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1.
Chem Commun (Camb) ; 56(18): 2759-2762, 2020 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-32022003

RESUMEN

We describe a colorimetric and fluorescent probe 3a to detect cellular peroxynitrite with high selectivity and sensitivity. 3a was successfully applied in the bioimaging of exogenous and endogenous peroxynitrite in living cells. The up-regulation of peroxynitrite in cancer cells and normal cells during 5-fluorouracil treatment was finally monitored.


Asunto(s)
Antineoplásicos/farmacología , Colorantes Fluorescentes/farmacología , Fluorouracilo/farmacología , Ácido Peroxinitroso/biosíntesis , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Colorantes Fluorescentes/química , Fluorouracilo/química , Humanos , Células MCF-7 , Estructura Molecular , Imagen Óptica , Ácido Peroxinitroso/química , Relación Estructura-Actividad
3.
Chem Commun (Camb) ; 56(20): 3069-3072, 2020 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-32049075

RESUMEN

Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes (PtRu 1-4) have been synthesized and evaluated for their antitumor performance. Using the optimal complex, PtRu-1, we show that this water-soluble chimeric prodrug not only potently inhibits the metastasis and proliferation of tumor cells but also has an unexpectedly higher safety margin in animals compared with the traditionally-used, clinically approved drug cisplatin.


Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Niacina/farmacología , Platino (Metal)/farmacología , Rutenio/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/química , Cisplatino/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Niacina/química , Platino (Metal)/química , Rutenio/química , Relación Estructura-Actividad
5.
J Enzyme Inhib Med Chem ; 35(1): 414-423, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31899991

RESUMEN

A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.


Asunto(s)
Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Transcripción Genética/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
6.
J Enzyme Inhib Med Chem ; 35(1): 506-510, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31928252

RESUMEN

The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) cancer-associated isoforms hCA IX and - hCA XII is being able to also inhibit thioredoxin reductase was verified and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative stress, may both contribute to the observed antiproliferative profile of these compounds against many cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for designing innovative therapeutic agents.


Asunto(s)
Antineoplásicos/farmacología , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasas Carbónicas/metabolismo , Cumarinas/farmacología , Inhibidores Enzimáticos/farmacología , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Anhidrasa Carbónica IX/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cumarinas/síntesis química , Cumarinas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Células Tumorales Cultivadas
7.
J Enzyme Inhib Med Chem ; 35(1): 555-564, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31967481

RESUMEN

In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and three human cancer cell lines including A549, PC-3, and SMMC-7721. The results displayed that some of the compounds had good activities, especially 2-{4-[(3-Fluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 g), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5k) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 l) showed high antitumor activities against three cancer cell lines. Moreover, compound 5k could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G2/M phase at tested concentrations. Also, compound 5k could inhibit the EGFRwt-TK with IC50 value of 10 nM. Molecular docking data indicates that the compound 5k may exert inhibitory activity by forming stable hydrogen bonds with the R817, T830 amino acid residues and cation-Π interaction with the K72 residue of EGFRwt-TK.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinonas/farmacología , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Quinazolinonas/síntesis química , Quinazolinonas/química , Relación Estructura-Actividad
8.
Chem Biodivers ; 17(2): e1900659, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31995280

RESUMEN

Breast Cancer (BCa) is the most often diagnosed cancer among women who were in the late 1940's. Breast cancer growth is largely dependent on the expression of estrogen and progesterone receptor. Breast cancer cells may have one, both, or none of these receptors. The treatment for breast cancer may involve surgery, hormonal therapy (Tamoxifen, an aromatase inhibitor, etc.) and oral chemotherapeutic drugs. The molecular docking technique reported the findings on the potential binding modes of the 2-(2-bromo-3-nitrophenyl)-5-phenyl-1,3,4-oxadiazole derivatives with the estrogen receptor (PDB ID: 3ERT). The 1,3,4-oxadiazole derivatives 4a-4j have been synthesized and described by spectroscopic method. 2-(2-Bromo-6-nitrophenyl)-5-(4-bromophenyl)-1,3,4-oxadiazole (4c) was reconfirmed by single-crystal XRD. All the compounds have been tested in combination with generic Imatinib pharmaceutical drug against breast cancer cell lines isolated from Caucasian woman MCF-7, MDA-MB-453 and MCF-10A non-cancer cell lines. The compounds with the methoxy (in 4c) and methyl (in 4j) substitution were shown to have significant cytotoxicity, with 4c showing dose-dependent activation and decreased cell viability. The mechanism of action was reported by induced apoptosis and tested by a DNA enzyme inhibitor experiment (ELISA) for Methyl Transferase. Molecular dynamics simulations were made for hit molecule 4c to study the stability and interaction of the protein-ligand complex. The toxicity properties of ADME were calculated for all the compounds. All these results provide essential information for further clinical trials.


