RESUMEN
The introduction of selenium (Se) into organic scaffolds has been demonstrated to be a promising framework in the field of medicinal chemistry. A novel design of nonsteroidal anti-inflammatory drug (NSAID) derivatives based on a bioisosteric replacement via the incorporation of Se as diacyl diselenide is reported. The antioxidant activity was assessed using the DPPH radical scavenging assay. The new Se-NSAID derivatives bearing this unique combination showed antioxidant activity in a time- and dose-dependent manner, and also displayed different antiproliferative profiles in a panel of eight cancer cell lines as determined by the MTT assay. Ibuprofen derivative 5 was not only the most antioxidant agent, but also selectively induced toxicity in all the cancer cell lines tested (IC50 < 10 µM) while sparing nonmalignant cells, and induced apoptosis partially without enhancing the caspase 3/7 activity. Furthermore, NSAID derivative 5 significantly suppressed tumor growth in a subcutaneous colon cancer xenograft mouse model (10 mg/kg, TGI = 72%, and T/C = 38%) without exhibiting any apparent toxicity. To our knowledge, this work constitutes the first report on in vitro and in vivo anticancer activity of an unprecedented Se-NSAID hybrid derivative and its rational use for developing precursors for bioisosteric selenocompounds with appealing therapeutic applications.
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The norbornene scaffold has arisen as a promising structure in medicinal chemistry due to its possible therapeutic application in cancer treatment. The development of norbornene-based derivatives as potential chemotherapeutic agents is attracting significant attention. Here, we report an unprecedented review on the recent advances of investigations into the antitumoral efficacy of different compounds, including the abovementioned bicyclic scaffold in their structure, in combination with chemotherapeutic agents or forming metal complexes. The impact that structural modifications to these bicyclic compounds have on the antitumoral properties and the mechanisms by which these norbornene derivatives act are discussed in this review. In addition, the use of norbornene, and its related compounds, encapsulation in nanosystems for its use in cancer therapies is here detailed.
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This work reports the synthesis and characterization by Fourier transform infrared spectroscopy (FTIR), 1H, 13C, and 79Se nuclear magnetic resonance (NMR), mass spectrometry, and elemental analysis techniques as well as the in vitro evaluation of the leishmanicidal activity of 13 new selenophosphoramidate derivatives. Among the new compounds, four of them (compounds 1f, 1g, 2f, and 2g), which exhibited the best profiles, were tested against infected macrophages and were selected for further studies related to their leishmanicidal mechanism. In this regard, trypanothione redox system alteration was determined. Compound 1g, under similar conditions, was more effective than the corresponding references. In addition, theoretical calculations showed that this compound also presents most physicochemical and pharmacokinetic properties within the ranges expected for orally available drugs. It is believed that selenophosphoramidate functionalities may represent a scaffold to be explored toward the development of new agents for leishmania treatment.
Asunto(s)
Antiprotozoarios , Leishmania , Preparaciones Farmacéuticas , Selenio , Amidas , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Ácidos Fosfóricos , Selenio/farmacologíaRESUMEN
Chagas disease is usually caused by tropical infection with the insect-transmitted protozoan Trypanosoma cruzi. Currently, Chagas disease is a major public health concern worldwide due to globalization, and there are no treatments neither vaccines because of the long-term nature of the disease and its complex pathology. Current treatments are limited to two obsolete drugs, benznidazole and nifurtimox, which lead to serious drawbacks. Taking into account the urgent need for strict research efforts to find new therapies, here, we describe the in vitro and in vivo trypanocidal activity of a library of selected forty-eight selenocyanate and diselenide derivatives that exhibited leishmanicidal properties. The inclusion of selenium, an essential trace element, was due to the well-known extensive pharmacological activities for selenium compounds including parasitic diseases as T. cruzi. Here we present compound 8 as a potential compound that exhibits a better profile than benznidazole both in vitro and in vivo. It shows a fast-acting behaviour that could be attributed to its mode of action: it acts in a mitochondrion-dependent manner, causing cell death by bioenergetic collapse. This finding provides a step forward for the development of a new antichagasic agent.
