RESUMEN
A selective Oxone-induced oxidation of oleocanthal and oleacein, the two main secoiridoids of olive oil, to their bis-oxidized products is described. This protocol is based on a Baeyer-Villiger mechanism and the concentration of Oxone in the final solution. The bis-oxidation of the aldehydic compounds could be extended for the synthesis of various semisynthetic analogs. The obtained acids exhibit strong antioxidant activity, being efficient free radical scavengers.
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Aldehídos , Aceite de Oliva , Oxidación-Reducción , Aldehídos/química , Aceite de Oliva/química , Antioxidantes/química , Antioxidantes/farmacología , Fenoles/química , Furanos/química , Monoterpenos Ciclopentánicos/químicaRESUMEN
Aims: Drug resistance in ovarian cancer (OC) cells often leads to recurrence, metastasis, and high mortality rates among OC patients. Hydroxytyrosol (HT) has been reported to inhibit the proliferation of ovarian and other types of cancer cells. Here we synthesized a novel cyclohexane-hydroxytyrosol derivative (Chx-HT) for enhanced anticaner efficacy. We examined the growth-suppressing effect of Chx-HT on OC cells in vitro and in a xenograft mouse model and investigated the underlying mechanism. Results: We demonstrated that Chx-HT inhibits proliferation, promotes apoptosis, and remodels glucose and lipid metabolism by reducing fatty acid ß-oxidation while increasing glycolysis, de novo fatty acid synthesis (FAS), and lipid droplet (LD) accumulation, impairs mitochondrial respiration, and induces oxidative stress both in vitro and in vivo. In addition, Chx-HT blocks autophagic flux by obstructing the maturation of lysosomal cathepsins in the late stage, but also activates autophagy through the p-AMPK/p-mTOR/p-ULK1 pathway in response to energy deficit. Innovation and Conclusion: Reactive oxidative species (ROS) play a critical role in mediating the effects of Chx-HT on proliferation, apoptosis, autophagy, tricarboxylic acid (TCA) cycle, fatty acid ß-oxidation, and mitochondrial respiration, and the autophagic activation underlies the effects of Chx-HT on glycolysis, de novo FAS, and LD accumulation in OC cells. Cotreating OC cells with Chx-HT and autophagic inhibitor or glycolytic inhibitor results in an additive inhibition of proliferation. Our study indicates that Chx-HT stands for a promising OC therapeutic by ROS and autophagy blockade-mediated metabolic remodeling.
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Sixteen new 2-substituted quinazolines were synthesized using a straightforward methodology starting from 2-methoxybezoic acid or 3-methoxy-2-naphthoic acid. The anti-proliferative activity of the target compounds was evaluated against nine cancer cell lines. Additionally, all the compounds were screened for their potency and selectivity against a panel of 109 kinases and four bromodomains, using Differential Scanning Fluorimetry (DSF). Compound 17 bearing a 2-methoxyphenyl substitution along with a basic side chain displayed a remarkable profile against the majority of the tested cell lines.
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Antineoplásicos , Neoplasias , Humanos , Quinazolinas/farmacología , Línea Celular , Relación Estructura-Actividad , Antineoplásicos/farmacologíaRESUMEN
Novel amino-substituted pyridoquinazolinone derivatives have been designed and synthesized as potential c-MYC G-quadruplex (G4) ligands, employing an efficient methodology. All the new compounds exhibited moderate to good antiproliferative activity against the human osteosarcoma U2OS cell line. NMR and docking experiments revealed that the recently synthesized compounds interact with the Pu22 G-quadruplex in the c-MYC promoter region, establishing a 2:1 complex, with each molecule positioned over the tetrads at the 3'- and 5'-ends.
