scholarly journals Synthesis, Biological Evaluation and Docking Studies of Chalcone and Flavone Analogs as Antioxidants and Acetylcholinesterase Inhibitors

2019 ◽  
Vol 9 (3) ◽  
pp. 410 ◽  
Author(s):  
Laura Díaz-Rubio ◽  
Rufina Hernández-Martínez ◽  
Arturo Estolano-Cobián ◽  
Daniel Chávez-Velasco ◽  
Ricardo Salazar-Aranda ◽  
...  
Keyword(s):  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
Biological Evaluation ◽  
Chemotherapeutic Agents ◽  
Acetylcholinesterase Inhibition ◽  
Ache Inhibitors ◽  
Antioxidant Agents ◽  
Wide Range ◽  
Β Carotene

Several oxidative processes are related to a wide range of human chronic and degenerative diseases, like Alzheimer’s disease, which also has been related to cholinergic processes. Therefore, search for new or improved antioxidant molecules with acetylcholinesterase activity is essential to offer alternative chemotherapeutic agents to support current drug therapies. A series of chalcone (2a–2k) and flavone (3a–3k) analogs were synthesized, characterized, and evaluated as acetylcholinesterase (AChE) inhibitors, and antioxidant agents using 1,1-diphenyl-2-picrylhydrazyl (DPPH•), 2-2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS•), and β-carotene/linoleic acid bleaching assay. Compounds more active were 3j and 2k in DPPH with EC50 of 1 × 10−8 and 5.4 × 10−3 μg/mL, respectively; 2g and 3i in ABTS (1.14 × 10−2 and 1.9 × 10−3 μg/mL); 2e, 2f, 3f, 2j, and 3j exceeded the α-tocopherol control in the β-carotene assay (98–99% of antioxidant activity). At acetylcholinesterase inhibition assay, flavones were more active than chalcones; the best results were compounds 2d and 3d (IC50 21.5 and 26.8 µg/mL, respectively), suggesting that the presence of the nitro group enhances the inhibitory activity. The docking of these two structures were made to understand their interactions with the AChE receptor. Although further in vivo testing must be performed, our results represent an important step towards the identification of improved antioxidants and acetylcholinesterase inhibitors.

scholarly journals Emerging Molecular Receptors for the Specific-Target Delivery of Ruthenium and Gold Complexes into Cancer Cells

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3153
Author(s):  
João Franco Machado ◽  
João D. G. Correia ◽  
Tânia S. Morais
Keyword(s):  
Progesterone Receptors ◽  
Biological Evaluation ◽  
Cell Organelles ◽  
Gold Complexes ◽  
Main Research ◽  
Wide Range ◽  
Cancer Types ◽  
Organometallic Molecules ◽  
G Protein Coupled

Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.

scholarly journals Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1284 ◽  
Author(s):  
Guerini ◽  
Triggiani ◽  
Maddalo ◽  
Bonù ◽  
Frassine ◽  
...  
Keyword(s):  
Current Literature ◽  
Single Agent ◽  
Drug Repurposing ◽  
Chemotherapeutic Agents ◽  
Metastatic Spread ◽  
Multi Drug Resistance ◽  
Wide Range ◽  
Disease Site

Anticancer treatment efficacy is limited by the development of refractory tumor cells characterized by increased expression and activity of mechanisms promoting survival, proliferation, and metastatic spread. The present review summarizes the current literature regarding the use of the anthelmintic mebendazole (MBZ) as a repurposed drug in oncology with a focus on cells resistant to approved therapies, including so called “cancer stem cells”. Mebendazole meets many of the characteristics desirable for a repurposed drug: good and proven toxicity profile, pharmacokinetics allowing to reach therapeutic concentrations at disease site, ease of administration and low price. Several in vitro studies suggest that MBZ inhibits a wide range of factors involved in tumor progression such as tubulin polymerization, angiogenesis, pro-survival pathways, matrix metalloproteinases, and multi-drug resistance protein transporters. Mebendazole not only exhibits direct cytotoxic activity, but also synergizes with ionizing radiations and different chemotherapeutic agents and stimulates antitumoral immune response. In vivo, MBZ treatment as a single agent or in combination with chemotherapy led to the reduction or complete arrest of tumor growth, marked decrease of metastatic spread, and improvement of survival. Further investigations are warranted to confirm the clinical anti-neoplastic activity of MBZ and its safety in combination with other drugs in a clinical setting.