Asunto(s)
Antineoplásicos/síntesis química , Diseño de Drogas , Oxadiazoles/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Sitios de Unión , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasa 1/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Mesilato de Imatinib/farmacología , Conformación Molecular , Simulación del Acoplamiento Molecular , Oxadiazoles/metabolismo , Oxadiazoles/farmacología , Relación Estructura-Actividad
9.
Chem Commun (Camb) ; 56(12): 1784-1787, 2020 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-31950129

RESUMEN

Nanozymes have attracted extensive attention due to their great potential as alternatives to natural enzymes. Optical control as an external stimulus has become the most attractive method because of its high spatial and temporal resolution. Under the action of excitation light, free electrons on the surface of gold nanorods (GNRs) will collectively oscillate, which is called localized surface plasmon resonance (LSPR). This unique LSPR effect is promising in the application of plasmon-accelerated enzyme-like catalytic reactions. Pt-tipped gold nanorod-based nanozymes (Pt-GNRs) were synthesized by the modification of Pt nanoclusters onto the tips of GNRs. The as-prepared Pt-GNRs exhibited excellent enzyme-like catalytic activity toward hydrogen peroxide. Furthermore, it was found that the enzyme-like catalytic activity of Pt-GNRs could be notably enhanced using near-infrared (NIR) light irradiation, because of the photothermal effect and hot electron effect produced by the LSPR of GNRs. Finally, the catalytic activity and cytotoxicity of Pt-GNRs were evaluated in 4T1 cells, which further demonstrated that the Pt-GNR-based nanozymes possess great potential in cancer treatment.


Asunto(s)
Antineoplásicos/química , Oro/química , Nanopartículas del Metal/química , Platino (Metal)/química , Resonancia por Plasmón de Superficie , Antineoplásicos/farmacología , Catálisis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Oro/farmacología , Humanos , Rayos Infrarrojos , Platino (Metal)/farmacología , Relación Estructura-Actividad
10.
Chem Commun (Camb) ; 56(14): 2194-2197, 2020 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-31971170

RESUMEN

An Ugi, novel pseudo-Knoevenagel, ring expansion cascade reaction was discovered and utilized for the synthesis of aziridinyl succinimides in one-pot. Subsequently, densely functionalized aziridines and maleimides have been designed and synthesized through similar cascade reactions. The target compounds were prepared by means of a mild reaction and a simple operation procedure, which could be applicable to a broad scope of starting materials. This series of novel cascade reactions generates opportunities for the tailored synthesis of a wide range of biologically active scaffolds through tuneable Ugi inputs. Discovery of compound 8i with comparable potency to sorafenib in liver cancer cell lines could provide a new avenue for liver cancer drug discovery.


Asunto(s)
Antineoplásicos/farmacología , Aziridinas/farmacología , Maleimidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Aziridinas/síntesis química , Aziridinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Maleimidas/síntesis química , Maleimidas/química , Estructura Molecular
12.
Chem Commun (Camb) ; 56(15): 2320-2323, 2020 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-31990000

RESUMEN

Novel biotinylated diazido-Pt(iv) complexes exhibit high visible light photocytotoxicity while being stable in the dark. Photocytotoxicity and cellular accumulation of all-trans-[Pt(py)2(N3)2(biotin)(OH)] (2a) were enhanced significantly when bound to avidin; irradiation induced dramatic cellular morphological changes in human ovarian cancer cells treated with 2a.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Biotinilación , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Estructura Molecular , Imagen Óptica , Compuestos Organoplatinos/síntesis química , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/patología , Procesos Fotoquímicos , Relación Estructura-Actividad
13.
Phytochemistry ; 171: 112228, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31911265

