RESUMEN
Nonribosomal cyclic peptides (NRcPs) are structurally complex natural products and a vital pool of therapeutics, particularly antibiotics. Their structural diversity arises from the ability of the multidomain enzyme assembly lines, nonribosomal peptide synthetases (NRPSs), to utilize bespoke nonproteinogenic amino acids, modify the linear peptide during elongation, and catalyze an array of cyclization modes, e.g., head to tail, side chain to tail. The study and drug development of NRcPs are often limited by a lack of easy synthetic access to NRcPs and their analogues, with selective macrolactamization being a major bottleneck. Herein, we report a generally applicable chemical macrocyclization method of unprecedented speed and selectivity. Inspired by biosynthetic cyclization, it combines the deprotected linear biosynthetic precursor peptide sequence with a highly reactive C-terminus to produce NRcPs and analogues in minutes. The method was applied to several NRcPs of varying sequences, ring sizes, and cyclization modes including rufomycin, colistin, and gramicidin S with comparable success. We thus demonstrate that the linear order of modules in NRPS enzymes that determines peptide sequence encodes the key structural information to produce peptides conformationally biased toward macrocyclization. To fully exploit this conformational bias synthetically, a highly reactive C-terminal acyl azide is also required, alongside carefully balanced pH and solvent conditions. This allows for consistent, facile cyclization of exceptional speed, selectivity, and atom efficiency. This exciting macrolactamization method represents a new enabling technology for the biosynthetic study of NRcPs and their development as therapeutics.
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The mounting burden of antimicrobial resistance (AMR) is one of the most concerning threats to public health worldwide. With low economic incentives and a dwindling supply of new drugs in clinical pipelines, more innovative approaches to novel drug design and development are desperately required. Metal-based compounds are rapidly emerging as an alternative to organic drugs, as they have the ability to kill pathogens via metal-specific modes of action. We herein review recent advances in metal-based antibacterial agents, including metal complexes, metal ions and catalytic metallodrugs. The review concludes with a perspective on the rational design of metal-based antibiotics, and how we can exploit their unique properties to tackle AMR.
Asunto(s)
Complejos de Coordinación , Complejos de Coordinación/farmacología , Antibacterianos/farmacología , MetalesRESUMEN
Antimicrobial resistance (AMR) is a growing global problem with more than 1 million deaths due to AMR infection in 2019 alone. New and innovative therapeutics are required to overcome this challenge. Antimicrobial photodynamic therapy (aPDT) is a rapidly growing area of research poised to provide much needed help in the fight against AMR. aPDT works by administering a photosensitizer (PS) that is activated only when irradiated with light, allowing high spatiotemporal control and selectivity. The PS typically generates reactive oxygen species (ROS), which can damage a variety of key biological targets, potentially circumventing existing resistance mechanisms. Metal complexes are well known to display excellent optoelectronic properties, and recent focus has begun to shift towards their application in tackling microbial infections. Herein, we review the last five years of progress in the emerging field of small-molecule metal complex PSs for aPDT.
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Antiinfecciosos , Infecciones Bacterianas , Complejos de Coordinación , Fotoquimioterapia , Humanos , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológicoRESUMEN
The delivery of lipophilic dyes, such as BODIPY 505/515, to cells is often hindered by their low aqueous solubility, necessitating the use of organic solvents to facilitate the delivery, which unfortunately compromises the viability of the cells. In this work, we demonstrate the generation of novel composite hydrogel microparticles loaded with BODIPY 505/515, which can be used to deliver the dye to microalgal cells to stain the intracellular lipids. The microparticles were prepared by combining polymeric micelles with hydrogel technology to obtain microparticles of enhanced loading capacity. The generated hydrogel microparticles were tested by incubation with Phaeodactylum tricornutum algal cells. The cells were rapidly and successfully stained by the dye-containing microparticles, and their viability was not affected by the staining process. The method can also be used to stain other types of microalgal cells, such as Nannochloropsis gaditana cells. We therefore believe that this work offers a versatile and useful solution to important cell-staining problems in biotechnology.
