RESUMEN
Breast cancer is one of the leading causes of death in the female population because of the resistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubility and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxycurcumin magnesium complex (DiMeOC-Mg, (4)) with beta-cyclodextrin (DiMeOC-Mg-BCD, (5)) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media phosphate buffer saline (PBS) was improved by a factor of 6x over the free metal complex (4). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and signal transducer and activator of transcription-3 (STAT3) expression levels on MD Anderson metastasis breast-231 cancer (MDA-MB-231) cell lines. Results of an antitumor assay in an in ovo model showed up to 30% inhibition of tumor growth for breast cancer (MDA-MB-231) when using (5) (0.650 mg/kg dose) and 17.29% inhibition with the free homoleptic metal complex (1.5 mg/kg dose, (4)). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new compound (5) exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.
Asunto(s)
Antineoplásicos , Curcumina , Curcumina/análogos & derivados , Magnesio , beta-Ciclodextrinas , beta-Ciclodextrinas/química , Curcumina/farmacología , Curcumina/química , Curcumina/farmacocinética , Humanos , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Magnesio/química , Apoptosis/efectos de los fármacos , Femenino , Línea Celular Tumoral , Factor de Transcripción STAT3/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Movimiento Celular/efectos de los fármacos , Solubilidad , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Embrión de Pollo , Metaloproteinasa 9 de la Matriz/metabolismoRESUMEN
The aim to access linked tetravanadate [V4O12]4- anion with mixed copper(II) complexes, using α-amino acids and phenanthroline-derived ligands, resulted in the formation of four copper(II) complexes [Cu(dmb)(Gly)(OH2)]2[Cu(dmb)(Gly)]2[V4O12]·9H2O (1) [Cu(dmb)(Lys)]2[V4O12]·8H2O (2), [Cu(dmp)2][V4O12]·C2H5OH·11H2O (3), and [Cu(dmp)(Gly)Cl]·2H2O (4), where dmb = 4,4'-dimethioxy-2,2'-bipyridine; Gly = glycine; Lys = lysine; and dmp = 2,9-dimethyl-1,10-phenanthroline. The [V4O12]4- anion is functionalized with mixed copper(II) units in 1 and 2; while in 3, it acts as a counterion of two [Cu(dmp)]2+ units. Compound 4 crystallized as a unit that did not incorporate the vanadium cluster. All compounds present magnetic couplings arising from Cuâ¯O/Cuâ¯Cu bridges. Stability studies of water-soluble 3 and 4 by UV-Vis spectroscopy in cell culture medium confirmed the robustness of 3, while 4 appears to undergo ligand scrambling over time, resulting partially in the stable species [Cu(dmp)2]+ that was also identified by electrospray ionization mass spectrometry at m/z = 479. The in vitro cytotoxicity activity of 3 and 4 was determined in six cancer cell lines; the healthy cell line COS-7 was also included for comparative purposes. MCF-7 cells were more sensitive to compound 3 with an IC50 value of 12 ± 1.2 nmol. The tested compounds did not show lipid peroxidation in the TBARS assay, ruling out a mechanism of action via reactive oxygen species formation. Both compounds inhibited cell migration at 5 µM in wound-healing assays using MCF-7, PC-3, and SKLU-1 cell lines, opening a new window to study the anti-metastatic effect of mixed vanadium-copper(II) systems.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Humanos , Cobre/farmacología , Cobre/química , Antineoplásicos/química , Fenantrolinas/química , Vanadio/farmacología , ADN/química , Células MCF-7 , Aniones , Fenómenos Magnéticos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , LigandosRESUMEN