RESUMEN

A previously undescribed taraxerene-type triterpenoid possessing a class of rare natural taraxerene triterpenoid possessing skeleton with 14, 28-lactone, two undescribed oleane-type triterpenoids, and twenty-five known triterpenoids were isolated from Liquidambar formosana (Hamamelidaceae). The structures of undescribed compounds were determined on the basis of 1D and 2D NMR spectroscopic, HR-ESI-MS, and X-ray crystallographic data analysis. Among the isolates, ursolic acid, 3,6-dion-20(29)-lupen-28-oic acid, and 3-oxo-12α-hydroxyoleanan-28,13ß-olide induced a significant apoptosis in SMMC7721 cells in the flow cytometer experiment with apoptosis rates of 94.5%, 57.3% and 89.9% at 8.0 µM, respectively, exhibiting near equivalent apoptosis-inducing abilities to that positive drug taxol (apoptotic rate of 71.2% at 1.4 µM). Mechanism studies suggested that these three compounds could regulate the mitochondrial pathway by up-regulating the expressions of pro-apoptotic factors (Bad and Bax) and activating caspase-3 and caspase-9 to induce apoptosis. Further studies indicated that the pro-apoptotic effects of these three compounds were associated with PI3K-AKT pathway inhibition. Taken together, these studies provide evidence that triterpenoids from L. Fructus are promising candidates for the hepatocellular carcinoma therapy.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Liquidambar/química , Fitoquímicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Triterpenos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Fitoquímicos/química , Fitoquímicos/aislamiento & purificación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/aislamiento & purificación , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Triterpenos/química , Triterpenos/aislamiento & purificación , Células Tumorales Cultivadas
14.
Phytochemistry ; 171: 112248, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31918304

RESUMEN

The phytochemical investigation of the twig and leaf extracts of Goniothalamus tamirensis led to the isolation and identification of 15 compounds including three rare previously undescribed styryllactones, goniotamirenones A-C, together with 12 known compounds. (Z)-6-Styryl-5,6-dihydro-2-pyranone and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one are reported here for the first time as previously undescribed natural products. Their structures were elucidated by spectroscopic methods. Goniotamirenone A was synthesized via a [2 + 2] cycloaddition reaction of 6-styrrylpyran-2-one in quantitative yield. The absolute configurations of goniotamirenones B and C were identified from experimental and calculated ECD data, while the absolute configurations of (-)-5-acetoxygoniothalamin, (-)-isoaltholactone, parvistone E, and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one were identified by single-crystal X-ray diffraction analysis using Cu Kα radiation. The absolute configurations of the other related compounds were determined from comparisons of their ECD spectra with relevant compounds reported in the literature. (-)-5-Acetoxygoniothalamin exhibited potent cytotoxicity against the colon cancer cell line (HCT116) with an IC50 value of 8.6 µM which was better than the standard control (doxorubicin, IC50 = 9.7 µM), while (Z)-6-styryl-5,6-dihydro-2-pyranone was less active with an IC50 value of 22.1 µM.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Goniothalamus/química , Lactonas/farmacología , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Estirenos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Teoría Funcional de la Densidad , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Lactonas/química , Lactonas/aislamiento & purificación , Modelos Moleculares , Estructura Molecular , Fitoquímicos/química , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Estirenos/química , Estirenos/aislamiento & purificación
15.
Eur J Med Chem ; 188: 112021, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31901743

RESUMEN

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as carbonic anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human carbonic anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound 11b potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Sulfonamidas/farmacología , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Anhidrasa Carbónica IX/química , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/toxicidad , Dominio Catalítico , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Simulación del Acoplamiento Molecular , Pirimidinas/síntesis química , Pirimidinas/toxicidad , Pirroles/síntesis química , Pirroles/toxicidad , Sulfonamidas/síntesis química , Sulfonamidas/toxicidad
16.
Eur J Med Chem ; 188: 111988, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31901746

RESUMEN

In connection with our continued research to generate new aza-fused heteroaromatic chemical scaffolds, we developed a highly atom-economical three-component route to novel 3,4-dihydropyrrolo[1,2-a]pyrazine ring skeleton multi-functionalized on the pyrazine unit. This [4+1+1] annulation approach led us to gain access to a new N-fused bicyclic chemical space having two distinctive functional groups (heteroaryl and aroyl) in a trans manner. Investigation of anticancer activity of the synthesized compounds and their derivatives revealed that (3R*,4S*)-3-(4-bromophenyl)-4-(4-fluorobenzoyl)-2-(2-oxo-2-phenylethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2-ium bromide (3h) has potent anticancer activity. 3h significantly inhibited cell viability in prostate cancer cells (PC-3) and breast cancer cells (MCF-7) with IC50 value of 1.18 ± 0.05 µM and 1.95 ± 0.04 µM, respectively. In addition, 3h strongly reduced cell migration in a dose dependent manner, and induced apoptosis via caspase-3 activation and cleavage of PARP in PC-3 and MCF-7 cells. Our results in this study imply that 3h can be a potential anticancer agent against prostate cancer and breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Pirazinas/farmacología , Pirroles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Poli(ADP-Ribosa) Polimerasas/metabolismo , Pirazinas/síntesis química , Pirazinas/química , Pirroles/síntesis química , Pirroles/química
17.
Biophys Chem ; 258: 106316, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31986436