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Microalgas , Microfluídica , Hidrogeles , Coloración y Etiquetado , ColorantesRESUMEN
Pseudomonas aeruginosa is of major concern for cystic fibrosis patients where this infection can be fatal. With the emergence of drug-resistant strains, there is an urgent need to develop novel antibiotics against P. aeruginosa. MurB is a promising target for novel antibiotic development as it is involved in the cell wall biosynthesis. MurB has been shown to be essential in P. aeruginosa, and importantly, no MurB homologue exists in eukaryotic cells. A fragment-based drug discovery approach was used to target Pa MurB. This led to the identification of a number of fragments, which were shown to bind to MurB. One fragment, a phenylpyrazole scaffold, was shown by ITC to bind with an affinity of Kd = 2.88 mM (LE 0.23). Using a structure guided approach, different substitutions were synthesized and the initial fragment was optimized to obtain a small molecule with Kd = 3.57 µM (LE 0.35).
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Antibacterianos/química , Proteínas Bacterianas/antagonistas & inhibidores , Oxidorreductasas/antagonistas & inhibidores , Pseudomonas aeruginosa/enzimología , Antibacterianos/metabolismo , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Proteínas Bacterianas/metabolismo , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Fibrosis Quística/complicaciones , Fibrosis Quística/mortalidad , Fibrosis Quística/patología , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Conformación Molecular , Simulación del Acoplamiento Molecular , Oxidorreductasas/metabolismo , Infecciones por Pseudomonas/complicaciones , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacología , Pirazoles/uso terapéuticoRESUMEN
The occurrence of drug-resistant bacteria is drastically rising and new and effective antibiotic classes are urgently needed. However, most of the compounds in development are minor modifications of previously used drugs to which bacteria can easily develop resistance. The investigation of inorganic and organometallic compounds as antibiotics is an alternative approach that holds great promises due to the ability of such molecules to trigger metal-specific mechanisms of action, which results in lethal consequences for pathogens. In this review, a selection of concepts to rationally design inorganic and organometallic antibiotics is discussed, highlighting their advantages by comparing them to classical drug discovery programmes. The review concludes with a short perspective for the future of antibiotic drug development and the role metal-based compounds will play in the field.
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Antibacterianos , Bacterias , Antibacterianos/farmacología , Descubrimiento de DrogasRESUMEN
Fungal infections represent a global problem, notably for immunocompromised patients in hospital, COVID-19 patient wards and care home settings, and the ever-increasing emergence of multidrug resistant fungal strains is a sword of Damocles hanging over many healthcare systems. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this study, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (1a-4a). Very importantly, enzyme inhibition and chemogenomic profiling demonstrated that lanosterol 14α-demethylase, as for fluconazole, was the main target of the most active compound of the series, (N-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy-N-methyl-3-(1H-1,2,4-triazol-1-yl)propan-1-aminium chloride, 2a). Transmission electron microscopy (TEM) studies suggested that 2a induced a loss in cell wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of 2a was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, 2a showed activity towards azole-resistant strains. This finding is very interesting since the primary target of 2a is the same as that of fluconazole, emphasizing the role played by the organometallic moiety. In vivo experiments in a mice model of Candida infections revealed that 2a reduced the fungal growth and dissemination but also ameliorated immunopathology, a finding suggesting that 2a is active in vivo with added activity on the host innate immune response.
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Coenzyme A (CoA) is a ubiquitous cofactor present in all living cells and estimated to be required for up to 9% of intracellular enzymatic reactions. Mycobacterium tuberculosis (Mtb) relies on its own ability to biosynthesize CoA to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the pathway to CoA biosynthesis is recognized as a potential source of novel tuberculosis drug targets. In prior work, we genetically validated CoaBC as a bactericidal drug target in Mtb in vitro and in vivo. Here, we describe the identification of compound 1f, a small molecule inhibitor of the 4'-phosphopantothenoyl-l-cysteine synthetase (PPCS; CoaB) domain of the bifunctional Mtb CoaBC, and show that this compound displays on-target activity in Mtb. Compound 1f was found to inhibit CoaBC uncompetitively with respect to 4'-phosphopantothenate, the substrate for the CoaB-catalyzed reaction. Furthermore, metabolomic profiling of wild-type Mtb H37Rv following exposure to compound 1f produced a signature consistent with perturbations in pantothenate and CoA biosynthesis. As the first report of a direct small molecule inhibitor of Mtb CoaBC displaying target-selective whole-cell activity, this study confirms the druggability of CoaBC and chemically validates this target.
