RESUMEN
To explore potent anticancer agent based on artemisinin scaffold, a series of 10-O-phenyl ethers derivatives containing dihydropyrazolyl or pyrazolyl moiety have been designed and synthesized. Their structures were determined by LC-MS and ¹H-NMR date. Inhibitory effects of the target compounds in human breast cancer MCF-7, MCF/Adr, MDA-MB-231 cells and prostate cell line PC-3 were determined by MTT assay. Those derivatives displayed good antiproliferative activity against the tested cancer cells. Particularly, target compounds exhibited significant cytotoxicity against drug-resistance cells MCF/Adr, which was worthy for further investigation.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Artemisininas/química , Éteres Fenílicos/síntesis química , Éteres Fenílicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Relación Estructura-ActividadRESUMEN
The obligate intracellular parasite, Trypanosoma cruzi is the etiologic agent of Chagas disease or American trypanosomiasis, which is the most prevalent parasitic disease in the Americas. The present chemotherapy to control this illness is still deficient particularly in the chronic stage of the disease. The ergosterol biosynthesis pathway has received much attention as a molecular target for the development of new drugs for Chagas disease. Especially, inhibitors of the enzymatic activity of squalene synthase were shown to be effective compounds on T. cruzi proliferation in in vitro assays. In the present study we designed, synthesized and evaluated the effect of a number of isosteric analogues of WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, on T. cruzi growth in tissue culture cells. The selenium-containing derivatives turned out to be extremely potent inhibitors of T. cruzi growth. Certainly, 3-phenoxyphenoxyethyl, 4-phenoxyphenoxyethyl, 4-(3-fluorophenoxy)phenoxyethyl, 3-(3-fluorophenoxy)phenoxyethyl selenocyanates and (±)-5-phenoxy-2-(selenocyanatomethyl)-2,3-dihydrobenzofuran arose as relevant members of this family of compounds, which exhibited effective ED50 values of 0.084⯵M, 0.11⯵M, 0.083,⯵M, 0.085, and 0.075⯵M, respectively. The results indicate that compounds bearing the selenocyanate moiety are at least two orders of magnitude more potent than the corresponding skeleton counterpart bearing the thiocyanate group. Surprisingly, these compounds exhibited excellent selectively index values ranging from 900 to 1800 making these molecules promising candidates as antiparasitic agents.
Asunto(s)
Éteres Fenílicos/farmacología , Selenio/farmacología , Tiocianatos/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Éteres Fenílicos/síntesis química , Éteres Fenílicos/química , Selenio/química , Relación Estructura-Actividad , Tiocianatos/síntesis química , Tiocianatos/química , Tripanocidas/síntesis química , Tripanocidas/química , Trypanosoma cruzi/citología , Trypanosoma cruzi/crecimiento & desarrollo , Células VeroRESUMEN
Matrix metalloproteinase (MMP)-2 knockout (KO) mice show impaired neurological recovery after spinal cord injury (SCI), suggesting that this proteinase is critical to recovery processes. However, this finding in the KO has been confounded by a compensatory increase in MMP-9. We synthesized the thiirane mechanism-based inhibitor ND-378 and document that it is a potent (nanomolar) and selective slow-binding inhibitor of MMP-2 that does not inhibit the closely related MMP-9 and MMP-14. ND-378 crosses the blood-spinal cord barrier, achieving therapeutic concentrations in the injured spinal cord. Spinal-cord injured mice treated with ND-378 showed no change in long-term neurological outcomes, suggesting that MMP-2 is not a key determinant of locomotor recovery.
Asunto(s)
Metaloproteinasa 2 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Éteres Fenílicos/farmacología , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/enzimología , Médula Espinal/enzimología , Sulfonas/farmacología , Animales , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Masculino , Metaloproteinasa 14 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/farmacocinética , Ratones , Ratones Noqueados , Simulación del Acoplamiento Molecular , Estructura Molecular , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Éteres Fenílicos/síntesis química , Éteres Fenílicos/farmacocinética , Recuperación de la Función/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Sulfonas/síntesis química , Sulfonas/farmacocinéticaRESUMEN
We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Éteres Fenílicos/química , Inhibidores de Proteínas Quinasas/química , Piridazinas/química , Pirroles/química , Sitios de Unión , Dominio Catalítico , Evaluación Preclínica de Medicamentos , Janus Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Éteres Fenílicos/síntesis química , Éteres Fenílicos/metabolismo , Unión Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
In this paper, we present some elements of our optimization program to decouple triclosan's specific FabI effect from its nonspecific cytotoxic component. The implementation of this strategy delivered highly specific, potent, and nonbiocidal new FabI inhibitors. We also disclose some preclinical data of one of their representatives, 83, a novel antibacterial compound active against resistant staphylococci and some clinically relevant Gram negative bacteria that is currently undergoing clinical trials.