RESUMEN

The present study describes the investigation of the binding modes of potential anti-cancerous nitrophenyl derivatives of 2-(x-nitrophenyl)-5-nitrobenzimidazole with calf thymus DNA. The -2-(x-nitrophenyl)-5-nitrobenzimidazoles under investigation differ only in position x of nitro group in nitrophenyl substituent relative to benzimidazole moiety leading to 1-NPNB (x = 2), 2-NPNB (x = 3) and 3-NPNB (x = 4). The DFT calculations predicted that derivatives were electrochemically reducible which was then confirmed by cyclic voltammetry. In cyclic voltammetry, the second reversible peak was dependent on first irreversible reduction. This revealed that electrochemical irreversible process was governed by some other process which was then followed by reversible second electron transfer. Thus, ECE (electron transfer leading to coupled chemical reaction followed by another electron transfer process) mechanism was attributed for electrochemical reduction. Experimental results based on UV-Vis spectroscopy vaguely showed intercalation of 1-NPNB, 2-NPNB and 3-NPNB into DNA which was assisted by cyclic voltammetry. However, thermal melting and florescence spectroscopy unambiguously established intercalation for all three compounds. Molecular docking analysis ascertained in pocket stacking of 5-nitrobenzimidazole moiety in 1-NPNB and 2-NPNB while nitro phenyl substitution in 3-NPNB stacks between DNA base pair during intercalation which was in agreement with DFT computed molecular geometry. Therefore, the relative positions of nitro group and 5-nitrobenzimidazole moieties in 2-(x-nitrophenyl)- 5-nitrobenzimidazole influenced the DNA binding pattern of compounds during intercalation. The cytotoxicity of these compounds was comparable to standard drug doxorubicin against both cancerous (MCF-7) and normal (MCF-10A) breast cells which depicts their anti-cancerous potential.


Asunto(s)
Antineoplásicos/química , Bencimidazoles/química , ADN/química , Animales , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Sitios de Unión , Bovinos , Línea Celular , Proliferación Celular/efectos de los fármacos , Teoría Funcional de la Densidad , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxidación-Reducción , Relación Estructura-Actividad
18.
Chem Commun (Camb) ; 56(16): 2415-2418, 2020 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-31994584
19.
Chem Biodivers ; 17(1): e1900547, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31916685

RESUMEN

Four previously unreported chromones, 5-hydroxy-2-(hydroxymethyl)-8-methoxy-4H-chromen-4-one (1), (5R,7S)-5,7-dihydroxy-2-propyl-5,6,7,8-tetrahydro-4H-chromen-4-one (2), (5R,7S)-5,7-dihydroxy-2-methyl-5,6,7,8-tetrahydro-4H-chromen-4-one (3), and (5R,7S)-5,7-dihydroxy-2-[(E)-prop-1-en-1-yl]-5,6,7,8-tetrahydro-4H-chromen-4-one (4), as well as one known analogue 5-hydroxy-2-methyl-4H-chromen-4-one (5) were isolated from the fermentation broth of the endophytic fungus Colletotrichum gloeosporioides derived from the mangrove Ceriops tagal. Their structures were elucidated based on extensive spectroscopic analyses. The absolute configurations of 2-4 were determined by comparison the experimental and calculated electronic circular dichroism (ECD) spectra. Compound 2 showed cytotoxic activity against A549 cell line with the IC50 value of 0.094 mm.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Cromonas/aislamiento & purificación , Cromonas/farmacología , Colletotrichum/química , Células A549 , Antineoplásicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Cromonas/química , Teoría Funcional de la Densidad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-Actividad
20.
Chemistry ; 26(9): 1947-1952, 2020 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-31909511

RESUMEN

Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N')PtIV compounds derived from amine-imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs.


Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Resistencia a Antineoplásicos , Platino (Metal)/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/farmacología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Complejos de Coordinación/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Conformación Molecular , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Espectrometría de Fluorescencia
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