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Breast cancer is a multifactor disease, and many drug combination therapies are applied for its treatment. Selenium derivatives represent a promising potential anti-breast cancer treatment. This study reports the cytotoxic activity of forty-one amides and phosphoramidates containing selenium against five cancer cell lines (MCF-7, CCRF-CEM, HT-29, HTB-54 and PC-3) and two nonmalignant cell lines (184B5 and BEAS-2B). MCF-7 cells were the most sensitive and the selenoamides I.1f and I.2f and the selenium phosphoramidate II.2d, with GI50 values ranging from 0.08 to 0.93 µM, were chosen for further studies. Additionally, radical scavenging activity for all the compounds was determined using DPPH and ABTS colorimetric assays. Phosphoramidates turned out to be inactive as radical scavengers. No correlation was observed for the antioxidant activity and the cytotoxic effect, except for compounds I.1e and I.2f, which showed dual antioxidant and antitumor activity. The type of programmed cell death and cell cycle arrest were determined, and the results provided evidence that I.1f and I.2f induced cell death via autophagy, while the derivative II.2d provoked apoptosis. In addition, Western blot analysis corroborated these mechanisms with an increase in Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels for I.1f and I.2f, as well as an increase in BAX, p21 and p53 accompanied by a decrease in BCL-2 levels for derivative II.2d.
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Aspirin (ASA) has attracted wide interest of numerous scientists worldwide thanks to its chemopreventive and chemotherapeutic effects, particularly in colorectal cancer (CRC). Incorporation of selenium (Se) atom into ASA has greatly increased their anti-tumoral efficacy in CRC compared with the organic counterparts without the Se functionality, such as the promising antitumoral methylseleno-ASA analog (1a). Nevertheless, the efficacy of compound 1a in cancer cells is compromised due to its poor solubility and volatile nature. Thus, 1a has been formulated with native α-, ß- and γ-cyclodextrin (CD), a modified ß-CD (hydroxypropyl ß-CD, HP-ß-CD) and Pluronic F127, all of them non-toxic, biodegradable and FDA approved. Water solubility of 1a is enhanced with ß- and HP- ß-CDs and Pluronic F127. Compound 1a forms inclusion complexes with the CDs and was incorporated in the hydrophobic core of the F127 micelles. Herein, we evaluated the cytotoxic potential of 1a, alone or formulated with ß- and HP- ß-CDs or Pluronic F127, against CRC cells. Remarkably, 1a formulations demonstrated more sustained antitumoral activity toward CRC cells. Hence, ß-CD, HP-ß-CD and Pluronic F127 might be excellent vehicles to improve pharmacological properties of organoselenium compounds with solubility issues and volatile nature.
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Antineoplásicos/uso terapéutico , Aspirina/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacología , Aspirina/química , Aspirina/farmacología , Proliferación Celular/efectos de los fármacos , Liberación de Fármacos , Células HT29 , Humanos , Micelas , Poloxámero/química , Espectroscopía de Protones por Resonancia Magnética , Solubilidad , Espectrometría de Fluorescencia , Agua/química , beta-Ciclodextrinas/químicaRESUMEN
Two new series of 28 selenocyanate and diselenide derivatives containing amide moieties were designed, synthesized, and evaluated for their leishmanicidal activity against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Eleven compounds exhibited excellent leishmanicidal activity with EC50 values lower than the reference drug miltefosine (EC50 = 2.84 µM). In addition, for six of them the selectivity index ranged from 9 to >1,442, greater than both references used. The most potent and selective compounds were compounds 2h, 2k, and 2m that displayed EC50 values of 0.52, 1.19, and 0.50 µM, respectively, and a high selectivity index (SI) when tested against THP-1 monocytic cells (SI = >1,442, >672, and >1,100, respectively). These derivatives showed an efficacy similar to that of the reference drugs but much better SI values. They also showed interesting activity values against infected macrophages. Trypanothione reductase (TryR) activity and intracellular thiol level measurement assays were performed for the three best compounds in an attempt to elucidate their mechanism of action. Despite that the new analogs exhibited comparable or better inhibitory activities than the reference TryR inhibitors, more studies are necessary to confirm this result. In summary, our findings suggest that the three compounds described here could constitute leading leishmanicidal drug candidates.
