RESUMEN
Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC50 = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC50 = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC50 values in the nanomolar range (9-252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.
Asunto(s)
Antiinflamatorios no Esteroideos , Inhibidores de la Ciclooxigenasa 2 , Humanos , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Estructura Molecular , Antiinflamatorios no Esteroideos/farmacologíaRESUMEN
The folding and export of proteins and hydrolysis of unfolded proteins are disbalanced in the endoplasmic reticulum (ER) of cancer cells, leading to so-called ER stress. Agents further augmenting this effect are used as anticancer drugs including clinically approved proteasome inhibitors bortezomib and carfilzomib. However, these drugs can affect normal cells, which also rely strongly on ER functions, leading, for example, to accumulation of reactive oxygen species (ROS). To address this problem, we have developed ER-targeted prodrugs activated only in cancer cells in the presence of elevated ROS amounts. These compounds are conjugates of cholic acid with N-alkylaminoferrocene-based prodrugs. We confirmed their accumulation in the ER of cancer cells, their anticancer efficacy, and cancer cell specificity. These prodrugs induce ER stress, attenuate mitochondrial membrane potential, and generate mitochondrial ROS leading to cell death via necrosis. We also demonstrated that the new prodrugs are activated in vivo in Nemeth-Kellner lymphoma (NK/Ly) murine model.
Asunto(s)
Antineoplásicos/farmacología , Retículo Endoplásmico/efectos de los fármacos , Linfoma/tratamiento farmacológico , Profármacos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Antineoplásicos/química , Retículo Endoplásmico/metabolismo , Humanos , Linfoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Profármacos/químicaRESUMEN
Based on the significant anti-inflammatory activity of natural quinone primin (5a), series of 1,4-benzoquinones, hydroquinones, and related resorcinols were designed, synthesized, characterized and tested for their ability to inhibit the activity of cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) enzymes. Structural modifications resulted in the identification of two compounds 5b (2-methoxy-6-undecyl-1,4-benzoquinone) and 6b (2-methoxy-6-undecyl-1,4-hydroquinone) as potent dual COX/5-LOX inhibitors. The IC50 values evaluated in vitro using enzymatic assay were for compound 5b IC50 = 1.07, 0.57, and 0.34 µM and for compound 6b IC50 = 1.07, 0.55, and 0.28 µM for COX-1, COX-2, and 5-LOX enzyme, respectively. In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC50 = 0.14 µM; reference inhibitor zileuton IC50 = 0.66 µM) from the tested compounds while its inhibitory potential against COX enzymes (IC50 = 2.65 and 2.71 µM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC50 = 4.50 and 2.46 µM, respectively). The most important structural modification leading to increased inhibitory activity towards both COXs and 5-LOX was the elongation of alkyl chain in position 6 from 5 to 11 carbons. Moreover, the monoacetylation in ortho position of bromo-hydroquinone 13 led to the discovery of potent (IC50 = 0.17 µM) 5-LOX inhibitor 17 (2-bromo-6-methoxy-1,4-benzoquinone) while bromination stabilized the hydroquinone form. Docking analysis revealed the interaction of compounds with Tyr355 and Arg120 in the catalytic site of COX enzymes, while the hydrophobic parts of the molecules filled the hydrophobic substrate channel leading up to Tyr385. In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity.
Asunto(s)
Benzoquinonas/química , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Resorcinoles/química , Dominio Catalítico , Simulación por Computador , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/síntesis química , Simulación del Acoplamiento Molecular , Oxidación-Reducción , Análisis Espectral/métodos , Relación Estructura-ActividadRESUMEN
Cancer cells produce elevated levels of reactive oxygen species, which has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, in which a prodrug reacts with ROS. However, at low micromolar concentrations of the prodrugs and ROS, the activation is usually inefficient. Herein, we propose and validate a potentially general approach for solving this intrinsic problem of ROS-dependent prodrugs. In particular, known prodrug 4-(N-ferrocenyl-N-benzylaminocarbonyloxymethyl)phenylboronic acid pinacol ester was converted into its lysosome-specific analogue. Since lysosomes contain a higher concentration of active ROS than the cytoplasm, activation of the prodrug was facilitated with respect to the parent compound. Moreover, it was found to exhibit high anticancer activity in a variety of cancer cell lines (IC50 =3.5-7.2â µm) and inâ vivo (40â mg kg-1 , NK/Ly murine model) but remained weakly toxic towards non-malignant cells (IC50 =15-30â µm).
Asunto(s)
Antineoplásicos/farmacología , Lisosomas/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Profármacos/farmacología , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Animales , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lisosomas/metabolismo , Ratones , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Profármacos/química , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
This review covers the chemical reactions, synthesis, and biological activities of tetracyclic diterpenoids including ent-kauranes, ent-beyeranes, ent-atisanes, ingenanes, tyglianes, stemodanes, stemaranes, sordarin, salvileucalin B, harringtonolide and hainanolidol. It comprises of the un-reviewed references from the year 2000.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/farmacología , Diterpenos/síntesis química , Diterpenos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Bacterias/efectos de los fármacos , Productos Biológicos/síntesis química , Productos Biológicos/química , Proliferación Celular/efectos de los fármacos , Diterpenos/química , Hongos/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
Receptor-mediated endocytosis is an integral part of signal transduction as it mediates signal attenuation and provides spatial and temporal dimensions to signaling events. One of the best-studied leucine-rich repeat receptor-like kinases in plants, BRASSINOSTEROID INSENSITIVE 1 (BRI1), perceives its ligand, the brassinosteroid (BR) hormone, at the cell surface and is constitutively endocytosed. However, the importance of endocytosis for BR signaling remains unclear. Here we developed a bioactive, fluorescent BR analog, Alexa Fluor 647-castasterone (AFCS), and visualized the endocytosis of BRI1-AFCS complexes in living Arabidopsis thaliana cells. Impairment of endocytosis dependent on clathrin and the guanine nucleotide exchange factor for ARF GTPases (ARF-GEF) GNOM enhanced BR signaling by retaining active BRI1-ligand complexes at the plasma membrane. Increasing the trans-Golgi network/early endosome pool of BRI1-BR complexes did not affect BR signaling. Our findings provide what is to our knowledge the first visualization of receptor-ligand complexes in plants and reveal clathrin- and ARF-GEF-dependent endocytic regulation of BR signaling from the plasma membrane.
Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Carbocianinas/química , Membrana Celular/metabolismo , Colestanoles/metabolismo , Endocitosis , Colorantes Fluorescentes/química , Proteínas Quinasas/metabolismo , Transducción de Señal , Arabidopsis/enzimología , Arabidopsis/ultraestructura , Proteínas de Arabidopsis/antagonistas & inhibidores , Proteínas de Arabidopsis/genética , Brasinoesteroides/química , Brasinoesteroides/metabolismo , Membrana Celular/ultraestructura , Colestanoles/química , Relación Dosis-Respuesta a Droga , Endosomas/enzimología , Endosomas/metabolismo , Endosomas/ultraestructura , Proteínas Fluorescentes Verdes/genética , Cinética , Meristema/enzimología , Meristema/metabolismo , Meristema/ultraestructura , Microscopía Confocal , Estructura Molecular , Reguladores del Crecimiento de las Plantas , Proteínas Quinasas/genética , Transporte de Proteínas , Plantones/enzimología , Plantones/metabolismo , Plantones/ultraestructura , Vacuolas/enzimología , Vacuolas/metabolismo , Vacuolas/ultraestructuraRESUMEN
Flavonoids and their photochemical transformations play an important role in biological processes in nature. Synthetic photochemistry allows access to molecules that cannot be obtained via more conventional methods. This review covers all published synthetic photochemical transformations of the different classes of flavonoids. It is first comprehensive review on the photochemistry of flavonoids.
Asunto(s)
Flavonoides/química , Procesos Fotoquímicos , Flavanonas , Flavonas/química , Flavonoles/química , Hidrógeno/químicaRESUMEN
The first total synthesis of the indole alkaloids (+/-)-aplicyanins A, B, and E, plus 17 analogues, all in racemic form, is reported. Modifications to the parent compound included changing the number of bromine substituents on the indole, the nature of the substituents on the indole nitrogen (H, Me, or OMe), and/or the oxidation level of the heterocyclic core tetrahydropyrimidine. Each compound was screened against three human tumor cell lines, and 14 of the newly synthesized compounds showed considerable cytotoxicity. The assay results were used to establish structure-activity relationships. These results suggest that the presence of the bromine at position 5 of the indole is critical to activity, as well as the acetyl group on the imine nitrogen does in some compounds.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Alcaloides Indólicos/síntesis química , Alcaloides Indólicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
In general, the structural requirements postulated for a high brassinolide activity are: 2alpha,3alpha-diol, 6-ketone or better 7-oxalactone in B-ring, A/B trans fused ring junction, a cis C-22,C-23-diol preferentially with RR configurations, and a C-24 methyl or ethyl substituent [Takatsuto S, Yazawa N, Ikekawa N, Takematsu T, Takeuchi Y, Koguchi M. Structure-activity relationship of brassinosteroids. Phytochemistry 1983;22:2437-41; Thompson MJ, Meudt WJ, Mandava NB, Dutky SR, Lusby WR, Spaulding DW. Synthesis of brassinosteroids and relationship of structure to plant growth-promoting effects. Steroids 1982;39:89-105]. We found that the 3alpha,4alpha-diols 4, 6 and 8 are more active than the 2alpha,3alpha-diols 3, 5 and 7 [Sísa M, Budesínský M, Kohout L. Synthesis of 7a-homo and 7a,7b-dihomo-5alpha-cholestane analogues of brassinolide. Collect Czech Chem Commun 2003;68:2171-89]. This fact is in strong contrast with the structure requirements mentioned above. Our hypothesis suggests that the lower activity of 2alpha,3alpha-diols and/or the higher activity of 3alpha,4alpha-diols could be explained by twisting and distortion of the molecule due to the seven- or eight-membered B-ring and also by the position of a carbonyl group relative to the A-ring diol. 3D-SAR computer methodologies as alignments and overlaps of GRID maps and 3D-QSAR analysis GRID-GOLPE (CoMFA-like) were used as an effort to explain the higher bioactivity of 3alpha,4alpha-diols 4, 6 and 8 in comparison with the 2alpha,3alpha-diols 3, 5 and 7 of B-ring enlarged brassinosteroids.
Asunto(s)
Bioensayo/métodos , Colestanoles/metabolismo , Fabaceae/metabolismo , Modelos Moleculares , Compuestos Policíclicos/metabolismo , Esteroides Heterocíclicos/metabolismo , Brasinoesteroides , Colestanoles/química , Análisis de los Mínimos Cuadrados , Conformación Molecular , Compuestos Policíclicos/química , Análisis de Componente Principal , Esteroides Heterocíclicos/química , Relación Estructura-ActividadRESUMEN
New androstane brassinosteroids with 17beta-ester groups - butyrates, heptafluorobutyrates, and laurates (4-18) - were prepared. Brassinolide activity was evaluated using both the bean second internode bioassay and the rice lamina inclination test. Brassinosteroid 16 was found to be the most active by the bean second internode bioassay. This activity in the bean second internode bioassay corresponded with the field yield, while the RLIT bioassay does not.