scholarly journals Phytochemical Characterization and Biological Evaluation of the Aqueous and Supercritical Fluid Extracts from Salvia sclareoides Brot

2017 ◽  
Vol 15 (1) ◽  
pp. 82-91
Author(s):  
Daniela Batista ◽  
Pedro L. Falé ◽  
Maria L. Serralheiro ◽  
Maria-Eduarda Araújo ◽  
Catarina Dias ◽  
...  
Keyword(s):  
Linoleic Acid ◽  
Supercritical Fluid ◽  
Antioxidant Properties ◽  
Biological Properties ◽  
Biological Evaluation ◽  
Cyclooxygenase 1 ◽  
Wide Range ◽  
Anti Inflammatory ◽  
Β Carotene

AbstractPlants belonging to the genus Salvia (Lamiaceae) are known to have a wide range of biological properties. In this work, extracts obtained from the aerial parts of Salvia sclareoides Brot. were evaluated to investigate their chemical composition, toxicity, bioactivity, and stability under in vitro gastrointestinal conditions. The composition of the supercritical fluid extract was determined by GC and GC-MS, while the identification of the infusion constituents was performed by HPLC-DAD and LC-MS. The in vitro cytotoxicity of both extracts (0-2 mg/mL) was evaluated in Caco-2 cell lines by the MTT assay. The anti-inflammatory and anticholinesterase activities were determined through the inhibition of cyclooxygenase-1 and acetylcholinesterase enzymes, while β-carotene/linoleic acid bleaching test and the DPPH assays were used to evaluate the antioxidant activity. The infusion inhibited cyclooxygenase-1 (IC50 = 271.0 μg/mL), and acetylcholinesterase (IC50 = 487.7 μg/ mL) enzymes, also demonstrated significant antioxidant properties, as evaluated by the DPPH (IC50 = 10.4 μg/mL) and β-carotene/linoleic acid (IC50 = 30.0 μg/mL) assays. No remarkable alterations in the composition or in the bioactivities of the infusion were observed after in vitro digestion, which supports the potential of S. sclareoides as a source of bioactive ingredients with neuroprotective, anti-inflammatory and antioxidant properties.

scholarly journals Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 920
Author(s):  
Xiaoyan Chen ◽  
Angela Winstead ◽  
Hongtao Yu ◽  
Jiangnan Peng
Keyword(s):  
Drug Resistance ◽  
Mechanism Of Action ◽  
Covalent Binding ◽  
Chemotherapeutic Agents ◽  
Stabilizing Agents ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Wide Range ◽  
Unique Mechanism

Microtubule stabilizing agents, such as paclitaxel, docetaxel, and cabazitaxel have been among the most used chemotherapeutic agents in the last decades for the treatment of a wide range of cancers in the clinic. One of the concerns that limit their use in clinical practice is their intrinsic and acquired drug resistance, which is common to most anti-cancer chemotherapeutics. Taccalonolides are a new class of microtubule stabilizers isolated from the roots of a few species in the genus of Tacca. In early studies, taccalonolides demonstrated different effects on interphase and mitotic microtubules from those of paclitaxel and laulimalide suggesting a unique mechanism of action. This prompts the exploration of new taccalonolides with various functionalities through the identification of minor constituents of natural origin and semi-synthesis. The experiments on the new highly potent taccalonolides indicated that taccalonolides possessed a unique mechanism of covalently binding to the microtubule. An X-ray diffraction analysis of a crystal of taccalonolides AJ binding to tubulin indicated that the covalent binding site is at β-tubulin D226. Taccalonolides circumvent all three mechanisms of taxane drug resistance both in vitro and in vivo. To improve the activity, the structure modification through semi-synthesis was conducted and the structure-activity relationships (SARs) was analyzed based on natural and semi-synthetical taccalonolides. The C22–C23 epoxide can significantly increase the antiproliferation potency of taccalonolides due to the covalent link of C22 and the carboxylic group of D226. Great progress has been seen in the last few years in the understanding of the mechanism of this class of microtube-stabilizing agents. This review summarizes the structure diversity, structure-activity relationships (SARs), mechanism of action, and in vivo activities of taccalonolides.