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Antiprotozoarios , Preparaciones Farmacéuticas , Selenio , Amidas , Antiprotozoarios/farmacología , Humanos , NADH NADPH Oxidorreductasas , Selenio/farmacologíaRESUMEN
Selenium compounds are pivotal in medicinal chemistry for their antitumoral and antioxidant properties. Forty seven acylselenoureas have been designed and synthesized following a fragment-based approach. Different scaffolds, including carbo- and hetero-cycles, along with mono- and bi-cyclic moieties, have been linked to the selenium containing skeleton. The dose- and time-dependent radical scavenging activity for all of the compounds were assessed using the in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assays. Some of them showed a greater radical scavenging capacity at low doses and shorter times than ascorbic acid. Therefore, four compounds were evaluated to test their protective effects against H2O2-induced oxidative stress. One derivative protected cells against H2O2-induced damage, increasing cell survival by up to 3.6-fold. Additionally, in vitro cytotoxic activity of all compounds was screened against several cancer cells. Eight compounds were selected to determine their half maximal inhibitory concentration (IC50) values towards breast and lung cancer cells, along with their selectivity indexes. The breast cancer cells turned out to be much more sensitive than the lung. Two compounds (5d and 10a) stood out with IC50 values between 4.2 µM and 8.0 µM towards MCF-7 and T47D cells, with selectivity indexes greater than 22.9. In addition, compound 10b exhibited dual antioxidant and cytotoxic activities. Although further evidence is needed, the acylselenourea scaffold could be a feasible frame to develop new dual agents.
RESUMEN
Incorporation of selenium (Se) atom into small molecules can substantially enhance their antioxidant, anti-inflammatory, antimutagenic, antitumoral or chemopreventive, antiviral, antibacterial, antifungal, antiparasitic, and neuroprotective effects. Specifically, selenazo compounds have received great attention owing to their chemical properties, pharmaceutical applications, and low toxicity. In this Perspective, we compile extensive literature evidence with the description and discussion of the most recent advances in different selenazo and selenadiazo motifs as potential pharmacological candidates. We also provide some perspectives on the challenges and future directions in the advancement of these selenazo compounds, each of which could generate drug candidates for various diseases.
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Azoles/uso terapéutico , Compuestos de Organoselenio/uso terapéutico , Animales , Azoles/química , Azoles/farmacología , Línea Celular Tumoral , Desarrollo de Medicamentos , Humanos , Isoindoles , Estructura Molecular , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacologíaRESUMEN
An effective and straightforward synthesis of 3-seleno functionalized indolinone (5) involving Vilsmeier reagent is presented. Likewise, a procedure to achieve lactamization of diclofenac with excellent yields by using hydrides is also ascertained. Compound 5 exhibited impressive growth inhibition in most of the cell lines in an NCI-60 panel, particularly towards resistant breast cancer cells.
RESUMEN
A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC50) values lower than that for the reference drug miltefosine (EC50, 2.84 µM). In addition, the derivatives 9, 11, 42, and 47, with EC50 between 1.1 and 1.95 µM, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.
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Antiprotozoarios/síntesis química , Antiprotozoarios/uso terapéutico , Leishmania infantum/efectos de los fármacos , Compuestos de Organoselenio/química , Tiourea/química , Urea/análogos & derivados , Urea/química , Antiprotozoarios/química , Humanos , Leishmania infantum/patogenicidad , Macrófagos/parasitología , NADH NADPH Oxidorreductasas/metabolismo , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
For the first time, a simple methodology for the chemical synthesis and use of highly reactive 4-methylenoxazol-5(4H)-ones from serine is presented. These dehydroalanine derivatives, which resemble the natural 4-methylidenimidazole-5-one (MIO) cofactor present in lyases and aminomutases, undergo rapid reaction with carbon nucleophiles such as silyl enol ethers, as well as cycloaddition reactions with diazo compounds and reactive dienes, under very mild conditions and without any need for metal catalysts or ring-strain activation, offering potential for bioconjugation.
