RESUMEN
New thiazole-clubbed piperazine derivatives were designed, synthesized, evaluated for their inhibitory capabilities against human acetylcholinesterase and butyrylcholinesterase (hAChE and/or hBuChE) and ß-amyloid (Aß) aggregation, and investigated for their metal chelating potential as multitarget agents for the treatment of Alzheimer's disease. Compounds 10, 19-21, and 24 showed the highest hAChE inhibitory activity at submicromolar concentrations, of which compound 10 was the most potent with a half-maximal inhibitory concentration (IC50) value of 0.151 µM. Compounds 10 and 20 showed the best hBuChE inhibitory activities (IC50 values of 0.135 and 0.103 µM, respectively), in addition to remarkable Aß1-42 aggregation inhibitory activities and metal chelating capabilities. Both compounds were further evaluated against human neuroblastoma SH-SY5Y and PC12 neuronal cells, where they proved noncytotoxic at their active concentrations against hAChE or hBuChE. They also offered a significant neuroprotective effect against Aß25-35-induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Compound 10 displayed acceptable physicochemical properties and could pass the blood-brain barrier. The molecular docking study revealed the good binding interactions of compound 10 with the key amino acids of both the catalytic active site and the peripheral anionic site of hAChE, explaining its significant potency.
Asunto(s)
Acetilcolinesterasa , Enfermedad de Alzheimer , Péptidos beta-Amiloides , Inhibidores de la Colinesterasa , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Piperazinas , Tiazoles , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Estructura-Actividad , Tiazoles/farmacología , Tiazoles/síntesis química , Tiazoles/química , Piperazinas/farmacología , Piperazinas/síntesis química , Piperazinas/química , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Acetilcolinesterasa/metabolismo , Ratas , Estructura Molecular , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Células PC12 , Butirilcolinesterasa/metabolismo , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Simulación por ComputadorRESUMEN
A novel series of triazole-benzohydrazone hybrids was efficiently designed and synthesized as antiproliferative agents, targeting different kinases. All compounds were screened via the National Cancer Institute (NCI) against 60 cancer cell lines, where compounds 16, 17, and 18 exhibited growth inhibition percent (GI%) of various leukemia subpanels with values of 70.33%, 64.13%, and 76.03%, respectively. Compound 18 showed broad-spectrum antiproliferative efficacy toward most cancer cells, with outstanding potency regarding melanoma (MALME-3M GI% = 101.82%) and breast cancer cell lines (MCF7 GI% = 85.87%), while proving safe toward the WI-38 normal cell line, compared to doxorubicin. Multikinase investigation including vascular endothelial growth factor receptor 2 (VEGFR-2), mesenchymal epithelial transition factor (c-Met), proto-oncogene B-Raf, mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, and phosphoinositide 3-kinase was accomplished to reveal its plausible mechanism of action, giving the ultimate potency against both VEGFR-2 and c-Met with IC50 values of 0.055 and 0.042 µM, respectively, while displaying moderate to good inhibition concerning the remaining kinases. DNA binding capability was excluded using the methyl green colorimetric assay. Further, it exhibited both early and late apoptotic induction by about 16- and 9.4-fold over the control, respectively, triggering cell cycle arrest in the G2/M phase. Physicochemical properties and bioavailability radar plot inferred drug-likeness characteristics for compound 18. The molecular docking study assessed the binding pattern with the active sites of c-Met and VEGFR-2.
Asunto(s)
Antineoplásicos , Ácidos Triyodobenzoicos , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Triazoles/farmacología , Triazoles/química , Fosfatidilinositol 3-Quinasas/metabolismo , Factor A de Crecimiento Endotelial Vascular/farmacología , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Estructura MolecularRESUMEN
Certain sulfathiazole-triazolo chalcone hybrids were identified as anticancer agents with dual vascular endothelial growth factor receptor-2 (VEGFR-2)/epidermal growth factor receptor (EGFR) kinase inhibitory effect. All of the compounds were evaluated for their cytotoxic activity against the MCF-7 and HepG-2 tumor cell lines. Compounds 11g, 11h, and 11j exhibited the most potent antiproliferative activity against both cancer cell lines, with good safety toward WI-38 normal cells. Thus, they were further assessed for VEGFR-2 inhibitory activity. They have suppressed VEGFR-2 enzyme at IC50 of 0.316, 0.076, and 0.189 µM, respectively in comparison to sorafenib (IC50 = 0.035 µM). EGFR enzyme inhibition was further screened for the most potent inhibitors, 11h and 11j, where they displayed enhanced potency with IC50 of 0.085 and 0.108 µM, respectively, compared to erlotinib (IC50 = 0.037 µM). Compounds 11h and 11j were additionally investigated for inhibition of comparable kinases, PDGFR-ß and B-Raf, where results assessed adequate selectivity of both compounds toward the VEGFR-2 and EGFR kinases. Furthermore, the wound healing assay of compound 11h manifested a percent wound closure of 65.18% in MCF-7 cells compared to doxorubicin (58.51%) and untreated cells (97.77%), proving its antiangiogenic activity. The cell cycle assay of MCF-7 cells treated with 11h demonstrated cell cycle arrest at the S phase. Moreover, compound 11h induced apoptosis with a 44-fold increase compared to that induced in the control MCF-7 cells. Molecular docking results of compounds 11h and 11j established their efficacies, and in silico studies showed convenient safety profiles with drug-likeness properties.