Asunto(s)
Mycobacterium tuberculosis , Péptido Sintasas/antagonistas & inhibidores , Coenzima A , Cisteína/análogos & derivados , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/genética , Ácido Pantoténico/análogos & derivados , Péptido Sintasas/genéticaRESUMEN
Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.
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Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Carboxiliasas/antagonistas & inhibidores , Mycobacterium smegmatis/enzimología , Mycobacterium tuberculosis/efectos de los fármacos , Péptido Sintasas/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico/efectos de los fármacos , Antituberculosos/uso terapéutico , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/ultraestructura , Carboxiliasas/genética , Carboxiliasas/metabolismo , Carboxiliasas/ultraestructura , Coenzima A/biosíntesis , Cristalografía por Rayos X , Pruebas de Enzimas , Técnicas de Silenciamiento del Gen , Ensayos Analíticos de Alto Rendimiento , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/genética , Péptido Sintasas/genética , Péptido Sintasas/metabolismo , Péptido Sintasas/ultraestructura , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiologíaRESUMEN
CoaBC, part of the vital coenzyme A biosynthetic pathway in bacteria, has recently been validated as a promising antimicrobial target. In this work, we employed native ion mobility-mass spectrometry to gain structural insights into the phosphopantothenoylcysteine synthetase domain of E. coli CoaBC. Moreover, native mass spectrometry was validated as a screening tool to identify novel inhibitors of this enzyme, highlighting the utility and versatility of this technique both for structural biology and for drug discovery.
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Carboxiliasas/química , Evaluación Preclínica de Medicamentos/métodos , Proteínas de Escherichia coli/química , Escherichia coli/enzimología , Espectrometría de Masas/métodos , Complejos Multienzimáticos/química , Péptido Sintasas/química , Carboxiliasas/antagonistas & inhibidores , Carboxiliasas/metabolismo , Dimerización , Inhibidores Enzimáticos/química , Escherichia coli/química , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/metabolismo , Cinética , Complejos Multienzimáticos/antagonistas & inhibidores , Complejos Multienzimáticos/metabolismo , Péptido Sintasas/antagonistas & inhibidores , Péptido Sintasas/metabolismo , Dominios ProteicosRESUMEN
We present the design, synthesis, characterization and biological evaluation of new ferrocenyl and ruthenocenyl derivatives of the organic antimalarial mefloquine, a drug also known for its antischistosomal activity. The two metallocenyl derivatives prepared (3 and 4) demonstrated comparable activity to mefloquine against adult-stage Schistosoma mansoni in vitro. Importantly, both compounds were found to have lower toxicity in all cell lines than mefloquine itself. Administration of a 200 mg kg-1 oral dose of 3 and 4 to S. mansoni-infected mice did not significantly reduce worm burden, contrary to mefloquine.
RESUMEN
BACKGROUND: Schistosomiasis is one of the most harmful parasitic diseases worldwide, praziquantel being the only drug in widespread use to treat it. We recently demonstrated that ferrocenyl, ruthenocenyl and benzyl derivatives of oxamniquine (Fc-OXA, Rc-OXA and Bn-OXA) are promising antischistosomal drug candidates. METHODS: In this study we assessed the tegumental damage of these three derivatives of oxamniquine using scanning electron microscopy. Adult Schistosoma mansoni and S. haematobium were exposed to a concentration of 100 µM of each drug and incubated for 4-120 h, according to their onset of action and activity. RESULTS: While on S. mansoni the fastest acting compound was Fc-OXA, which revealed high activity after 4 h of incubation, on S. haematobium, Rc-OXA revealed the quickest onset, being lethal on all males within 24 h. In both species studied, the three derivatives showed the same patterns of tegumental damage consisting of blebs, sloughing and tegument rupturing all over the body. Additionally, on S. mansoni distinct patterns of tegumental damage were observed for each of the compounds: tissue ruptures in the gynaecophoric canal for Fc-OXA, loss of spines for Rc-OXA and oral sucker rupture for Bn-OXA. CONCLUSIONS: Our study confirmed that Fc-OXA, Rc-OXA and Bn-OXA are promising broad spectrum antischistosomal drug candidates. All derivatives show fast in vitro activity against S. mansoni and S. haematobium while validating the previous finding that the parent drug oxamniquine is less active in vitro under the conditions described. This work sets the base for further studies on the identification of a lead oxamniquine derivative, with the aim of identifying a molecule with the potential to become a new drug for human use.