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Oxazoles/química , Compuestos Azo/química , Reacción de Cicloadición , Éteres/química , Compuestos de Organosilicio/química , Oxazoles/síntesis químicaRESUMEN
Twenty-seven novel benzo[c][1,2,5]selenadiazole-5-carboxylic acid (BSCA) derivatives were designed and synthesized. Anti-proliferative activity of these structures was tested in vitro against a panel of five human cancer cell lines, including prostate (PC-3), colon (HT-29), leukemia (CCRF-CEM), lung (HTB-54) and breast (MCF-7). Four compounds (5, 6, 7 and 19) showed potent inhibitory activity with GI50 values below 10⯵M in at least one of the cancer cell lines. The selectivity of these compounds was further examined in two non-malignant cell lines derived from breast (184B5) and lung (BEAS-2B). Compound 7 exhibited promising anti-proliferative activity (GI50â¯=â¯3.7⯵M) in MCF-7â¯cells, together with high selectivity index (SIâ¯>â¯27.1). The induction of cell death by compound 7 was independent of the apoptotic process and it did not affect cell cycle progression either. Likewise, radical scavenging properties of the new selenadiazole derivatives were confirmed by testing their ability to scavenge DPPH radicals. Four compounds (1, 2, 8 and 9) showed potent radical scavenging activity, compound 9 being the most effective. Overall, while compound 7 was identified as the most cell growth inhibitory agent and selectively toxic to cancer cells, compound 9 proved to be the most potent antioxidant among the selenadiazole derivatives synthesized. This series of compounds can serve as an excellent scaffold to achieve new and potent antioxidant compounds useful for several diseases, i.e. cancer, neurodegenerative, heart diseases and leishmaniasis, considering the high radical scavenging activity and low toxicity showed by most of the compounds.
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Antineoplásicos/farmacología , Depuradores de Radicales Libres/farmacología , Compuestos de Organoselenio/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/antagonistas & inhibidores , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Humanos , Modelos Moleculares , Estructura Molecular , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/química , Picratos/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The use of vaccines based on MUC1 glycopeptides is a promising approach to treat cancer. We present herein several sulfa-Tn antigens incorporated in MUC1 sequences that possess a variable linker between the carbohydrate (GalNAc) and the peptide backbone. The main conformations of these molecules in solution have been evaluated by combining NMR experiments and molecular dynamics simulations. The linker plays a key role in the modulation of the conformation of these compounds at different levels, blocking a direct contact between the sugar moiety and the backbone, promoting a helix-like conformation for the glycosylated residue and favoring the proper presentation of the sugar unit for molecular recognition events. The feasibility of these novel compounds as mimics of MUC1 antigens has been validated by the X-ray diffraction structure of one of these unnatural derivatives complexed to an anti-MUC1 monoclonal antibody. These features, together with potential lack of immune suppression, render these unnatural glycopeptides promising candidates for designing alternative therapeutic vaccines against cancer.
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Carbohidratos/química , Epítopos/química , Mucina-1/química , Anticuerpos Monoclonales/química , Antígenos de Neoplasias/química , Antígenos de Carbohidratos Asociados a Tumores/química , Vacunas contra el Cáncer/química , Glicopéptidos/química , Glicosilación , Humanos , Inmunosupresores/química , Espectroscopía de Resonancia Magnética , Complejo Mayor de Histocompatibilidad , Conformación Molecular , Simulación de Dinámica Molecular , Péptidos/química , Receptores de Antígenos de Linfocitos T/metabolismo , Solventes/química , Difracción de Rayos XRESUMEN
A second generation of chiral bicyclic dehydroalanines easily accessible from serine has been developed. These scaffolds behaved as excellent S-Michael acceptors when tri-O-acetyl-2-acetamido-2-deoxy-1-thio-α-d-galactopyranose (abbreviated as GalNAc-α-SH) was used as a nucleophile. This addition proceeds with total chemo- and stereoselectivity, complete atom economy, quickly, and at room temperature, making it a true click reaction. The Michael adducts were easily transformed into S-(2-acetamido-2-deoxy-α-d-galactopyranosyl)-l- and -d-cysteines, which can be regarded as mimics of the Tn antigen derived from l-Ser (α-d-GalNAc-l-Ser) and d-Ser (α-d-GalNAc-d-Ser), respectively.