Asunto(s)
Antiinfecciosos Locales/farmacología , Benzamidas/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Enoil-ACP Reductasa (NADH)/antagonistas & inhibidores , Bacterias Gramnegativas/efectos de los fármacos , Éteres Fenílicos/farmacología , Triclosán/farmacología , Animales , Antiinfecciosos Locales/síntesis química , Benzamidas/síntesis química , Células Cultivadas , Perros , Evaluación Preclínica de Medicamentos , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Éteres Fenílicos/síntesis química , Ratas , Relación Estructura-Actividad , Triclosán/síntesis químicaRESUMEN
Recently, remarkable microtubule inhibitor and anti-tumor activities of the bis(bibenzyl) marchantin C--isolated from liverworts like Marchantia polymorpha since 1983--were found. In this paper we describe the efficient total synthesis of this subtype of bis(bibenzylic) compounds with two biarylether connections. Two selectively methylated derivatives known as natural compounds marchantin O and P were synthesized for the first time by modification of the arene subunits and can now be considered as promising highly bioactive compounds.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Bibencilos/síntesis química , Bibencilos/farmacología , Marchantia/química , Éteres Fenílicos/síntesis química , Éteres Fenílicos/farmacología , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/química , Relación Estructura-ActividadRESUMEN
A structure-based approach has been adopted to develop 2'-substituted analogs of triclosan. The Cl at position 2' in ring B of triclosan was chemically substituted with other functional groups like NH(2), NO(2) and their inhibitory potencies against PfENR were determined. The binding energies of the 2' substituted analogs of triclosan for enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum were determined using Autodock. Based on the autodock results, we synthesized the potential compounds. The IC(50) and inhibition constant (K(i)) of 2' substituted analogs of triclosan were determined against purified PfENR. Among them, two compounds, 2-(2'-Amino-4'-chloro-phenoxy)-5-chloro-phenol (compound 4) and 5-chloro-2-(4'-chloro-2'-nitro-phenoxy)-phenol) (compound 5) exhibited good potencies. Compound 4 followed uncompetitive inhibition kinetics with crotonoyl CoA and competitive with NADH. It was shown to have an IC(50) of 110 nM; inhibition constant was 104 nM with the substrate and 61 nM with the cofactor. IC(50) of compound 5 was determined to be 229 nM. Compounds 4 and 5 showed significant inhibition of the parasite growth in P. falciparum culture.
Asunto(s)
Clorofenoles/síntesis química , Enoil-ACP Reductasa (NADH)/antagonistas & inhibidores , Éteres Fenílicos/síntesis química , Triclosán/análogos & derivados , Acilcoenzima A/metabolismo , Antimaláricos/síntesis química , Antimaláricos/química , Clorofenoles/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Cinética , Éteres Fenílicos/farmacología , Plasmodium falciparum/enzimología , Relación Estructura-Actividad , Triclosán/síntesis química , Triclosán/químicaAsunto(s)
Anestésicos Locales/toxicidad , Sistema Enzimático del Citocromo P-450/metabolismo , Éteres Fenílicos/toxicidad , Anestesia de Conducción , Anestesia Local , Anestésicos Locales/síntesis química , Anestésicos Locales/química , Animales , Química Farmacéutica , Excipientes , Dosificación Letal Mediana , Luminiscencia , Oxigenasas de Función Mixta/metabolismo , Parálisis/inducido químicamente , Éteres Fenílicos/síntesis química , Éteres Fenílicos/química , Ratas , Solventes , Relación Estructura-ActividadRESUMEN
A concise and convergent route to combretastatin D2 is described together with some preliminary biological data.
Asunto(s)
Antineoplásicos/síntesis química , Bibencilos/síntesis química , Lactonas/síntesis química , Éteres Fenílicos/síntesis química , Estilbenos/síntesis química , Antineoplásicos/farmacología , Bibencilos/farmacología , Ácidos Borónicos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Cristalografía por Rayos X , Células Endoteliales/efectos de los fármacos , Femenino , Humanos , Lactonas/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Estructura Molecular , Fenol/química , Éteres Fenílicos/farmacología , Plantas Medicinales/química , Estilbenos/farmacologíaRESUMEN
The discovery of a series of novel, potent, and highly selective inhibitors of the DNA damage control kinase chk2 is disclosed. Here we report the first SAR study around inhibitors of this kinase. High-throughput screening of purified human chk2 led to the identification of a novel series of 2-arylbenzimidazole inhibitors of the kinase. Optimization was facilitated using homology models of chk2 and docking of inhibitors, leading to the highly potent 2-arylbenzimidazole 2h (IC(50) 15 nM). Compound 2h is an ATP-competitive inhibitor of chk2 that dose dependently protects human CD4(+) and CD8(+) T-cells from apoptosis due to ionizing radiation. This work suggests that a selective small molecule inhibitor of chk2 could be a useful adjuvant to radiotherapy, increasing the therapeutic window of such treatment.