scholarly journals Microfluidics-Assisted Size Tuning and Biological Evaluation of PLGA Particles

2019 ◽  
Author(s):  
Maria Camilla Operti ◽  
Yusuf Dölen ◽  
Jibbe Keulen ◽  
Eric A.W. van Dinther ◽  
Carl G. Figdor ◽  
...  
Keyword(s):  
Particle Size ◽  
Suppressor Cells ◽  
Drug Carriers ◽  
Production Method ◽  
Biological Evaluation ◽  
Particle Uptake ◽  
Wide Range ◽  
Formulation Parameters

Polymeric particles made up of biodegradable and biocompatible polymers such as poly(lactic-co-glycolic acid) (PLGA) are promising tools for several biomedical applications including drug delivery. Particular emphasis is placed on the size and surface functionality of these systems as they are regarded as the main protagonists in dictating the particle behavior in vitro and in vivo. Current methods of manufacturing polymeric drug carriers offer a wide range of achievable particle sizes, however, they are unlikely to accurately control the size while maintaining the same production method and particle uniformity, as well as final production yield. Microfluidics technology has emerged as an efficient tool to manufacture particles in a highly controllable manner. Here, we report on tuning the size of PLGA particles at diameters ranging from sub-micron to microns using a single microfluidics device, and demonstrate how particle size influences the release characteristics, cellular uptake and in vivo clearance of these particles. Highly controlled production of PLGA particles with ~100 nm, ~200 nm and >1000 nm diameter is achieved through modification of flow and formulation parameters. Efficiency of particle uptake by dendritic cells and myeloid-derived suppressor cells isolated from mice is strongly correlated with particle size and is most efficient for ~100 nm particles. Particles systemically administered to mice mainly accumulate in liver and ~100 nm particles are cleared slower. Our study shows the direct relation between the particle size varied through microfluidics and the pharmacokinetics behavior of particles, which provides a further step towards the establishment of a customizable production process to generate tailor-made nanomedicines.

Cytotoxic Stilbenes and Derivatives as Promising Antimitotic Leads for Cancer Therapy

2019 ◽  
Vol 24 (36) ◽  
pp. 4270-4311 ◽  
Author(s):  
Célia Faustino ◽  
Ana P. Francisco ◽  
Vera M. S. Isca ◽  
Noélia Duarte
Keyword(s):  
Cancer Therapy ◽  
Targeted Delivery ◽  
Biological Evaluation ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Stable Configuration ◽  
Antiangiogenic Agents ◽  
Antitumor Effects

The growing incidence of cancer, the toxic side-effects associated with conventional chemotherapeutic agents and the development of multidrug resistance (MDR) drive the search for novel and more effective drugs with multi-target activity and selectivity towards cancer cells. Stilbenes are a group of naturally occurring phenolic compounds of plant origin derived from the phenylpropanoid pathway that may exist as cis- or trans-isomers. Although the trans-isomer is the more common and stable configuration, resveratrol being a representative compound, cis-stilbenes are potent cytotoxic agents that bind to and inhibit tubulin polymerization, destabilizing microtubules. This review summarizes the chemistry and biological evaluation of cytotoxic stilbenes and their synthetic derivatives as promising antimitotic leads for cancer therapy, focusing on the most potent compounds, the combretastatins. Combretastatins isolated from the South African bushwillow Combretum caffrum are among the most potent antimitotic and vascular disrupting agents (VDAs) of natural origin. Preclinical studies have demonstrated their potent antitumor effects in a wide variety of tumors, both in vitro and in vivo, being currently under evaluation in phase 2 and phase 3 clinical trials for several types of solid tumors. Topics covered herein include synthetic medicinal chemistry, modes of action, structure-activity relationships (SAR), preclinical and clinical studies as VDAs in cancer therapy, either as single agents or in combination with cytotoxic anticancer drugs, antiangiogenic agents, or radiation therapy, and development of appropriate formulations based on nanocarriers (e.g., liposomes, nanoemulsions, polymeric, lipid and ceramic nanoparticles, carbon nanotubes) for improved bioavailability and targeted delivery of combretastatins to the tumor vasculature.