The crystal structure determination of metal complexes of curcuminoids is a relevant topic to assess their unequivocal molecular structure. We report herein the first two X-ray crystal structures of homoleptic metal complexes of a curcuminoid, namely Dimethoxycurcumin (DiMeOC), with gallium and indium. Such successful achievement can be attributed to the suppression of interactions from the phenolic groups, which favor an appropriate molecular setup, rendering Dimethoxycurcumin gallium ((DiMeOC)2-Ga) and Dimethoxycurcumin indium ((DiMeOC)3-In) crystals. Surprisingly, the conformation of ligands in the crystal structures shows differences in each metal complex. Thus, the ligands in the (DiMeOC)2-Ga complex show two different conformers in the two molecules of the asymmetric unit. However, the ligands in the (DiMeOC)3-In complex exhibit three different conformations within the same molecule of the asymmetric unit, constituting the first such case described for an ML3 complex. The cytotoxic activity of the (DiMeOC)2-Ga complex is 4-fold higher than cisplatin against the K562 cell line and has comparable activity towards U251 and PC-3 cell lines. Interestingly, this complex exhibit three times lesser toxicity than cisplatin and even slightly lesser cytotoxicity than curcumin itself.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Galio , Galio/farmacología , Galio/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Cisplatino , Indio/química , Diarilheptanoides , Línea Celular Tumoral , Ligandos , Antineoplásicos/farmacologíaRESUMEN
To aid the possible prevention of multidrug resistance in tumors and cause lower toxicity, a set of sixteen novel dihydropyridine carboxylic acids derivatives 3a-p were produced; thus, the activation of various ynones with triflic anhydride was performed, involving a nucleophilic addition of several bis(trimethylsilyl) ketene acetals, achieving good yields requiring easy workup. The target molecules were unequivocally characterized by common spectroscopic methods. In addition, two of the tested compounds (3a, and 3b) were selected to perform in silico studies due to the highest cytotoxic activity towards the HCT-15 cell line (7.94 ± 1.6 µM and 9.24 ± 0.9 µM, respectively). Employing theoretical calculations with density functional theory (DFT) using the B3LYP/6-311++G(d,p) showed that the molecular parameters correlate adequately with the experimental results. In contrast, predictions employing Osiris Property Explorer showed that compounds 3a and 3b present physicochemical characteristics that would likely make it an orally active drug. Moreover, the performance of Docking studies with proteins related to the apoptosis pathway allowed a proposal of which compounds could interact with PARP-1 protein. Pondering the obtained results (synthesis, in silico, and cytotoxic activity) of the target compounds, they can be judged as suitable antineoplastic agent candidates.
Asunto(s)
Antineoplásicos , Dihidropiridinas , Neoplasias , Humanos , Línea Celular , Antineoplásicos/química , Compuestos Orgánicos , Ácidos Carboxílicos/farmacología , Dihidropiridinas/farmacología , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Estructura MolecularRESUMEN
The first single crystal structure of the homoleptic copper (II) ML2 complex (M=Cu (II), L = curcumin) was obtained and its structure was elucidated by X-ray diffraction showing a square planar geometry, also confirmed by EPR. The supramolecular arrangement is supported by C-H···O interactions and the solvent (MeOH) plays an important role in stabilizing the crystal packing Crystallinity was additionally assessed by XRD patterns. The log P value of the complex (2.3 ± 0.15) was determined showing the improvement in water solubility. The cytotoxic activity of the complex against six cancer cell lines substantially surpasses that of curcumin itself, and it is particularly selective against leukemia (K562) and human glioblastoma (U251) cell lines, with similar antioxidant activity to BHT. This constitutes the first crystal structure of pristine curcumin complexed with a metal ion.
RESUMEN
From the bioactive extract of the euphorbiaceous Croton niveus Jacq., three previously unreported ent-rosane diterpenes have been isolated and characterized by conventional methods, in addition to the known compounds lupeol, cajucarinolide and some phytosterols. Two of the ent-rosane diterpenes displayed activity against HCT-15 and PC-3 cancer cell lines, and the results of docking calculations of these compounds with NF-κB and STAT3 receptors agreed with the proposed mode of action of diterpenes against PC-3 cells.