Asunto(s)
Bencimidazoles/síntesis química , Éteres Fenílicos/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Protectores contra Radiación/síntesis química , Adenosina Trifosfato/química , Apoptosis/efectos de los fármacos , Bencimidazoles/química , Bencimidazoles/farmacología , Sitios de Unión , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de la radiación , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de la radiación , Quinasa de Punto de Control 2 , Daño del ADN , Rayos gamma , Humanos , Técnicas In Vitro , Modelos Moleculares , Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Proteínas Serina-Treonina Quinasas/química , Protectores contra Radiación/química , Protectores contra Radiación/farmacología , Relación Estructura-ActividadRESUMEN
Photosensitizers play a crucial role in the photodynamic therapy (PDT) of cancer. In this study, a third-generation aryl ether dendrimer porphyrin with 32 primary amine groups on the periphery, [NH2CH2CH2NHCO]32DPZn, and pH-sensitive, polyion complex micelles (PIC) composed of the porphyrin dendrimer and PEG-b-poly(aspartic acid), were evaluated as new photosensitizers (PSs) for PDT in the Lewis Lung Carcinoma (LLC) cell line. The preliminary photophysical characteristics of [NH2CH2CH2NHCO]32DPZn and the corresponding micelles were investigated. Electrostatic assembly resulted in a red-shift of the Soret peak of the porphyrin core and the enhanced fluorescence. Compared to the dendrimer porphyrin [NH2CH2CH2NHCO]32DPZn, relatively low cellular uptake of dendrimer porphyrin [NH2CH2CH2NHCO]32DPZn incorporated in the PIC micelle was observed, yet the latter exhibited enhanced photodynamic efficacy on the LLC cell line. Importantly, the use of PIC micelles as a delivery system reduced the dark toxicity of the cationic dendrimer porphyrin, probably due to the biocompatible PEG shell of the micelles.
Asunto(s)
Portadores de Fármacos/farmacología , Metaloporfirinas/farmacología , Micelas , Neoplasias/terapia , Éteres Fenílicos/farmacología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/química , Animales , Ácido Aspártico/química , Carcinoma Pulmonar de Lewis/patología , Predicción , Sustancias Macromoleculares , Metaloporfirinas/síntesis química , Metaloporfirinas/metabolismo , Nanotecnología , Éteres Fenílicos/síntesis química , Éteres Fenílicos/metabolismo , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/farmacología , Fototerapia , Polietilenglicoles/química , Polietilenglicoles/farmacología , Polímeros , Proteínas/química , Proteínas/farmacología , Espectrometría de Fluorescencia , Células Tumorales CultivadasRESUMEN
Several drugs bearing the 4-phenoxyphenoxy skeleton and other closely related structures were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the etiologic agent of Chagas' disease. The new class of drugs was envisioned by modifying the nonpolar 4-phenoxyphenoxy moiety replacing selected aromatic protons by different groups via electrophilic aromatic substitution reactions as well as introducing a sulfur atom at the polar extreme. Of the designed compounds, sulfur-containing derivatives were shown to be potent antireplicative agents against T. cruzi. Among these drugs, 4-phenoxyphenoxyethyl thiocyanate (compound 56) proved to be an extremely active growth inhibitor of the epimastigote forms of T. cruzi and displayed an IC50 of 2.2 microM. Under the same assay conditions, this drug was much more active than Nifurtimox, one of the drugs currently in clinical use to control this disease. This thiocyanate derivative was also a very active inhibitor against the intracellular form of the parasite at the nanomolar level. Other sulfur derivatives prepared also exhibited very potent antiproliferative action against T. cruzi. The presence of a sulfur atom at the polar extreme for this family of compounds seems to be very important for biological action because this atom was always associated with high inhibition values. 4-Phenoxyphenoxyethyl thiocyanate presents very good prospective not only as a lead drug but also as a potential chemotherapeutic agent.
Asunto(s)
Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Tiocianatos/química , Tiocianatos/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Evaluación Preclínica de Medicamentos , Nifurtimox/farmacología , Éteres Fenílicos/síntesis química , Relación Estructura-Actividad , Tiocianatos/síntesis química , Tripanocidas/síntesis química , Trypanosoma cruzi/crecimiento & desarrolloRESUMEN
The 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives 3-5 were synthesized and screened as potential antidepressant agents by the reserpine interaction test in mice and the evaluation of reuptake inhibition of biogenic amines in pig brain synaptosomal fractions. In addition, their anticonvulsant activity, tested by pentyleneetrazole antagonism, and approximate acute toxicity were evaluated. In vivo and in vitro tests showed that compounds 3 and 5 possess a biological activity comparable to that of the antidepressant drug viloxazine.