scholarly journals 2-Arylidene-1-indandiones as Pleiotropic Agents with Antioxidant and Inhibitory Enzymes Activities

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4411 ◽  
Author(s):  
Olympia Kouzi ◽  
Eleni Pontiki ◽  
Dimitra Hadjipavlou-Litina
Keyword(s):  
Antioxidant Activities ◽  
Biological Activities ◽  
Knoevenagel Reaction ◽  
The Novel ◽  
Hydrophobic Domain ◽  
Antioxidant Agents ◽  
Wide Range ◽  
Anti Inflammatory

Indandiones are a relatively new group of compounds presenting a wide range of biological activities. The synthesis of these compounds was performed via a Knoevenagel reaction between an aldehyde and 1,3-indandione and were obtained with a yield up to 54%. IR, 1H-Nucleic Magnetic Resonance (NMR), 13C-NMR, LC/MS ESI+ and elemental analysis were used for the confirmation of the structures of the novel derivatives. Lipophilicity values of compounds were calculated theoretically and experimentally by reversed chromatography method as values RM. The novel derivatives were studied through in vitro and in vivo experiments for their activity as anti-inflammatory and antioxidant agents and as inhibitors of lipoxygenase, trypsin, and thrombin. The inhibition of the carrageenin-induced paw edema (CPE) was also determined for representative structures. In the above series of experiments, we find that all the compounds showed moderate to satisfying interaction with the stable DPPH free radical in relation to the concentration and the time 2-arylidene-1-indandione (10) was the strongest. We observed moderate or very low antioxidant activities for selected compounds in the decolorization assay with ABTS+•. Most of the compounds showed high anti-lipid peroxidation of linoleic acid induced by AAPH.2-arylidene-1-indandione (7) showed a strongly inhibited soybean LOX. Only 2-arylidene-1-indandione (3) showed moderate scavenging activity of superoxide anion, whereas 2-arylidene-1-indandione (8) and 2-arylidene-1-indandione (9) showed very strong inhibition on proteolysis. 2-arylidene-1-indandione (8) highly inhibited serine protease thrombin. 2-arylidene-1-indandiones (7, 8 and 9) can be used as lead multifunctional molecules. The compounds were active for the inhibition of the CPE (30–57%) with 2-arylidene-1-indandione (1) being the most potent (57%). According to the predicted results a great number of the derivatives can cross the Blood–Brain Barrier (BBB), act in CNS and easily transported, diffused, and absorbed. Efforts are conducted a) to correlate quantitatively the in vitro/in vivo results with the most important physicochemical properties of the structural components of the molecules and b) to clarify the correlation of actions among them to propose a possible mechanism of action. Hydration energy as EHYDR and highest occupied molecular orbital (HOMO) better describe their antioxidant profile whereas the lipophilicity as RM values governs the in vivo anti-inflammatory activity. Docking studies are performed and showed that soybean LOX oxidation was prevented by blocking into the hydrophobic domain the substrates to the active site.

scholarly journals Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors

Molecules ◽  
2016 ◽  
Vol 21 (2) ◽  
pp. 193 ◽  
Author(s):  
Susimaire Mantoani ◽  
Talita Chierrito ◽  
Adriana Vilela ◽  
Carmen Cardoso ◽  
Ana Martínez ◽  
...  
Keyword(s):  
Binding Site ◽  
Neurodegenerative Disorder ◽  
Acetylcholinesterase Inhibitors ◽  
Synaptic Cleft ◽  
Biological Evaluation ◽  
Ache Inhibitor ◽  
Synthetic Approach ◽  
Chemical Library ◽  
Ache Inhibitors ◽  
Ic50 Values

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the β-amyloid (Aβ) protein, acting as a chaperone and increasing the number and neurotoxicity of Aβ fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with Aβ, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC50 values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization.