Asunto(s)
Antineoplásicos , Croton , Diterpenos de Tipo Kaurano , Diterpenos , Euphorbiaceae , Estructura Molecular , Diterpenos/farmacología , Antineoplásicos/farmacologíaRESUMEN
We report herein the synthesis and characterization of three heterocyclic curcuminoid ligands and their homoleptic metal complexes with magnesium and copper. Thus, N-methyl-2-pyrrolecarboxaldehyde, Furan-2-carboxaldehyde, and 2-Thiophenecarboxaldehyde were condensed with 2,4-pentanedione-boron trioxide complex. The first N-methyl-2-pyrrole curcuminoid and its Mg(II) complex are reported. All curcuminoid ligands and their corresponding metal complexes were characterized by infrared spectroscopy (IR), liquid state nuclear magnetic resonance (LSNMR), electron paramagnetic resonance (EPR), mass spectrometry (MS) and single crystal X-ray diffraction (SCXRD). The ThiopheneCurc-Cu (9) constitutes the first case of a "conformationally-heteroleptic" complex. The unique six-peaks star arrangement for the ThiopheneCurc ligand derived from the supramolecular description is reported. The metal complexes of FuranCurc-Mg (5) and ThiopheneCurc-Cu (9) have a good antioxidant effect (IC50 = 11.26 ± 1.73 and 10.30 ± 0.59 µM), three and two times higher than their free ligands respectively. Additionally, (5) shows remarkable cytotoxicity against colon cancer adenocarcinoma cell line HCT-15, comparable to that of cisplatin, with a negligible toxic effect in vitro towards a healthy monkey kidney cell line (COS-7).
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Diarilheptanoides , Complejos de Coordinación/química , Cisplatino , Antioxidantes/farmacología , Espectroscopía de Resonancia por Spin del Electrón , Cobre/química , Cristalografía por Rayos X , Ligandos , Antineoplásicos/químicaRESUMEN
The semisynthesis of novel derivatives of lupeyl palmitate and 3ß-palmitoyloxy-olean-12-ene by introduction of a pyrazine at C-2 / C-3 and modifications of the relatively unexplored C-30 position of lupeol derivatives was conducted, and their cytotoxic and anti-inflammatory activities were evaluated. The derivatives 7, 10 and 11 significantly inhibited the tumor cell lines U251, K562, HCT-15, MCF-7 and SKLU-1, and compounds 7 and 11 were more active (IC50 25.4 ± 2.0 µM and 7.1 ± 0.4 µM, respectively) than the positive control (etoposide (IC50 31.5 ± 2.2 µM) in the tumor line PC-3. Introduction of the pyrazine at C-2 / C-3 in compounds 1 and 2 or modification at C-30 of compound 1 decreased the anti-inflammatory activity in the TPA-induced mouse ear edema. Following the results of the PASS online evaluation of the potential biological activity of the natural compounds and their derivatives, the inhibition of pNF-κB translocation to the prostate cancer (PC-3) cell nucleus was investigated and the binding mode of compounds 7, 10 and 11 with the human NF-κB receptor was explored by a molecular docking study. These derivatives bound directly or close to the amino acids that form the DNA recognition site. The ADMET physicochemical parameters of the fifteen compounds were further analyzed in silico using Molinspiration calculations indicating the potential of compounds 7, 10 and 11 for further investigation.
Asunto(s)
Antineoplásicos , Triterpenos , Animales , Antiinflamatorios/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Masculino , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Triterpenos Pentacíclicos/farmacología , Pirazinas , Relación Estructura-Actividad , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
Chromenes are compounds that may be useful for inhibiting topoisomerase and cytochrome, enzymes involved in the growth of cancer and fungal cells, respectively. The aim of this study was to synthesize a series of some novel 2-amino-3-cyano-4-aryl-6,7-methylendioxy-4H-chromenes 4a-o and 2-amino-3-cyano-5,7-dimethoxy-4-aryl-4H-chromenes 6a-h by a three-component reaction, and test these derivatives for anticancer and antifungal activity. Compounds 4a and 4b were more active than cisplatin (9) and topotecan (7) in SK-LU-1 cells, and more active than 9 in PC-3 cells. An evaluation was also made of the series of compounds 4 and 6 as potential antifungal agents against six Candida strains, finding their MIC50 to be less than or equal to that of fluconazole (8). Molecular docking studies are herein reported, for the interaction of 4 and 6 with topoisomerase IB and the active site of CYP51 of Candida spp. Compounds 4a-o and 6a-h interacted in a similar way as 7 with key amino acids of the active site of topoisomerase IB and showed better binding energy than 8 at the active site of CYP51. Hence, 4a-o and 6a-h are good candidates for further research, having demonstrated their dual inhibition of enzymes that participate in the growth of cancer and fungal cells.