Asunto(s)
Chalcona , Chalconas , Humanos , Chalconas/farmacología , Simulación del Acoplamiento Molecular , Factor A de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Relación Estructura-Actividad , Receptores ErbB , Células MCF-7 , Chalcona/farmacología , SulfatiazolesRESUMEN
Oral cancer is one of the most common cancer types. Many factors can express certain genes that cause the proliferation of oral tissues. Overexpressed genes were detected in oral cancer patients; three were highly impacted. FAP, FN1, and MMP1 were the targeted genes that showed inhibition results in silico by ginsenoside C and Rg1. Approved drugs were retrieved from the DrugBank database. The docking scores show an excellent interaction between the ligands and the targeted macromolecules. Further molecular dynamics simulations showed the binding stability of the proposed natural products. This work recommends repurposing ginsenoside C and Rg1 as potential binders for the selected targets and endorses future experimental validation for the treatment of oral cancer.
RESUMEN
Skin wound healing is one of the most challenging processes for skin reconstruction, especially after severe injuries. In our study, nanofiber membranes were prepared for wound healing using an electrospinning process, where the prepared nanofibers were made of different weight ratios of polycaprolactone and bioactive glass that can induce the growth of new tissue. The membranes showed smooth and uniform nanofibers with an average diameter of 118 nm. FTIR and XRD results indicated no chemical interactions of polycaprolactone and bioactive glass and an increase in polycaprolactone crystallinity by the incorporation of bioactive glass nanoparticles. Nanofibers containing 5% w/w of bioactive glass were selected to be loaded with atorvastatin, considering their best mechanical properties compared to the other prepared nanofibers (3, 10, and 20% w/w bioactive glass). Atorvastatin can speed up the tissue healing process, and it was loaded into the selected nanofibers using a dip-coating technique with ethyl cellulose as a coating polymer. The study of the in vitro drug release found that atorvastatin-loaded nanofibers with a 10% coating polymer revealed gradual drug release compared to the non-coated nanofibers and nanofibers coated with 5% ethyl cellulose. Integration of atorvastatin and bioactive glass with polycaprolactone nanofibers showed superior wound closure results in the human skin fibroblast cell line. The results from this study highlight the ability of polycaprolactone-bioactive glass-based fibers loaded with atorvastatin to stimulate skin wound healing.
RESUMEN
Polyetheretherketone (PEEK) polymer is a widely accepted implantable biomaterial in the biomedical field. However, PEEK has a low elastic modulus (E-modulus) as well as a bio-inert nature which is not conductive to rapid bone cell attachment, hence, producing delayed or weak bone-implant integration. Multiwalled carbon nanotubes (MWCNTs) represent one of the strongest known materials that could be added to a polymer to improve its mechanical properties. Bioactive glasses (BGs) can form hydroxyapatite deposits on their surfaces and form a tight bond with the bone, thus, their incorporation into the PEEK matrix may improve its bioactivity. METHODS: Eight groups were formulated according to the type and percentage of modification of PEEK by MWCNTs and BGs. Group 1: Pure PEEK (P), Group 2: P + 3% MWCNTs (PC3), Group 3: P + 5% MWCNTs (PC5), Group 4: P + 5% BGs (PG5), Group 5: P + 10% BGs (PG10), Group 6: P + 3% MWCNTs + 5% BGs (PC3G5), Group 7: P + 3% MWCNTs + 10% BGs (PC3G10), and Group 8: P + 5% MWCNTs + 5% BGs (PC5G5). Characterization of the vacuum-pressed PEEK and PEEK composite specimens was done using FE-SEM, EDS, FT-IR and TF-XRD. Three-point load test was done to obtain the flexural strength (F.S) and the E-modulus of the specimens. Wettability was determined by measuring the contact angle with distilled water. In-vitro bioactivity was determined after immersion of specimens in simulated body fluid (SBF). Moreover, the effect of the specimens on osteoblastic cell viability was evaluated. RESULTS: Three-point load test results have shown an improvement in both F.S. and E-modulus for groups PC5, PC3G5 and PC5G5. The lowest contact angle was obtained for group PC5G5 followed by the PC3G10 group. All specimens containing BGs showed the formation of hydroxyapatite-like deposits after their immersion in SBF, as well as an improvement in osteoblastic cell viability compared to PEEK. CONCLUSION: PC3G10, PC3G5 and PG10, groups are promising for the fabrication of patient-specific implants that can be used in low-stress-bearing areas.