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Compuestos Organometálicos/farmacología , Oxamniquina/farmacología , Schistosoma haematobium/anatomía & histología , Schistosoma haematobium/efectos de los fármacos , Schistosoma mansoni/anatomía & histología , Schistosoma mansoni/efectos de los fármacos , Animales , Femenino , Concentración 50 Inhibidora , Ratones , Microscopía Electrónica de Rastreo , Compuestos Organometálicos/química , Oxamniquina/química , Schistosoma mansoni/ultraestructura , Esquistosomiasis/parasitología , Esquistosomicidas/farmacologíaRESUMEN
Interstrand cross-links (ICLs) are toxic DNA lesions interfering with DNA metabolism that are induced by widely used anticancer drugs. They have long been considered absolute roadblocks for replication forks, implicating complex DNA repair processes at stalled or converging replication forks. Recent evidence challenged this view, proposing that single forks traverse ICLs by yet elusive mechanisms. Combining ICL immunolabeling and single-molecule approaches in human cells, we now show that ICL induction leads to global replication fork slowing, involving forks not directly challenged by ICLs. Active fork slowing is linked to rapid recruitment of RAD51 to replicating chromatin and to RAD51/ZRANB3-mediated fork reversal. This global modulation of fork speed and architecture requires ATR activation, promotes single-fork ICL traverse-here, directly visualized by electron microscopy-and prevents chromosomal breakage by untimely ICL processing. We propose that global fork slowing by remodeling provides more time for template repair and promotes bypass of residual lesions, limiting fork-associated processing.
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Rotura Cromosómica , Daño del ADN/genética , Replicación del ADN/genética , ADN/metabolismo , Western Blotting , Línea Celular Tumoral , Ensayo Cometa , ADN/genética , ADN/ultraestructura , Daño del ADN/fisiología , Replicación del ADN/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Microscopía Electrónica , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismoRESUMEN
Schistosomiasis is a parasitic disease that affects more than 250 million people annually, mostly children in poor, tropical, rural areas. Only one treatment (praziquantel) is available, putting control efforts at risk should resistance occur. In pursuit of treatment alternatives, we derivatized an old antischistosomal agent, oxamniquine (OXA). Four organometallic derivatives of OXA were synthesized and tested against Schistosoma mansoni in vitro and in vivo. Of these, a ferrocenyl derivative, 1, killed larval and adult worms 24 h postexposure in vitro, in contrast to OXA, which lacks in vitro activity against adult worms. A dose of 200 mg/kg of 1 completely eliminated the worm burden in mice. Subsequently, a ruthenocenyl (5) and a benzyl derivative (6) of OXA were synthesized to probe the importance of the ferrocenyl group in 1. Compounds 1, 5, and 6 were lethal to both S. mansoni and S. haematobium adults in vitro. In vivo, at 100 mg/kg, all three compounds revealed S. mansoni worm burden reductions of 76 to 93%, commensurate with OXA. Our findings present three compounds with activity against S. mansoni in vitro, comparable activity in vivo, and high activity against S. haematobium in vitro. These compounds may possess a different binding mode or mode of action compared to OXA and present excellent starting points for further SAR studies.