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Neoplasias Óseas , G-Cuádruplex , Osteosarcoma , Humanos , Línea Celular , Regiones Promotoras GenéticasRESUMEN
Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by poor prognosis and limited treatment options. Oleuropein and oleocanthal are bioactive chemicals found in extra-virgin olive oil; they have been shown to have anti-cancer potential. In this study, we examined the inhibitory effects of these two natural compounds, on MDA-MB-231 and MDA-MB-468 TNBC cell lines. The human TNBC MDA-MB-231 and MDA-MB-468 cell lines were treated with oleuropein or oleocanthal at ranging concentrations for 48 h. After determining the optimum concentration to reach IC50, using the sulforhodamine B assay, total RNA was extracted after 12, 24, and 48 h from treated and untreated cells. Poly(A)-RNA selection was conducted, followed by library construction and RNA sequencing. Differential gene expression (DEG) analysis was performed to identify DEGs between treated and untreated cells. Pathway analysis was carried out using the KEGG and GO databases. Oleuropein and oleocanthal considerably reduced the proliferation of TNBC cells, with oleocanthal having a slightly stronger effect than oleuropein. Furthermore, multi-time series RNA sequencing showed that the expression profile of TNBC cells was significantly altered after treatment with these compounds, with temporal dynamics and groups of genes consistently affected at all time points. Pathway analysis revealed several significant pathways associated with TNBC, including cell death, apoptotic process, programmed cell death, response to stress, mitotic cell cycle process, cell division, and cancer progression. Our findings suggest that oleuropein and oleocanthal have potential therapeutic benefits for TNBC and can be further investigated as alternative treatment options.
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Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Expresión Génica , ARNRESUMEN
With the current massive increases in drug-resistant microbial infection as well as the significant role of fungal infections in the death toll of COVID-19, discovering new antifungals is extremely important. Natural and synthetic xanthones are promising derivatives, although only few reports have demonstrated their antifungal mechanism of action in detail. Newly synthetized by us xanthone derivative 44 exhibited strong antifungal activity against reference and fluconazole resistant C. albicans strains. Our results indicate that the most active compounds 42 and 44 are not substrates for fungal ABC transporters (Cdr1p and Cdr2p) and Mdr1p, the main representative of the major facilitator superfamily efflux pumps, membrane proteins that are responsible for the development of resistance. Moreover, fungicidal mode of action reduces the probability of persistent or recurrent infections and resistance development. In this light, the demonstrated killing activity of the examined derivatives is their undoubted advantage. Novel synthesized compounds exhibited moderate cytotoxicity against human cell lines, although the selectivity index value for human pathogenic strains remained favourable. Our results also indicate that novel synthetized compounds 42 and 44 with antifungal activity target yeast topoisomerase II activity. In summary, further validation of xanthones applicability as antifungals is highly valuable.
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COVID-19 , Xantonas , Humanos , Antifúngicos/química , Proteínas Fúngicas/metabolismo , Candida albicans/metabolismo , Fluconazol/farmacología , Xantonas/farmacología , Xantonas/metabolismo , Pruebas de Sensibilidad Microbiana , Farmacorresistencia FúngicaRESUMEN
Resveratrol, a naturally occurring stilbene, exhibits numerous beneficial health effects. Various studies have demonstrated its diverse biological actions, including anti-oxidant, anti-inflammatory, and anti-platelet properties, thereby supporting its potential for cardio protection, neuroprotection, and anti-cancer activity. However, a significant limitation of resveratrol is its weak bioavailability. To overcome this challenge, multiple research groups have investigated the synthesis of new resveratrol derivatives to enhance bioavailability and pharmacological activities. Nevertheless, there are limited data on the effects of resveratrol derivatives on platelet function. Therefore, the objective of this study was to synthesize resveratrol methoxy derivatives and evaluate their anti-platelet and anti-proliferative activity. Platelet-rich plasma (PRP) obtained from healthy volunteers was utilized to assess the derivatives' ability to inhibit platelet aggregation induced by platelet activating factor (PAF), adenosine diphosphate (ADP), and thrombin receptor activating peptide (TRAP). Additionally, the derivatives' anti-tumor activity was evaluated against the proliferation of PC-3 and HCT116 cells. The results revealed that some methoxy derivatives of resveratrol exhibited comparable or even superior anti-platelet activity compared to the original compound. The most potent derivative was the 4'-methoxy derivative, which demonstrated approximately 2.5 orders of magnitude higher anti-platelet activity against TRAP-induced platelet aggregation, indicating its potential as an anti-platelet agent. Concerning in silico studies, the 4'-methyl group of 4'-methoxy derivative is oriented similarly to the fluorophenyl-pyridyl group of Vorapaxar, buried in a hydrophobic cavity. In terms of their anti-tumor activity, 3-MRESV exhibited the highest potency in PC-3 cells, while 3,4'-DMRESV and TMRESV showed the greatest efficacy in HCT116 cells. In conclusion, methoxy derivatives of resveratrol possess similar or improved anti-platelet and anti-cancer effects, thereby holding potential as bioactive compounds in various pathological conditions.