RESUMEN
Ten compounds, including a new anti-inflammatory acyl triterpene, 3ß-palmitoyloxy-1ß,11α-dihydroxy-olean-12-ene, were isolated from the bioactive organic extract prepared from the leaves of Sapium lateriflorum (syn: S. nitidum). The isolated compounds were screened for their cytotoxic activity against selected human cancer cell lines and did not display significant activity. They were also evaluated as anti-inflammatory agents in mouse models (TPA-induced edema in the ear and in a carrageenan-induced paw edema model). The results indicated that the new compound, 3ß-palmitoyloxy-1ß,11α-dihydroxy-olean-12-ene, was the compound with major anti-inflammatory activity similar to that of indomethacin, being the hydroxyl at C-11 important for the observed activity. The results of docking studies of the 3ß-palmitoyloxy esters of olean-12-ene with NF-κB and with COX-2 receptors were consistent with possible molecular mechanisms of the anti-inflammatory activity.
Asunto(s)
Antiinflamatorios/farmacología , Edema/tratamiento farmacológico , Ésteres/farmacología , Sapium/química , Animales , Antiinflamatorios/aislamiento & purificación , Línea Celular Tumoral , Edema/inducido químicamente , Ésteres/aislamiento & purificación , Humanos , México , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Hojas de la Planta/químicaRESUMEN
Metal-based drugs, including lanthanide complexes, have been extremely effective in clinical treatments against various diseases and have raised major interest in recent decades. Hence, in this work, a series of lanthanum (III) and cerium (III) complexes, including Schiff base ligands derived from (1H-benzimidazol-2-yl)aniline, salicylaldehyde, and 2,4-dihydroxybenzaldehyde were synthesized and characterized using different spectroscopic methods. Besides their cytotoxic activities, they were examined in human U-937 cells, primate kidney non-cancerous COS-7, and six other, different human tumor cell lines: U251, PC-3, K562, HCT-15, MCF-7, and SK-LU-1. In addition, the synthesized compounds were screened for in vitro antiparasitic activity against Leishmania braziliensis, Plasmodium falciparum, and Trypanosoma cruzi. Additionally, antibacterial activities were examined against two Gram-positive strains (S. aureus ATCC® 25923, L. monocytogenes ATCC® 19115) and two Gram-negative strains (E. coli ATCC® 25922, P. aeruginosa ATCC® 27583) using the microdilution method. The lanthanide complexes generally exhibited increased biological activity compared with the free Schiff base ligands. Interactions between the tested compounds and model membranes were examined using differential scanning calorimetry (DSC), and interactions with calf thymus DNA (CT-DNA) were investigated by ultraviolet (UV) absorption. Molecular docking studies were performed using leishmanin (1LML), cruzain (4PI3), P. falciparum alpha-tubulin (GenBank sequence CAA34101 [453 aa]), and S.aureus penicillin-binding protein 2a (PBP2A; 5M18) as the protein receptors. The results lead to the conclusion that the synthesized compounds exhibited a notable effect on model membranes imitating mammalian and bacterial membranes and rolled along DNA strands through groove interactions. Interactions between the compounds and studied receptors depended primarily on ligand structures in the molecular docking study.
RESUMEN
A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/metabolismo , Azoles/química , Azoles/metabolismo , Citotoxinas/química , Citotoxinas/metabolismo , Simulación del Acoplamiento Molecular/métodos , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Azoles/síntesis química , Azoles/farmacología , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citotoxinas/síntesis química , Citotoxinas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Receptor alfa de Estrógeno/metabolismo , Humanos , Células MCF-7 , Estructura Molecular , Células PC-3 , Relación Estructura-Actividad , Tamoxifeno/metabolismo , Tamoxifeno/farmacologíaRESUMEN
Abstract The protoanemonin, a natural furanone, was synthesized from (Z)-4-bromo-5-(bromomethylene)-furan-2(5H)-one by a reductive dehalogenation reaction with zinc. The 5-(dibromomethylene)-2(5H)-furanone and (E)-5-(bromomethylene)-2(5H)-furanone were also synthetized from levulinic acid bromination and acid promoted cyclization. The antiproliferative activity of all synthesized compounds against the human cancer cell lines PC-3 (prostate) and U-251 (glioblastoma) was investigated. The results showed that all the obtained furanones are more active than the reference drug cisplatin, with iC50 values in the range of 0.31 ± 0.02 to 7.30 ± 0.08 µM. However, (E)-5-(bromomethylene)-2(5H)-furanone, with a bromine atom in the double bond, was the most active, and demonstrated to be about 25-fold more active than the reference drug cisplatin.