Asunto(s)
Nanotubos de Carbono , Humanos , Espectroscopía Infrarroja por Transformada de Fourier , Polímeros , Polietilenglicoles/química , Cetonas/química , Durapatita/químicaRESUMEN
Multi-target inhibitors represent useful anticancer agents with superior therapeutic attributes. Here in, two novel series of benzimidazole-triazole hybrids were designed, synthesised as multi-target EGFR, VEGFR-2 and Topo II inhibitors, and evaluated for anticancer activity. Compounds 5a and 6g were the most potent analogues against four cancer cell lines, HepG-2, HCT-116, MCF-7 and HeLa, and were further evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 5a was especially good inhibitor for EGFR (IC50 = 0.086 µM) compared to Gefitinib (IC50 = 0.052 µM), moderate VEGFR-2 inhibitor (IC50 = 0.107 µM) compared to Sorafenib (IC50 = 0.0482 µM), and stronger Topo II inhibitor (IC50 = 2.52 µM) than Doxorubicin (IC50 = 3.62 µM). Compound 6g exhibited moderate EGFR and VEGFR-2 inhibition and weaker Topo II inhibition. DNA binding assay, cell cycle analysis, apoptotic induction, molecular docking, and physicochemical studies were additionally implemented to explore the plausible mechanism of the active compounds.
Asunto(s)
Antineoplásicos , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Estructura Molecular , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Triazoles/farmacología , Proliferación Celular , Antineoplásicos/farmacología , Antineoplásicos/química , Receptores ErbB/metabolismo , Bencimidazoles/farmacología , Bencimidazoles/química , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
N-rich organic materials bearing polyphenolic moieties in their building networks and nanoscale porosities are very demanding in the context of designing efficient biomaterials or drug carriers for the cancer treatment. Here, we report the synthesis of a new triazine-based secondary-amine- and imine-linked polyphenolic porous organic polymer material TrzTFPPOP and explored its potential for in vitro anticancer activity on the human colorectal carcinoma (HCT 116) cell line. This functionalized (-OH, -NH-, -C=N-) organic material displayed an exceptionally high BET surface area of 2140 m2 g-1 along with hierarchical porosity (micropores and mesopores), and it induced apoptotic changes leading to high efficiency in colon cancer cell destruction via p53-regulated DNA damage pathway. The IC30, IC50, and IC70 values obtained from the MTT assay are 1.24, 3.25, and 5.25 µg/mL, respectively.
Asunto(s)
Neoplasias Colorrectales , Polímeros , Humanos , Porosidad , Polímeros/farmacología , Células HCT116 , Portadores de Fármacos , Neoplasias Colorrectales/tratamiento farmacológicoRESUMEN
Targeted therapy has emerged to be the cornerstone of advanced cancer treatment, allowing for more selectivity and avoiding the common drug toxicity and resistance. Identification of potential targets having vital role in growth and survival of cancer cells got much easier with the aid of the recent advances in high throughput screening approaches. Various protein kinases came into focus as valuable targets in cancer therapy. Meanwhile, benzimidazole-based scaffolds have gained significant attention as promising protein kinase inhibitors with high potency and varied selectivity. Great diversity of these scaffolds has inspired the medicinal chemists to inspect the effect of structural changes upon inhibitory activity on the molecular level through modeling studies. The present review gathers all the considerable attempts to develop benzimidazole-based compounds; designed as protein kinase inhibitors with anticancer activity since 2015; that target aurora kinase, CDK, CK2, EGFR, FGFR, and VEGFR-2; to allow further development and progression regarding benzimidazoles.
Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Aurora Quinasas/metabolismo , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Receptores ErbB/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial VascularRESUMEN
Three series of new benzimidazole hybrids were designed and synthesized as promising human TopoII inhibitors. They were characterized by different spectroscopic techniques (1H, 13C NMR, ESI-MS and IR). All hybrids (6-23) were screened for their in vitro antiproliferative activity against five human cancer cell lines namely; HepG-2, MCF-7, PC-3, HCT-116 and Hela. Compound 21 showed the most potent anticancer activity against all cancer cell lines, with IC50 range of 2.82 to 12.59 µM, while proving safe towards normal cells WI-38 (IC50 = 31.89 µM) compared to the reference drug doxorubicin (IC50 = 6.72 µM). The most active candidates 13, 20, 21, 22 and 23 were further assessed for their human TopoII inhibition. The best of which, compounds 13 and 20 showed IC50 of 6.72 and 8.18 µM respectively compared to staurosporine (IC50 = 4.64 µM). Further mechanistic studies for compound 13 showed cell cycle arrest at S-phase by 51.29 % and a significant increase in the total apoptosis by 62.5 folds. Furthermore, apoptosis study proved that it induced apoptosis by decreasing both IAP and Bcl-2, activating caspases 3, 8 and 9, and increasing accumulation of ROS in HepG-2 cells. Besides, it decreased transcription factors' binding activity to DNA. Comparative molecular docking study was performed between the most potent TopoII inhibitors 13 and 20, and the least potent one 23 to relate the binding pattern with TopoII catalytic active site to the biological activity, where all results came in agreement with the biological results. Additional molecular modeling studies including surface mapping and contact preferences were performed to emphasize the importance of hydrophobicity. Physicochemical calculations were assessed where compounds 13 and 20 represented very promising orally active drug candidates.
Asunto(s)
Antineoplásicos , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Bencimidazoles/farmacología , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Imidazoles , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas , TiofenosRESUMEN
Based on modulation of the monastrol scaffold, two series of pyrimidinone derivatives, 3a-e and 5a-k, were designed, synthesized, and investigated for their in vitro anticancer activity. Compound 5j exhibited the most potent cytotoxic activity against four cancer cell lines, including HCT-116, HeLa, HEPG-2, and MCF-7, with IC50 values of 3.75-5.13 µM, while proving to be safe in the normal human cell line WI-38, with a selectivity index value of 13.7 on HCT-116 cells. Compounds 3d, 3e, and 5h-j were further assessed for their Eg5 inhibitory activity, where 3d and 5h-j showed high Eg5 inhibition with IC50 values of 28.48, 24.22, 18.90, and 12.89 µM, respectively, when compared to monastrol (IC50 = 14.89 µM). Cell cycle distribution of HCT-116 cells monitored with compound 5j illustrated that the cell cycle was arrested at the G2/M phase, with considerable apoptotic effect. A molecular docking study was performed to investigate the mode of action of the synthesized anticancer agents as Eg5 inhibitors.
Asunto(s)
Antineoplásicos , Pirimidinonas , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirimidinas , Pirimidinonas/farmacología , Relación Estructura-Actividad , TionasRESUMEN
Three-dimensional (3D) matrices scaffolds play a noteworthy role in promoting cell generation and propagation. In this study, scaffolds prepared from chitosan/polyvinyl alcohol loaded with/without an osteoporotic drug (risedronate) and nano-bioactive glass (nBG) have been developed to promote healing of bone defects. The scaffolds were characterized by scanning electron microscopy (SEM), porosity test as well as mechanical strength. The pattern of drug release and ability to promote the proliferation of Saos-2osteosarcoma cells had also been reported. Osteogenic potential of the scaffolds was evaluated by testing their effect on healing critical-sized dog's mandibular bone defects. Increasing chitosan and nBG in the porous scaffolds induced decrease in drug release, increased the scaffold's strength and supported their cell proliferation, alkaline phosphatase (ALP) activities, as well as increased calcium deposition. Histological and histomorphometric results demonstrated newly formed bone trabeculae inside critical-sized mandibular defects when treated with scaffolds. Trabecular thickness, bone volume/tissue volume and the percentage of mature collagen fibers increased in groups treated with scaffolds loaded with 10% nBG and risedronate or loaded with 30% nBG with/without risedronate compared with those treated with non-loaded scaffolds and empty control groups. These findings confirmed the potential osteogenic activity of chitosan/polyvinyl alcohol-based scaffolds loaded with risedronate and nBG.