RESUMEN
In recent years, our group has reported the highly diastereoselective acid-catalyzed N,O-acetalization/intramolecular transcarbamoylation cascade of reactions between protected α-amino acid derivatives (Ser and Thr) and tetramethoxyalkanes. The resulting oligocyclic N,O-acetals have been used as excellent chiral building blocks for asymmetric transformations such as diastereoselective alkylation of the α-position. We now evaluate the scope of the reaction with related non-natural α-amino acid derivatives. A combined experimental and theoretical study reveals the key influence of the α-carbon substitution (serine versus α-methylserine) and the relative configuration of α-/ß-carbons (threonine versus allo-threonine) in the thermodynamic stability of the products and, as a consequence, the stereochemical outcome of the reaction. Notably, the complete diastereoselectivity achieved with natural amino acid precursors is completely lost with their non-natural analogues.
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Acetales/química , Aminoácidos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Serina/química , Treonina/química , Estereoisomerismo , TermodinámicaRESUMEN
Stereoselective sulfa-Michael addition of appropriately protected thiocarbohydrates to chiral dehydroalanines has been developed as a key step in the synthesis of biologically important cysteine derivatives, such as S-(ß-D-glucopyranosyl)-D-cysteine, which has not been synthesized to date, and S-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-L-cysteine, which could be considered as a mimic of Tn antigen. The corresponding diamide derivative was also synthesized and analyzed from a conformational viewpoint, and its bound state with a lectin was studied.
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Alanina/análogos & derivados , Antígenos de Carbohidratos Asociados a Tumores/química , Carbohidratos/química , Cisteína/síntesis química , Alanina/química , Cisteína/análogos & derivados , Cisteína/química , Diamida/síntesis química , Diamida/química , Glicosilación , Modelos Moleculares , Conformación MolecularRESUMEN
A totally stereocontrolled C-Michael addition of serine-equivalent C-nucleophiles to tri-O-benzyl-2-nitro-d-galactal was used as the key step to synthesize several pyrano[3,2-b]pyrrole structures. These scaffolds could be regarded as conformationally restricted Tn antigen mimics, as we have demonstrated by biological assays. The pyranose rings retain their (4)C1 chair conformation, as shown by molecular modeling and NMR spectroscopy. The expected bioactivity was established by a competition-tailored enzyme-linked lectin assay using both soybean and Vicia villosa agglutinins as model lectins. The facile described synthetic route and the strategic combination of computational and experimental techniques to reveal conformational features and bioactivity demonstrate the prepared glycomimics to be promising candidates for further exploitation of this scaffold to give glycans for lectin blocking and vaccination.
Asunto(s)
Antígenos de Carbohidratos Asociados a Tumores/química , Glicopéptidos/química , Lectinas/química , Lectinas de Plantas/química , Lectinas de Plantas/síntesis química , Polisacáridos/química , Antígenos de Carbohidratos Asociados a Tumores/inmunología , Diseño de Fármacos , Espectroscopía de Resonancia Magnética , EstereoisomerismoRESUMEN
The asymmetric sulfa-Michael additions of appropriately protected L- and D-cysteine derivatives to new chiral dehydroamino acid derivatives have been developed as key steps in the synthesis of biologically important cysteine derivatives, such as lanthionine (Lan) and ß-methyllanthionine (MeLan), which are unusual bis-α-amino acids found in the emerging lantibiotics such as nisin.
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Alanina/análogos & derivados , Materiales Biomiméticos/síntesis química , Sulfuros/síntesis química , Alanina/síntesis química , Aminoácidos/química , Estructura Molecular , EstereoisomerismoRESUMEN
A domino process that involves a Michael-type addition followed by a Dieckmann reaction mediated by the participation of the cyclic carbamate group is the key step in the synthesis of both enantiomers of α-(hydroxymethyl)glutamic acid (HMG).