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Plaquetas , Agregación Plaquetaria , Humanos , Resveratrol/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Pruebas de Función PlaquetariaRESUMEN
Hyperlipidemia results in endothelial dysfunction, which is intimately associated with disturbed mitochondrial homeostasis, and is a real risk factor for cardiovascular diseases (CVDs). Triphenylphosphonium (TPP+)-HT, constructed by linking a mitochondrial-targeting moiety TPP+ to hydroxytyrosol (HT), enters the cell and accumulates in mitochondria and is thus an important candidate drug for preventing hyperlipidemia-induced endothelial injury. In the present study, we found that TPP-HT has a better anti-inflammatory effect than HT. In vivo, TPP-HT significantly prevented hyperlipidemia-induced adverse changes in the serological lipid panel, as well as endothelial and mitochondrial dysfunction of the thoracic aorta. Similarly, in vitro, TPP-HT exhibited similar protective effects in palmitate (PA)-induced endothelial dysfunction, particularly enhanced expression of the mitochondrial ETC complex II, recovered FoxO1 expression in PA-injured human aorta endothelial cells (HAECs) and promoted FoxO1 nuclear translocation. We further demonstrated that FoxO1 plays a pivotal role in regulating ATP production in the presence of TPP-HT by using the siFoxO1 knockdown technique. Simultaneously, TPP-HT enhanced Nrf2 nuclear translocation, consistent with the in vivo findings of immunofluorescence, and the antioxidant effect of TPP-HT was almost entirely blocked by siNrf2. Concomitantly, TPP-HT's anti-inflammatory effects in the current study were primarily mediated via the p38 MAPK/NF-κB signaling pathway in addition to the FoxO1 and Nrf2 pathways. In brief, our findings suggest that mitochondria-targeted TPP-HT prevents lipotoxicity induced endothelial dysfunction by enhancing mitochondrial function and redox balance by promoting FoxO1 and Nrf2 nuclear translocation.
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Quantitation of chromophore-free analytes is always a challenge. To this purpose, derivatization of the analyte constitutes a common strategy, leading to a product with a strong signal. In the current study, a novel xanthone analogue was utilized for the first time for the derivatization of pregabalin, a model analyte with a primary amine moiety that lacks a chromophore. The fact that only the xanthene-based derivative, formed after the derivatization reaction fluoresces, enables avoiding its chromatographic separation from the reagent and thus reducing the analysis time of a series of samples in 1-2 min via a plate reader. The reaction conditions were optimized via a central composite design (CCD), with fluorescence signal as the measure of the yield. The following factors that affect the derivatization reaction were chosen: (a) temperature, (b) reaction time, and (c) triethylamine solution volume used to drive the reaction to completion. After the identification of the optimal conditions, the method was validated according to ICH guidelines, using a fluorescence plate reader for signal measurement (λex = 540, λem = 615 nm). Finally, the newly developed high-throughput method was applied to the determination of drug content in pregabalin bulk.