Resumen La protoanemonina, una furanona de origen natural, fue sintetizada a partir de la (Z)-4-bromo-5-(bromometilen)-furan-2(5H)-ona mediante una deshalogenación reductiva con zinc. La 5-(dibromometilen)-2(5H)-furanona y la (E)-5-(bromometilen)-2(5H)-furanona también fueron sintetizadas a partir del ácido levulínico mediante bromación y posterior ciclación promovida por ácido. Se investigó la actividad antiproliferativa de todos los compuestos sintetizados en las líneas celulares de cáncer humano PC-3 (próstata) y U-251 (glioblastoma). Los resultados demostraron que todas las furanonas obtenidas son más activas que el fármaco de referencia cisplatino, con un intervalo de Ci50 de 0,31 ± 0,02 hasta 7,30 ± 0,08 µM. Sin embargo, la (E)-5-(bromometilen)-2(5H)-furanona, con un átomo de bromo en el doble enlace, demostró ser 25 veces más activa que el fármaco de referencia cisplatino.
Resumo Protoanemonina, uma furanona natural, foi sintetizada de (Z)-4-bromo-5-(bromometileno)-furan-2(5H)-ona por desalógenação redutora do zinco. Também foram sintetizados 5-(Dibromometileno)-2(5H)-furanona e (E)-5-(Bromometileno)-2(5H)-furanona a partir da brominação com ácido levulínico e ciclização promovida por ácido. Foi investigada a atividade antiproliferativa de todos os compostos sintetizados nas linhas celulares humanas de câncer PC-3 (próstata) e U-251 (glioblastoma). Os resultados mostram que todos os furanonas obtidos são mais ativos que a cisplatina do medicamento de referência, com intervalo Ci50 de 0,31 ± 0,02 até 7,30 ± 0,08 µM. Entretanto, a mais ativa foi a (E)-5-(Bromometileno)-2(5H)-furanona, que com um átomo de bromo na dupla ligação exocíclica, provou ser 25 vezes mais ativa que a medicamento de referência cisplatina.
RESUMEN
A series of Pt(II) complexes of the type [Pt(1,10-phenanthroline)(SArFn)2] (SArFn = SC6H3-3,4-F2(1); SC6F4-4-H (2); SC6F5(3)) were synthesized from [Pt(1,10-phenanthroline)(Cl)2] and [Pb(SArFn)2] via metathesis reactions. The complexes were fully characterized including the unambiguous determination of their molecular structures by single-crystal X-ray diffraction techniques, showing the metal centers to be into a slightly distorted square-planar environments. The in vitro cytotoxic activity of the complexes was evaluated on six cancerous cell lines, i.e: glial cells of nervous central system (U-251), prostate (PC-3), leukemia (K-562), colon (HCT-15), breast (MCF-7) and lung (SKLU-1); we also included a healthy cell line of COS-7 (African green monkey kidney) for comparative purposes. We found that complex 2 was selective for PC-3. In addition, the IC50 values for the series of complexes were determined using the U-251, HCT-15 and SKLU-1 cancerous cell lines, as well as in the healthy cell line (COS-7), where complex 1 exhibited the best activity, with IC50 values going from 4.56 to 4.78 µM. These studies where further complemented with DNA docking theoretical calculations and DNA affinity experiments.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/farmacología , Fenantrolinas/química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cristalografía por Rayos X/métodos , Humanos , Técnicas In Vitro , Estructura Molecular , Neoplasias/patología , Compuestos Organoplatinos/química , Relación Estructura-ActividadRESUMEN
Curcumin and its derivatives have been extensively studied for their remarkable medicinal properties, and their chemical synthesis has been an important step in the optimization of well-controlled laboratory production. A family of new compounds that mimic the structure of curcumin and curcuminoids, here named retro-curcuminoids (7-14), was synthesized and characterized using 1D ¹H- and 13C-NMR, IR, and mass spectrometry; the X-ray structure of 7, 8, 9, 10, 12, 13, and 14 are reported here for the first time. The main structural feature of these compounds is the reverse linkage of the two aromatic moieties, where the acid chloride moiety is linked to the phenolic group while preserving α, ß-unsaturated ketone functionality. The cytotoxic screening of 7, 8, 9, and 10 at 50 and 10 µg/mL was carried out with human cancer cell lines K562, MCF-7, and SKLU-1. Lipid peroxidation on rat brain was also tested for compounds 7 and 10. Compounds 7, 8, and 10 showed relevant cytotoxic activity against these cancer cell lines, and 10 showed a protective effect against lipid peroxidation. The molecular resemblance to curcuminoids and analogs with ortho substituents suggests a potential source of useful bioactive compounds.