Asunto(s)
Preparaciones Farmacéuticas , Andamios del Tejido , Animales , Perros , Vidrio , Osteogénesis , Porosidad , Ácido RisedrónicoRESUMEN
Nano-fiber composites have shown promising potential in biomedical and biotechnological applications. Herein, novel nano-fiber composites constituting a blend of polyvinyl alcohol (PVA) and chitosan (CS) along with different weight ratios of nano-bioactive glass (BG) were prepared by electrospinning. Nano-fibers incorporating 10% (by wt.) of BG were uniform, dense and defect-free with a diameter of 20-125 nm. The model osteoporotic drug (Risedronate sodium) was blended with the electrospinning forming solution and the in-vitro drug release was further studied. About 30% of the drug was released after only 30 min and the release pattern was sustained over 96 h. Drug release took place through a two-stage intra-particle diffusion mechanism. BG-incorporated nano-fibers markedly retarded the drug release profile relative to their BG-free counterparts. They also enhanced the drug release efficiency by releasing 93 ± 4% of the drug. The developed nano-fiber composites can be potentially used as drug-delivery vehicles due to their efficiency and sustained drug release capacity.
Asunto(s)
Quitosano/química , Nanocompuestos/química , Alcohol Polivinílico/química , Preparaciones de Acción Retardada/química , Vidrio/químicaRESUMEN
This work investigates the bioactivity of novel silver-doped (BG-Ag) and gold-doped (BG-Au) quaternary 46S6 bioactive glasses synthesized via a semi-solid-state technique. A pseudo-second-order kinetic model successfully predicted the in vitro uptake kinetic profiles of the initial ion-exchange release of Ca in simulated body fluid, the subsequent Si release, and finally, the adsorption of Ca and P onto the bioactive glasses. Doping with silver nanoparticles enhanced the rate of P uptake by up to approximately 90%; whereas doping with gold nanoparticles improved Ca and P uptake rates by up to about 7 and 2 times, respectively; as well as Ca uptake capacity by up to about 19%. The results revealed that the combined effect of Ca and Si release, and possibly the release of silver and gold ions into solution, influenced apatite formation due to their effect on Ca and P uptake rate and capacity. In general, gold-doped bioactive glasses are favoured for enhancing Ca and P uptake rates in addition to Ca uptake capacity. However, silver-doped bioactive glasses being less expensive can be utilized for applications targeting rapid healing. In vitro studies showed that BG, BG-Ag and BG-Au had no cytotoxic effects on osteosarcoma MG-63 cells, while they exhibited a remarkable cell proliferation even at low concentration. The prepared bioactive glass doped with noble metal nanoparticles could be potentially used in bone regeneration applications.
RESUMEN
Three new series of phenyl dihydropyridazinone derivatives 4b-8i have been designed, synthesized and evaluated for their anticancer activity against different cancer cell lines. Nine compounds showed strong inhibitory activity, among which compound 8b exhibited potent activity against PC-3 cell line with IC50 value of 7.83 µM in comparison to sorafenib (IC50 11.53 µM). Compounds 6a, 6c, 7f-h and 8a-d were further screened for their B-Raf inhibitory activity where seven compounds 7f-h and 8a-d showed high B-Raf inhibition with ranges of IC50 values 70.65-84.14 nM and 24.97-44.60 nM, respectively when compared to sorafenib (IC50 44.05 nM). Among the tested compounds, 8b was the most potent B-Raf inhibitor with IC50 value of 24.79 nM. Cell cycle analysis of MCF-7 cells treated with 8b showed cell cycle arrest at G2-M phase with significant apoptotic effect. Molecular modeling study was performed to understand the binding mode of the most active synthesized compounds with B-Raf enzyme.
Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Piridazinas/uso terapéutico , Antineoplásicos/farmacología , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Piridazinas/farmacología , Relación Estructura-ActividadRESUMEN
In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing.