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Colorantes , Xantonas , Aminas , Indicadores y Reactivos , PregabalinaRESUMEN
Repurposing existing drugs, as well as natural and artificial sweeteners for novel therapeutic indications could speed up the drug discovery process since numerous associated risks and costs for drug development can be surpassed. In this study, natural and artificial sweeteners have been evaluated by in silico and experimental studies for their potency to inhibit lipoxygenase enzyme, an enzyme participating in the inflammation pathway. A variety of different methods pinpointed that aspartame inhibits the lipoxygenase isoform 1 (LOX-1). In particular, "LOX-aspartame" complex, that was predicted by docking studies, was further evaluated by Molecular Dynamics (MD) simulations in order to assess the stability of the complex. The binding energy of the complex has been calculated after MD simulations using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method. Furthermore, Quantum Mechanics/Molecular Mechanics (QM/MM) calculations have been applied for geometry optimization of the "enzyme-ligand" complex. After having fully characterized the "LOX-aspartame" complex in silico, followed in vitro biological assays confirmed that aspartame inhibits LOX-1 (IC50=50 ± 3.0 µΜ) and blocks its biological response. The atomic details of aspartame's interaction profile with LOX-1 were revealed through Saturation Transfer Difference (STD) NMR (Nuclear Magnetic Resonance). Finally, aspartame was also tested with Molecular Docking and Molecular Dynamics studies for its potent binding to a number of different LOX isoforms of many organisms, including human. The in silico methods indicated that aspartame could serve as a novel starting point for drug design against LOX enzyme. Communicated by Ramaswamy H. Sarma.
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Aspartame , Edulcorantes , Humanos , Simulación del Acoplamiento Molecular , Aspartame/farmacología , Simulación de Dinámica Molecular , Antiinflamatorios/farmacología , Lipooxigenasas , Receptores Depuradores de Clase ERESUMEN
In this study, a series of novel substituted pyrazolo[3,4-c]pyridin-5-ylamidines was synthesized and their cytotoxicity against three cancer cell lines (MDA-MB-231, HT-1080, PC-3), as well as a human normal cell line (AG01523) was evaluated. A number of derivatives could strongly reduce cancer cells proliferation and exhibit apoptotic induction capability, while reasonable structure-activity relationships could be extracted. Certain analogues were endowed with low toxicity against normal cells. Cell cycle analysis revealed that most of the active compounds induced a G0/G1 arrest of HT-1080 cells. Moreover, the potential mechanisms of the cytotoxic activity of the promising compounds were investigated in HT-1080 cells, upon study of their effects on the phosphorylation of Akt, ERK and p38 MAPK. Most of the active derivatives inhibit phosphorylation of Akt and ERK and/or induce p38 MAPK phosphorylation, providing a potential indication on the mode of action of this class.
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Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Several new amino-substituted aza-acridine derivatives bearing a basic side chain have been designed and synthesized. The antiproliferative activity of the target compounds has been evaluated against three cancer cell lines-namely HCT-116 (colorectal), the uterine sarcoma MES-SA, and its doxorubicin-resistant variant MES-SA/Dx5. A limited number of the new acridines showed marginal cytotoxicity against the tested cell lines; nevertheless, these analogues possessed a similar substitution pattern. The moderate biological activity of these derivatives was attributed to their instability in aqueous media, which has been studied by mass spectrometry and computational chemistry experiments at the density functional level of theory (DFT).
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Acridinas/química , Acridinas/farmacología , Compuestos Aza/química , Compuestos Aza/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Células HCT116 , Humanos , Sarcoma/tratamiento farmacológico , Neoplasias Uterinas/tratamiento farmacológicoRESUMEN
Oleocanthal and oleacein are known for a wide range of beneficial activities in human health and the prevention of diseases. The inability to isolate significant and pure amounts of these natural compounds and their demanding synthesis lead to the development of an efficient, five-step, three-pot procedure. The synthesis is performed by a convenient biomimetic approach, starting from oleuropein, an abundant raw material in olive leaves, through the mixed anhydride of oleoside. The method is stereocontrolled and provides an efficient approach to the synthesis of various oleocanthal analogues; thus, a small library of four compounds was prepared with 35-45% overall yield.