Asunto(s)
Antineoplásicos , Curcumina/análogos & derivados , Estirenos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Ácidos Cumáricos/química , Cristalografía por Rayos X , Humanos , Células MCF-7 , Masculino , Resonancia Magnética Nuclear Biomolecular , Ratas , Ratas WistarRESUMEN
Pregnane derivatives are studied as agents for the treatment of different hormone-dependent diseases. The biological importance of these steroids is based on their potential use against cancer. In this study, we report the synthesis, characterization and biological activity of two pregnane derivatives with a triazole (3ß-hydroxy-21-(1H-1,2,4-triazol-1-yl)pregna-5,16-dien-20-one; T-OH) or imidazole (3ß-hydroxy-21-(1H-imidazol-1-yl)pregna-5,16-dien-20-one; I-OH) moieties at C-21. These derivatives were synthesized from 16-dehydropregnenolone acetate. The activity on cell proliferation of the compounds was measured on three human cancer cells lines: prostate cancer (PC-3), breast cancer (MCF7) and lung cancer (SK-LU-1). The cytotoxic and antiproliferative effects of T-OH and I-OH were assessed by using SBR and XTT methods, respectively. The gene expressions were evaluated by real time PCR. In addition, results were complemented by docking studies and transactivation assays using an expression vector to progesterone and androgen receptor. Results show that the two compounds inhibited the three cell lines proliferation in a dose-dependent manner. Compound I-OH downregulated the gene expression of the cyclins D1 and E1 in PC-3 and MFC7 cells; however, effect upon Ki-67, EAG1, BIM or survivin genes was not observed. Docking studies show poor interaction with the steroid receptors. Nevertheless, the transactivation assays show a weak antagonist effect of I-OH on progesterone receptor but not androgenic or antiandrogenic actions. In conclusion, the synthesized compounds inhibited cell proliferation as well as genes key to cell cycle of PC-3 and MCF7 cell lines. Therefore, these compounds could be considered a good starting point for the development of novel therapeutic alternatives to treat cancer.
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Antineoplásicos/síntesis química , Imidazoles/síntesis química , Pregnadienos/síntesis química , Triazoles/síntesis química , Antineoplásicos/farmacología , Apoptosis , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Imidazoles/farmacología , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Pregnadienos/farmacología , Triazoles/farmacología , Vitamina D3 24-Hidroxilasa/metabolismoRESUMEN
Bentonites, naturally occurring clays, are produced industrially because of their adsorbent capacity but little is known about their effects on human health. This manuscript reports on the effect of bentonites on cell growth behaviour. Bentonites collected from India (Bent-India), Hungary (Bent-Hungary), Argentina (Bent-Argentina), and Indonesia (Bent-Indonesia) were studied. All four bentonites were screened in-vitro against two human cancer cell lines [U251 (central nervous system, glioblastoma) and SKLU-1 (lung adenocarcinoma)] supplied by the National Cancer Institute (USA). Bentonites induced growth inhibition in the presence of U251 cells, and growth increment in the presence of SKLU-1 cells, showing that interactions between bentonite and cell surfaces were highly specific. The proliferation response for U251 cells was explained because clay surfaces controlled the levels of metabolic growth components, thereby inhibiting the development of high-grade gliomas, particularly primary glioblastomas. On the other hand, the proliferation response for SKLU-1 was explained by an exacerbated growth favoured by swelling, and concomitant accumulation of solutes, and their hydration and transformation via clay-surface mediated reactions.
