAE resulted to be simple and economical and with results equivalent with those obtained using traditional sample preparation procedures as MAE with the advantage of being in good agreement with the principles of green analytical chemistry.
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In the search for a more effective chemotherapy for the treatment of Human African Trypanosomiasis, a disease caused by the parasite Trypanosoma brucei, the development of ferrocenyl compounds has arisen as a promising strategy. In this work, five new Pd-Fe heterobimetallic [PdII(L)(dppf)](PF6) compounds, including 8-hydroxyquinolyl derivatives HL1-HL5 as bioactive ligands and dppf = 1,1'-bis(diphenylphosphino)ferrocene as the organometallic co-ligand, were synthesized and fully characterized in the solid state and in solution. Molecular structures of three compounds were solved by single crystal X-ray diffraction methods. The compounds displayed submicromolar or micromolar IC50 values against bloodstream T. brucei (IC50: 0.33-1.2 µM), and good selectivity towards the pathogen (SI: 4-102) with respect to mammalian macrophages (cell line J774). The new Pd complexes proved to be 2-fold to 45-fold more potent than the drug nifurtimox but most of them are less active than their Pt analogues. Potential molecular targets were studied. The complexes interact with DNA but they do not alter the intracellular thiol-redox homeostasis of the parasite. In order to understand and predict the main structural determinants on the anti-T. brucei activity, a search of quantitative structure-activity relationships (QSAR) was performed including all the [M(L)(dppf)](PF6) complexes, where M = Pd(ii) or Pt(ii), currently and previously developed by us. The correlation obtained shows the relevance of the electronic effects, the lipophilicity and the type of metal. According to the QSAR study, compounds with electron-withdrawing ligands, higher lipophilicity and harboring Pt would result in higher T. brucei cytotoxicity. From the whole series of [M(L)(dppf)](PF6) compounds developed, where M = Pt(ii) or Pd(ii) and HL = 8-hydroxyquinolyl derivatives, Pt-dppf-L4 (IC50 = 0.14 µM, SI = 48) was selected to perform an exploratory pre-clinical study in infected mice. This hit compound lacks acute toxicity when applied to animals in the dose/regimen described and exerts an anti-proliferative effect on parasites, which extends animal survival but is not curative.
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Antiparasitarios/química , Antiparasitarios/farmacología , Compuestos Ferrosos/química , Hierro/química , Metalocenos/química , Oxiquinolina/química , Paladio/química , Ligandos , Relación Estructura-Actividad CuantitativaRESUMEN
Searching for a more effective chemotherapy for the treatment of Human African trypanosomiasis, the disease caused by the parasite Trypanosoma brucei, and cancer, in the current work five new [PtII(L)(dppf)](PF6) compounds, with HLâ¯=â¯8-hydroxyquinoline derivatives and dppfâ¯=â¯1,1'-bis(diphenylphosphino)ferrocene, were synthesized and fully characterized. Crystal structures of three compounds were solved by XRD. The compounds displayed fairly good activity against bloodstream T. brucei, with IC50 values in the submicromolar range (IC50: 0.14-0.93⯵M), and good selectivity towards the pathogen (SI: 11 - 48) with respect to mammalian macrophages (cell line J774). Coordination to the {Pt-dppf} moiety led, in most cases, to an enhancement of the activity in respect to the bioactive ligands (11 to 41 fold). Cytotoxicity was assessed against wildtype (A2780) and cisplatin-resistance (A2780cisR) ovarian cancer cell lines. Four [PtII(L)(dppf)](PF6) compounds were more active (IC50: 1.2-4.4⯵M) than cisplatin (IC50: 26.0⯵M) on A2780 cells and showed far superior activity than the reference drug against A2780cisR cells. Platinum levels in A2780 cells showed poor correlation between cellular uptake and the cytotoxic activity. All the complexes interacted with DNA and the most active ones induced reactive oxygen species (ROS) formation which suggested that the mechanism of action for these complexes may be mediated by oxidative stress and interaction with DNA that could act as a potential molecular target for this type of complexes. Some complexes of this series could be considered new hits for the development of prospective agents against trypanosomatid parasites and ovarian cancer.
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Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Ferrosos/química , Hidroxiquinolinas/química , Hierro/química , Platino (Metal)/química , Trypanosoma brucei brucei/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cricetulus , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Estructura Molecular , Especies Reactivas de Oxígeno/metabolismo , Difracción de Rayos XRESUMEN
Cancer is a disease that involves impaired genome stability with a high mortality index globally. Since its discovery, many have searched for effective treatment, assessing different molecules for their anticancer activity. One of the most studied sources for anticancer therapy is natural compounds and their derivates, like alkaloids, which are organic molecules containing nitrogen atoms in their structure. Among them, oxoisoaporphine and sampangine compounds are receiving increased attention due to their potential anticancer effects. Boldine has also been tested as an anticancer molecule. Boldine is the primary alkaloid extract from boldo, an endemic tree in Chile. These compounds and their derivatives have unique structural properties that potentially have an anticancer mechanism. Different studies showed that this molecule can target cancer cells through several mechanisms, including reactive oxygen species generation, DNA binding, and telomerase enzyme inhibition. In this review, we summarize the state-of-art research related to oxoisoaporphine, sampangine, and boldine, with emphasis on their structural characteristics and the relationship between structure, activity, methods of extraction or synthesis, and anticancer mechanism. With an effective cancer therapy still lacking, these three compounds are good candidates for new anticancer research.