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Aldehídos/síntesis química , Monoterpenos Ciclopentánicos/síntesis química , Glucósidos Iridoides/química , Olea/química , Fenoles/síntesis química , Hojas de la Planta/química , Biomimética , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
BACKGROUND: Purine isosteres are often endowed with interesting pharmacological properties, due to their involvement in cellular processes replacing the natural purines. Among these compounds, pyrazolopyridines are under active investigation for potential anticancer properties. OBJECTIVES: Based on previously discovered substituted pyrazolopyridines with promising antiproliferative activity, we designed and synthesized new, suitably substituted analogues aiming to investigate their potential activity and contribute to SAR studies of this class of bioactive compounds. METHODS: The new compounds were synthesized using suitably substituted 2-amino-4-picolines, which upon ring-closure provided substituted pyrazolo[3,4-c] pyridine-5-carbonitriles that served as key intermediates for the preparation of the target 3,5,7 trisubstituted derivatives. The antiproliferative activity of 31 new target derivatives was evaluated against three cancer cell lines (MIA PaCa-2, PC-3 and SCOV3), whereas cell-cycle perturbations of exponentially growing PC-3 cells, using three selected derivatives were also performed. RESULTS: Eight compounds displayed IC50 values in the low µM range, allowing the extraction of interesting SAR's. Two of the most potent compounds against all cell lines share a common pattern, by accumulating cells at the G0/G1 phase. From this project, a new carboxamidine-substituted hit has emerged. CONCLUSION: Among the new compounds, those possessing the 3-phenylpyrazolo[3,4-c]pyridine scaffold, proved to be worth investigating and the majority of them showed strong cytotoxic activity against all cell lines, with IC50 values ranging from 0.87-4.3 µM. A carboxamidine analogue that resulted from the synthetic procedure, proved to be highly active against the cancer cells and could be considered as a useful lead for further optimization.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diseño de Fármacos , Piridinas/síntesis química , Piridinas/farmacología , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Técnicas de Química Sintética , Humanos , Piridinas/químicaRESUMEN
Hydroxytyrosol and two other polyphenols of olive tree, hydroxytyrosol acetate and 3,4-dihydroxyphenylglycol, are known for a wide range of beneficial activities in human health and prevention from diseases. The inability to isolate high, pure amounts of these natural compounds and the difficult and laborious procedures for the synthesis of them led us to describe herein an efficient, easy, cheap, and scaling up synthetic procedure, from catechol, via microwave irradiation.
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Técnicas de Química Sintética , Metoxihidroxifenilglicol/análogos & derivados , Alcohol Feniletílico/análogos & derivados , Técnicas de Química Sintética/métodos , Humanos , Metoxihidroxifenilglicol/síntesis química , Metoxihidroxifenilglicol/química , Estructura Molecular , Alcohol Feniletílico/síntesis química , Alcohol Feniletílico/químicaRESUMEN
Urinary bladder cancer is a common malignancy, being characterized by substantial patient mortality and management cost. Its high somatic-mutation frequency and molecular heterogeneity usually renders tumors refractory to the applied regimens. Hitherto, methotrexate-vinblastine-adriamycin-cisplatin and gemcitabine-cisplatin represent the backbone of systemic chemotherapy. However, despite the initial chemosensitivity, the majority of treated patients will eventually develop chemoresistance, which severely reduces their survival expectancy. Since chromatin regulation genes are more frequently mutated in muscle-invasive bladder cancer, as compared to other epithelial tumors, targeted therapies against chromatin aberrations in chemoresistant clones may prove beneficial for the disease. "Acetyl-chromatin" homeostasis is regulated by the opposing functions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The HDAC/SIRT (super-)family contains 18 members, which are divided in five classes, with each family member being differentially expressed in normal urinary bladder tissues. Since a strong association between irregular HDAC expression/activity and tumorigenesis has been previously demonstrated, we herein attempt to review the accumulated published evidences that implicate HDACs/SIRTs as critical regulators in urothelial bladder cancer. Moreover, the most extensively investigated HDAC inhibitors (HDACis) are also analyzed, and the respective clinical trials are also described. Interestingly, it seems that HDACis should be preferably used in drug-combination therapeutic schemes, including radiation.