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Antihelmínticos/administración & dosificación , Compuestos Organometálicos/administración & dosificación , Oxamniquina/análogos & derivados , Esquistosomiasis Urinaria/tratamiento farmacológico , Esquistosomiasis mansoni/tratamiento farmacológico , Animales , Antihelmínticos/síntesis química , Antihelmínticos/química , Antihelmínticos/farmacología , Química Farmacéutica , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Schistosoma haematobium/efectos de los fármacos , Schistosoma mansoni/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Two [Ru(phen)2 dppz]2+ derivatives (phen=1,10-phenantroline, dppz=dipyrido[3,2-a:2',3'-c]phenazine) with different functional groups on the dppz ligand [dppz-7,8-(OMe)2 (1), dppz-7,8-(OH)2 (2)] have been synthesized, characterized and investigated as photosensitizers (PSs) for photodynamic therapy (PDT) against cancer. Both complexes showed intense red phosphorescence and promising singlet oxygen (1 O2 ) quantum yields of 75 % (1) and 54 % (2) in acetonitrile. Complex 1 (logPo/w =-0.52, 2.4â nmol Ru per mg protein) was found to be more lipophilic, having also a higher cellular uptake efficiency compared to 2 (logPo/w =-0.20, 0.9â nmol Ru per mg protein). Complex 1 localized evenly in HeLa cells whereas 2, was mainly visualized in the cell membrane by confocal microscopy. In the dark, complex 1 (IC50 =36.5â µm) was found to be more toxic than complex 2 (IC50 >100â µm) on a HeLa cells monolayer. Importantly, in view of PDT applications, both complexes were found to be non-toxic in the dark towards multicellular HeLa spheroids (IC50 >100â µm). Upon one-photon irradiation (420â nm, 9.27â J cm-2 ), 1 exhibited higher phototoxicity (IC50 =3.1â µm) than 2 (IC50 =16.7â µm) on HeLa cell monolayers. When two-photon irradiation (800â nm, 9.90â J cm-2 ) was applied, only 1 (IC50 =9.5â µm) was found to be active toward HeLa spheroids. This study demonstrates that the functional group on the intercalative ligand has a strong influence on the cellular localization and anticancer activity of RuII polypyridyl complexes.
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Complejos de Coordinación/química , Fármacos Fotosensibilizantes/química , Rutenio/química , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/sangre , Complejos de Coordinación/síntesis química , Complejos de Coordinación/toxicidad , Cristalografía por Rayos X , Células HeLa , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Luz , Microscopía Confocal , Conformación Molecular , Compuestos Organometálicos/química , Fotoquimioterapia , Fotones , Fármacos Fotosensibilizantes/sangre , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/toxicidad , Oxígeno Singlete/química , Oxígeno Singlete/metabolismo , Esferoides Celulares/citología , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismoRESUMEN
In this study, we present the design, synthesis, characterization and biological evaluation of structurally new ferrocenyl and ruthenocenyl derivatives of the organic anthelmintic monepantel (Zolvix®). All seven metallocenyl derivatives prepared (4a/b, 5a/b, 6a/b and 7) were isolated as racemates and characterized by 1H, 13C and 19F NMR spectroscopies, mass spectrometry, IR spectroscopy and elemental microanalysis. The molecular structures of four compounds (4a/b, 6a and 7) were further confirmed by X-ray crystallography. The biological activities of the organometallic intermediates (4a/b) and organometallic derivatives of monepantel (5a/b, 6a/b and 7) were evaluated in vitro using parasitic nematodes of major importance in livestock, namely Haemonchus contortus and Trichostrongylus colubriformis. Two ferrocenyl compounds (4a and 6a) showed nematocidal activity, while the analogous ruthenocenyl compounds (4b and 6b) were not active at the highest concentration tested (10 µg mL-1). In order to obtain insight into the difference in activity between ferrocenyl and ruthenocenyl derivatives, the potential of the compounds for reactive oxidative species (ROS) production in live cells was assessed. Interestingly, neither the ferrocenyl nor the ruthenocenyl compounds (4a/b and 6a/b) produced significant ROS in HeLa cells when checked after 22 h, potentially indicating a redox-independent activity of 4a and 6a on the parasites. The selectivity of the compounds on parasites was confirmed by investigating their cytotoxicity profiles. None of these compounds was toxic either to HeLa or MRC-5 cells. Thus, 4a and 6a could be considered as interesting leads for further development of new classes of anti-parasitic agents.