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Alcaloides , Antineoplásicos Fitogénicos , Aporfinas , Inhibidores Enzimáticos , Compuestos Heterocíclicos de 4 o más Anillos , Naftiridinas , Neoplasias/tratamiento farmacológico , Alcaloides/química , Alcaloides/uso terapéutico , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/uso terapéutico , Aporfinas/química , Aporfinas/uso terapéutico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Naftiridinas/química , Naftiridinas/uso terapéutico , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Telomerasa/antagonistas & inhibidores , Telomerasa/metabolismoRESUMEN
Searching for prospective agents against infectious diseases, four new ferrocenyl derivatives, [M(L)(dppf)4](PF6), with Mâ¯=â¯Pd(II) or Pt(II), dppfâ¯=â¯1,1'-bis(dipheny1phosphino) ferrocene and HLâ¯=â¯tropolone (HTrop) or hinokitiol (HHino), were synthesized and characterized. Complexes and ligands were evaluated against the bloodstream form of T. brucei, L. infantum amastigotes, M. tuberculosis (MTB) sensitive strain and MTB clinical isolates. Complexes showed a significant increase of the anti-T. brucei activity with respect to the free ligands (>28- and >46-fold for Trop and 6- and 22-fold for Hino coordinated to Pt-dppf and Pd-dppf, respectively), yielding IC50 valuesâ¯<â¯5⯵M. The complexes proved to be more potent than the antitrypanosomal drug Nifurtimox. The new ferrocenyl derivatives were more selective towards the parasite than the free ligands. The Pt compounds were less toxic on J774 murine macrophages (mammalian cell model), than the Pd ones, showing selectivity index values (SIâ¯=â¯IC50 murine macrophage/IC50T. brucei) up to 23. Generation of the {M-dppf} compounds lead to a slightly positive impact on the anti-leishmanial potency. Although the ferrocenyl derivatives were more active on sensitive MTB than the free ligands (MIC90â¯=â¯9.88-14.73⯵M), they showed low selectivity towards the pathogen. Related to the mechanism of action, the antiparasitic effect cannot be ascribed to an interference of the compounds with the thiol-redox homeostasis of the pathogen. Fluorescence measurements pointed at DNA as a probable target of the new compounds. [Pt(Trop)(dppf)](PF6) and [Pt(Hino)(dppf)](PF6) could be considered prospective anti-T. brucei agents that deserve further research.
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Antituberculosos , Compuestos Ferrosos , Mycobacterium tuberculosis/crecimiento & desarrollo , Tripanocidas , Trypanosoma brucei brucei/crecimiento & desarrollo , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Antituberculosos/farmacología , Línea Celular , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/química , Compuestos Ferrosos/farmacología , Humanos , Leishmania infantum/crecimiento & desarrollo , Ratones , Tripanocidas/química , Tripanocidas/farmacologíaRESUMEN
American Trypanosomiasis is a chronic infection discovered and described in 1909 by the Brazilian scientist Carlos Chagas. It is caused by the protozoan parasite Trypanosoma cruzi. Although it affects about 10million people in Latin America, the current chemotherapy is still inadequate. The discovery of new drugs is urgently needed. Our group is focused on the development of prospective metal-based drugs mainly based on bioactive ligands and pharmacologically interesting metal ions. In this work three new rhenium(I) tricarbonyl compounds fac-[ReI(CO)3Br(HL)] where HL=5-nitrofuryl containing thiosemicarbazones were synthesized and fully characterized in solution and in the solid state. The in vitro evaluation of the compounds on T. cruzi trypomastigotes (Dm28c strain) showed that the Re(I) compounds are 8 to 15 times more active than the reference drug Nifurtimox and show a 4 to 17 fold increase in activity in respect to the free (HL) ligands. Obtained compounds also show good selectivity indexes (IC50 endothelial cells Ea.hy926/IC50 T. cruzi (Dm28c tripomastigotes)). 1H NMR and MS studies, performed with time, showed that the fac-[Re(CO)3Br(HL)] species convert into the dimers [Re2(CO)6(L)2] in solution. Crystal structure of [ReI2(CO)6(L2)2], the product of complexes' dimerization, was solved. Related to the mechanism of action, the studied compounds do not generate radical oxygen species in the parasite (as 5-nitrofuryl derived thiosemicarbazones do) probably due to the unfavorable nitro reduction potential of the generated dimeric species. On the contrary, the compounds produce a decrease of the oxygen consumption rate of the parasites, maybe inhibiting their mitochondrial respiration.