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Carcinoma de Células Transicionales/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/enzimología , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Ensayos Clínicos como Asunto , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Neoplasias de la Vejiga Urinaria/enzimologíaRESUMEN
Fungal infections constitute an emerging threat and a prevalent health problem due to increasing number of immunocompromised people and pharmacological or other treatments aiming at viral infections, cancer or allergies. Currently used antifungals suffer from inefficiency, toxic side effects and developing drug-resistance. Additionally, over the last two decades no new classes of antifungals have been approved, emphasizing the urgent need for developing a novel generation of antifungals. Here, we investigate the antifungal activity of a series of chemically synthesized Hydroxytyrosol (HT) analogs. HT is one of the major phenolic compounds in olive oil, shown to possess radical-scavenging antioxidant, antiproliferative, proapoptotic and anti-inflammatory activities. No previous report has studied HT analogs as antifungals. We show that specific analogs have broad and strong antifungal activity, significantly stronger than the parent compound HT. Using Aspergillus nidulans as an in vivo cellular model system, we show that antifungal HT analogs have an unprecedented efficiency in fungal plasma membrane destruction. Importantly, antifungal HT analogs did not show toxicity in a mammalian cell line, whereas no resistance to HT analogs was obtained by standard mutagenesis. Our results open the way for the development of a novel, efficient and safer class of antifungals.
RESUMEN
OBJECTIVE: A series of novel 2,4-diaminosubstituted pyrrolo[3,2-d]pyrimidines was synthesized together with their corresponding 7-phenyl or 7-isopropyl counterparts. RESULTS: Among the target derivatives, the 7-substituted analogues exhibited interesting cytotoxic activity against a panel of PI3Kα related human breast cancer cell lines, namely MCF7, T47D, MDA-MB-231 and HCC1954. Selected compounds were tested for potential PI3Kα inhibitory activity as well as for their cytotoxic effect in prostate cancer cell lines (DU145 and PC3). CONCLUSION: Derivatives bearing a specific substitution pattern consisting of 7-phenyl as well as a 2-(4- aminocyclohexylamino) moiety (16c, 16f) display kinase inhibitory activity, elucidated on the basis of molecular simulation studies, which revealed their interaction with the DFG motif of the kinase.
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Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Aminación , Mama/efectos de los fármacos , Mama/metabolismo , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Masculino , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Próstata/efectos de los fármacos , Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
A number of new 3,7-disubstituted pyrazolo[3,4-c]pyridines have been designed and synthesized from suitable 2-aminopyridines. The antiproliferative activity of the derivatives was determined against the pancreatic MIA PaCa-2 and ovarian SCOV3 cancer cell-lines. IC50 values of the most promising analogue 46 lie in the submicromolar or low micromolar range. Furthermore, compound 46 shows similar inhibitory activities against DU145, A2058 and PC-3 cancer cells, blocks the cell cycle at the G0/G1 phase and induce apoptosis, as determined by the appearance of apoptotic nuclei.
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Pirazoles/química , Piridinas/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Espectroscopía de Resonancia Magnética , Pirazoles/farmacología , Piridinas/farmacologíaRESUMEN
Modified purine derivatives exemplified by pyrazolopyrimidines have emerged as highly selective inhibitors of several angiogenic receptor tyrosine kinases. Herein, we designed and synthesized a new series of substituted pyrazolopyridines and explored their ability to influence crucial pro-angiogenic attributes of endothelial cells. Four of the synthesized compounds, possessing analogous substitution pattern, were found able to inhibit at low micromolar concentrations endothelial cell proliferation, migration and differentiation, constitutively or in response to Vascular Endothelial Growth Factor (VEGF) and to attenuate VEGF-induced phosphorylation of VEGF receptor-2 and downstream kinases AKT and ERK1/2. Administration of effective compounds in mice delayed the growth of syngeneic Lewis lung carcinoma transplants and reduced tumor microvessel density, without causing toxicity. Genome-wide microarray and gene ontology analyses of treated endothelial cells revealed derivative 18c as the most efficient modulator of gene expression and "mitotic cell cycle/cell division" along with "cholesterol biosynthesis" as the most significantly altered biological processes.