Asunto(s)
Conservadores de la Densidad Ósea/síntesis química , Quitosano/síntesis química , Composición de Medicamentos/métodos , Nanopartículas/química , Clorhidrato de Raloxifeno/síntesis química , Tibia/efectos de los fármacos , Animales , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/metabolismo , Regeneración Ósea/efectos de los fármacos , Regeneración Ósea/fisiología , Quitosano/administración & dosificación , Quitosano/metabolismo , Modelos Animales de Enfermedad , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Implantes de Medicamentos/administración & dosificación , Implantes de Medicamentos/síntesis química , Implantes de Medicamentos/metabolismo , Vidrio/química , Masculino , Nanopartículas/administración & dosificación , Nanopartículas/metabolismo , Clorhidrato de Raloxifeno/administración & dosificación , Clorhidrato de Raloxifeno/metabolismo , Ratas , Ratas Sprague-Dawley , Tibia/lesiones , Tibia/metabolismo , Resultado del TratamientoRESUMEN
Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries.
Asunto(s)
Conservadores de la Densidad Ósea/administración & dosificación , Portadores de Fármacos/química , Implantes de Medicamentos/administración & dosificación , Fracturas Osteoporóticas/tratamiento farmacológico , Clorhidrato de Raloxifeno/administración & dosificación , Animales , Conservadores de la Densidad Ósea/farmacocinética , Huesos/efectos de los fármacos , Huesos/lesiones , Química Farmacéutica , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Implantes de Medicamentos/farmacocinética , Liberación de Fármacos , Humanos , Inyecciones Intralesiones , Masculino , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Porosidad , Clorhidrato de Raloxifeno/farmacocinética , Ratas , Propiedades de SuperficieRESUMEN
New quinolines substituted with various heterocycles and chalcone moieties were synthesized and evaluated as antitumor agents. All the synthesized compounds were in vitro screened against 60 human cancer cell lines. Compound 13 showed the highest cytotoxicity toward 58 cell lines, exhibiting distinct growth inhibition values (GI50 ) against the majority of them, including SR, HL-60 (TB) strains (leukemia), and MDA-MB-435 strains (melanoma), with GI50 values of 0.232, 0.260, and 0.300 µM, respectively. It exhibited great selectivity toward cancer cell lines, with less toxic effect against normal cells represented by skin fibroblast (BJ) and breast epithelial cell lines (MCF-10F). The enzyme inhibitory activity of compound 13 was evaluated against topoisomerase 1 (Topo 1), epidermal growth factor receptor and vascular endothelial growth factor receptor 2, where it displayed worthy Topo 1 inhibition activity with an IC50 value of 0.278 µM compared with camptothecin as a reference drug (IC50 0.224 µM). Docking studies were performed to investigate the recognition profile of compound 13 with the Topo 1 enzyme binding site.
Asunto(s)
Antineoplásicos/farmacología , ADN-Topoisomerasas de Tipo I/metabolismo , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Quinolinas/farmacología , Inhibidores de Topoisomerasa I/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Programas Informáticos , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/químicaRESUMEN
Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. All the new compounds were screened for their cytotoxic activity against A549 cancer cell line and VEGFR-2 inhibitory activity. Compounds 7h, 9a and 9l showed potent inhibitory activity against VEGFR-2 kinase with IC50 values of 87, 27 and 94â¯nM, respectively in comparison to sorafenib (IC50â¯=â¯180â¯nM) as a reference. Compounds 7h, 9a and 9l were further screened for their antitumor activity against specific resistant human cancer cell lines from different origins (Panc-1, OVCAR-3, HT29 and 786-O cell lines) where compound 7h showed significant cell death in most of them. Multi-kinase inhibition assays were performed for the most potent VEGFR-2 inhibitors where compound 7h showed enhanced potency towards EGFR, HER-2, c-MET and MER kinases. Cell cycle analysis of A549â¯cells treated with 9a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Ácidos Picolínicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Three new series of 2-phenyl benzimidazole-based derivatives were designed, synthesized, and evaluated for their in vitro cytotoxic activity against breast cancer (MCF-7) cell lines. Three compounds 8, 9, and 15 showed high cytotoxic activities, with IC50 values of 3.37, 6.30, and 5.84 µM, respectively, while they showed comparable cytotoxicity to the standard drug doxorubicin against human normal cells, including nontumorigenic breast epithelial cell line (MCF-10F), skin fibroblast cell line (BJ), and lung fibroblast cell line (MRC-5). Six of the synthesized compounds were screened against vascular endothelial growth factor receptor 2 (VEGFR-2) where compounds 8, 9, 12, and 15 exhibited an outstanding potency in comparison with sorafenib, with IC50 values of 6.7-8.9 nM. Molecular docking study assessed the good binding patterns of the most potent compounds with the reported conserved amino acids of VEGFR-2 active site.