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Bentonita/química , Silicatos de Aluminio , Argentina , Procesos de Crecimiento Celular , Línea Celular Tumoral , Arcilla , Humanos , India , Indonesia , Propiedades de SuperficieRESUMEN
The guaianolide 8-epi-mikanokryptin (1) and the melampolide 11Hß-11,13-dihydromicrantholide (2) along with known sesquiterpene lactones (3-13) and other constituents were isolated from the aerial parts of different populations of Mikania micrantha and Mikania cordifolia collected in several states of Mexico. The relative and absolute configurations of 1 were determined by X-ray diffraction and CD analysis, respectively. Considering the (1)H and (13)C NMR chemical shift similarities and the H-H coupling constant values, a [(1)D(14), (15)D5] conformation was established for micrantholides (2, 8-13). We tested nearly all the sesquiterpene lactones for antiproliferative activity in human cancer cell lines, and they exhibited moderate activity. Additionally, in a mouse ear model of edema induced by TPA, the anti-inflammatory activities were marginal.
Asunto(s)
Antiinflamatorios/química , Lactonas/química , Mikania/química , Extractos Vegetales/química , Sesquiterpenos/química , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Edema , Humanos , Concentración 50 Inhibidora , Lactonas/aislamiento & purificación , Lactonas/farmacología , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Componentes Aéreos de las Plantas/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Sesquiterpenos de Guayano/química , Sesquiterpenos de Guayano/aislamiento & purificación , Sesquiterpenos de Guayano/farmacologíaRESUMEN
Arsenopyrite (FeAsS) is one of the earth's primary mineral sources of As, yet its effects on cell damage remain largely unknown. This paper addresses the question whether FeAsS induces lipid peroxidation (LP), a major indicator of oxidative stress. Screening and monitoring of LP was conducted using Thiobarbituric Acid Reactive Substances (TBARSs) assay. The lipid source was supernatant of rat brain homogenates. The formation of TBARS by FeAsS was rapid and took place just after 10 min. Maximum TBARS levels (ca. 14 nmol TBARS per mg of protein) were observed after 1h and remained constant thereafter. Suspension fraction separations showed that dissolved and structural components contributed to LP. The formation of TBARS by soluble As, As(III) or As(V), compared to basal levels. The initiation of LP by FeAsS was consistent with a mechanism initiated by the Fe(3+)/O(2)(-) redox system, and differed initiated by Fe(2+)/O(2). The effectiveness of FeAsS and FeSO(4) as inducer compared, and surpassed that of AAPH. On the other hand, the initiation of LP by FeAsS is consistent with a mechanism initiated by perferryl ion and Fe(3+)/O(2)(-), and differs from the mechanism characteristic of FeSO(4) initiated by the Fe(2+)/O(2) redox system. Proposedly, FeAsS surfaces contain a mixture of Fe(3+) and Fe(2+) that, along with O(2) and O(2)(-), participate in multiple mechanisms of electron transfer. EPR determinations show decreases in DMPO-OH adduct signal in FeAsS suspensions after adding desferrioxamine-B (DFO-B), consistent with the idea that DFO-B serves as a radical scavenger.
Asunto(s)
Antioxidantes/farmacología , Deferoxamina/farmacología , Sustancias Peligrosas/toxicidad , Compuestos de Hierro/toxicidad , Minerales/toxicidad , Estrés Oxidativo , Sulfuros/toxicidad , Animales , Arsenicales , Óxidos N-Cíclicos/metabolismo , Peroxidación de Lípido , Masculino , Oxidación-Reducción , Ratas , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
The one-step synthesis of nanodevices based on PAMAM framework for targeted cancer therapy is described. Four water-soluble nanodevices (named fractions F1 to F4) were rightly separated by size discrimination, and characterized. From biological assays of cell growth inhibition percentage, the anticancer activity of Methotrexate (chemotherapeutic drug) as part of a nanodevice, generally increases over cancer cell lines and notably, in case of human lymphocytes, the cell growth inhibition percentage decreases drastically (more than 80%), thus, the nanodevices exhibited a favorable discrimination between healthy and diseased cells. From the characterization it can be conclude that the synthesized nanodevices provide a dual scenario of drug transportation: encapsulation and conjugation.