Isolation and preliminary characterization of ACNUresistant sublines of rat brain tumors in vivo

1992 ◽  
Vol 77 (3) ◽  
pp. 451-456 ◽  
Author(s):  
T. Ken Yoshida ◽  
Keiji Shimizu ◽  
Athanasios Koulousakis ◽  
Volker Sturm ◽  
Emile Beuls
Keyword(s):  
Brain Tumors ◽  
Rat Brain ◽  
Cell Lines ◽  
Resistant Cell ◽  
Chemotherapeutic Agents ◽  
Cross Resistance ◽  
Chemical Structures ◽  
Wide Range

✓ Two variant cells lines resistant to the nitrosourea derivative ACNU ((1-4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride), namely C6/ACNU and 9L/ACNU, were selected in vivo from rat brain tumors. Stable resistance to ACNU proved to be a characteristic of these cell lines, whether they were grown in vivo or in vitro. These cell lines exhibited a different pattern of cross-resistance to a wide range of chemotherapeutic agents with dissimilar chemical structures and mechanisms of action as compared with that of other ACNU-resistant cell lines established in vitro. Distinct cross-resistance was observed in both the C6/ACNU and 9L/ACNU cell lines to chloroethyl-nitrosoureas such as BCNU (carmustine), CCNU (lomustine), and methyl CCNU and, additionally, to vincristine, vinblastine, Adriamycin (doxorubicin), and arabinosylcytosine, but not to bleomycin, methotrexate, c/s-platinum, and 5-fluorouracil. This might point to a multifactorial mechanism of drug resistance in ACNU-resistant cell lines derived from rat C6 and 9L brain tumor cells.

Dextrins as Carriers for Drug Targeting: Reproducible Succinoylation as a Means to Introduce Pendant Groups

2001 ◽  
Vol 16 (5) ◽  
pp. 353-365 ◽  
Author(s):  
Dale Hreczuk-Hirst ◽  
Lisa German ◽  
Ruth Duncan
Keyword(s):  
Reaction Time ◽  
Drug Carrier ◽  
Biological Evaluation ◽  
Chemotherapeutic Agents ◽  
Reaction Conditions ◽  
Dialysis Solution ◽  
Polymeric Drug ◽  
Peritoneal Dialysis Solution

Dextrin (a-1,4 polyglucose) is in clinical use as a peritoneal dialysis solution and controlled drug delivery formulation. As a biodegradable polymer, dextrin has considerable potential as a polymeric drug carrier. Succinoylation, using dimethylaminopyridine (DMAP) as a catalyst, was used to conjugate chemotherapeutic agents, probes to follow biodistribution and probes to monitor intracellular fate. The aims of this study were to optimize the reaction conditions for the succinoylation (in respect of temperature and reaction time), to assess the suitability of succinoylated-dextrin as an intermediate for conjugation of drugs and probes selected to monitor pharmacokinetics (doxorubicin, tyrosinamide and biotin). The optimum temperature for succinoylation was 500C with a minimum of 8 h reaction time. Under these conditions succinoylation was reproducible with a coefficient of variation of < 10% and always gave a -50% yield. Different degrees of dextrin succinoylation (0.5-30 mol%) was achieved by variation of the reactants. Conjugation of doxorubicin to the succinoylated dextrin intermediate (15 or 34 mol%) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysulfosuccinimde (sulfo-NHS) reproducibly gave conjugates containing-9.0 wt% with < 1% of the total doxorubicin present as free drug. Tyrosinamide and biotin were bound to the succinoylated intermediate using carbodiimidazole (CDI). Dextrin-tyrosinamide conjugates were -1 mol% modified and the dextrin-biotin conjugates containing 6.8 wt% biotin. Succinoylation of dextrin is a non-polymer-disruptive method that can be used to reproducibly introduce pendant groups. The resultant conjugates are suitable for biological evaluation in in vitro and in vivo.

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