RESUMEN
The discovery of novel drugs against animal parasites is in high demand due to drug-resistance problems encountered around the world. Herein, the synthesis and characterization of 27 organic and organometallic derivatives of the recently launched nematocidal drug monepantel (Zolvix® ) are described. The compounds were isolated as racemates and were characterized by 1 H, 13 C, and 19 Fâ NMR spectroscopy, mass spectrometry, and IR spectroscopy, and their purity was verified by microanalysis. The molecular structures of nine compounds were confirmed by X-ray crystallography. The anthelmintic activity of the newly designed analogues was evaluated in vitro against the economically important parasites Haemonchus contortus and Trichostrongylus colubriformis. Moderate nematocidal activity was observed for nine of the 27 compounds. Three compounds were confirmed as potentiators of a known monepantel target, the ACR-23 ion channel. Production of reactive oxygen species may confer secondary activity to the organometallic analogues. Two compounds, namely, an organic precursor (3 a) and a cymantrene analogue (9 a), showed activities against microfilariae of Dirofilaria immitis in the low microgram per milliliter range.
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Aminoacetonitrilo/análogos & derivados , Antinematodos/química , Antiparasitarios/química , Resistencia a Medicamentos/efectos de los fármacos , Aminoacetonitrilo/química , Animales , Antinematodos/farmacología , Antiparasitarios/farmacología , Cristalografía por Rayos X , HaemonchusRESUMEN
An organometallic derivative of praziquantel was studied directly in worms by using inductively coupled plasma-mass spectrometry (ICP-MS) for quantification and synchrotron-based imaging. X-ray fluorescence (XRF) and IR absorption spectromicroscopy were used for the first time in combination to directly locate this organometallic drug candidate in schistosomes. The detection of both CO (IR) and Cr (XRF) signatures proved that the Cr(CO)3 core remained intact in the worms. Images showed a preferential accumulation at the worm's tegument, consistent with a possible targeting of the calcium channel but not excluding other biological targets inside the worm.
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Praziquantel/química , Schistosoma mansoni/química , Animales , Cromo/química , Espectrometría de Masas , Microscopía , Imagen Óptica , Praziquantel/síntesis química , Praziquantel/farmacología , Schistosoma mansoni/efectos de los fármacos , Schistosoma mansoni/metabolismo , Espectrofotometría Infrarroja , Estereoisomerismo , Espectroscopía de Absorción de Rayos XRESUMEN
In the recent years, there has been a growing interest in the use of novel approaches for the treatment of parasitic diseases such as schistosomiasis. Among the different approaches used, organometallic compounds were found to offer unique opportunities in the design of antiparasitic drug candidates. A ferrocenyl derivative, namely ferroquine, has even entered clinical trials as a novel antimalarial. In this short review, we report on the studies describing the use of organometallic compounds against schistosomiasis.
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Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Schistosoma/efectos de los fármacos , Esquistosomiasis/tratamiento farmacológico , Esquistosomicidas/química , Esquistosomicidas/farmacología , Animales , Antifúngicos/química , Antifúngicos/farmacología , Antimaláricos/química , Antimaláricos/farmacología , Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Humanos , Praziquantel/análogos & derivados , Praziquantel/farmacología , Esquistosomiasis/parasitologíaRESUMEN
Six substitutionally inert [Ru(II) (bipy)2 dppz](2+) derivatives (bipy=2,2'-bipyridine, dppz=dipyrido[3,2-a:2',3'-c]phenazine) bearing different functional groups on the dppz ligand [NH2 (1), OMe (2), OAc (3), OH (4), CH2 OH (5), CH2 Cl (6)] were synthesized and studied as potential photosensitizers (PSs) in photodynamic therapy (PDT). As also confirmed by DFT calculations, all complexes showed promising (1) O2 production quantum yields, well comparable with PSs available on the market. They can also efficiently intercalate into the DNA double helix, which is of high interest in view of DNA targeting. The cellular localization and uptake quantification of 1-6 were assessed by confocal microscopy and high-resolution continuum source atomic absorption spectrometry. Compound 1, and especially 2, showed very good uptake in cervical cancer cells (HeLa) with preferential nuclear accumulation. None of the compounds studied was found to be cytotoxic in the dark on both HeLa cells and, interestingly, on noncancerous MRC-5 cells (IC50 >100â µM). However, 1 and 2 showed very promising behavior with an increment of about 150 and 42 times, respectively, in their cytotoxicities upon light illumination at 420â nm in addition to a very good human plasma stability. As anticipated, the preferential nuclear accumulation of 1 and 2 and their very high DNA binding affinity resulted in very efficient DNA photocleavage, suggesting a DNA-based mode of phototoxic action.