scholarly journals SULFATION PATHWAYS: Potential benefits of a sulfated resveratrol derivative for topical application

2018 ◽  
Vol 61 (2) ◽  
pp. M27-M39 ◽  
Author(s):  
Marta Correia-da-Silva ◽  
Verónica Rocha ◽  
Cláudia Marques ◽  
Cláudia M Deus ◽  
Adriana Marques-Carvalho ◽  
...  
Keyword(s):  
Protein Content ◽  
Topical Application ◽  
In Silico ◽  
Water Solubility ◽  
Hacat Cell ◽  
Binding Free Energy ◽  
Water Soluble ◽  
Sirtuin 1 ◽  
Trypan Blue Exclusion

Resveratrol (RSV) is a polyphenolic compound with antioxidant, anti-inflammatory and anti-aging properties partly associated with sirtuin 1 (SIRT1)-activation in the skin. However, poor water solubility may limit RSV efficacy. This work aimed to clarify the interest of a new synthetic water-soluble RSV derivative (resveratrol glucoside sulfate, RSV-GS) for topical application. Resveratrol glucoside sulfate was synthesized using microwave-assisted sulfation. Cytotoxicity assays were performed with the keratinocyte HaCaT cell line, using MTT reduction, neutral red uptake, Alamar Blue/resazurin reduction, trypan blue exclusion and measurement of ATP concentration. Western blotting was used to evaluate SIRT1 protein content. Regarding SIRT1 binding, an in silico docking study was performed, using AutoDock Vina. Our results showed that the synthetic derivative RSV-GS was 1000 times more soluble in water than RSV and its non-sulfated glucoside. No relevant decrease in HaCaT cell viability was observed for concentrations up to 5 mM for RSV-GS, and up to 500 μM for resveratrol glucoside, while a significant decrease in HaCaT viability occurred from 100 μM for RSV. RSV-GS and RSV showed a similar behavior regarding protective effect against oxidative stress-induced cytotoxicity. SIRT1 protein content increased after treatment with 500 μM of RSV-GS and 100 μM of RSV. Moreover, in silico studies predicted that RSV-GS binds more stably to SIRT1 with a lower binding free energy than RSV. Although these results support the possible use of RSV-GS in topical formulations, in vivo safety and efficacy studies are needed before considering the use of RSV-GS in commercial products.

scholarly journals Considerable Improvement of Ursolic Acid Water Solubility by Its Encapsulation in Dendrimer Nanoparticles: Design, Synthesis and Physicochemical Characterization

Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2196 ◽  
Author(s):  
Silvana Alfei ◽  
Anna Maria Schito ◽  
Guendalina Zuccari
Keyword(s):  
Ursolic Acid ◽  
Water Solubility ◽  
Drug Loading ◽  
Physicochemical Characterization ◽  
Systemic Toxicity ◽  
Water Soluble ◽  
Design Synthesis ◽  
Pentacyclic Triterpenoid

Ursolic acid (UA) is a pentacyclic triterpenoid found in many medicinal plants and aromas endowed with numerous in vitro pharmacological activities, including antibacterial effects. Unfortunately, UA is poorly administered in vivo, due to its water insolubility, low bioavailability, and residual systemic toxicity, thus making urgent the development of water-soluble UA formulations. Dendrimers are nonpareil macromolecules possessing highly controlled size, shape, and architecture. In dendrimers with cationic surface, the contemporary presence of inner cavities and of hydrophilic peripheral functions, allows to encapsulate hydrophobic non-water-soluble drugs as UA, to enhance their water-solubility and stability, and to promote their protracted release, thus decreasing their systemic toxicity. In this paper, aiming at developing a new UA-based antibacterial agent administrable in vivo, we reported the physical entrapment of UA in a biodegradable not cytotoxic cationic dendrimer (G4K). UA-loaded dendrimer nanoparticles (UA-G4K) were obtained, which showed a drug loading (DL%) much higher than those previously reported, a protracted release profile governed by diffusion mechanisms, and no cytotoxicity. Also, UA-G4K was characterized by principal components analysis (PCA)-processed FTIR spectroscopy, by NMR and elemental analyses, and by dynamic light scattering experiments (DLS). The water solubility of UA-G4K was found to be 1868-fold times higher than that of pristine UA, thus making its clinical application feasible.

scholarly journals Identification of Structurally Similar Phytochemicals to Quercetin with High SIRT1 Binding Affinity and Improving Diabetic Wound Healing by Using In silico Approaches

2021 ◽  
Vol 12 (6) ◽  
pp. 7621-7632
Keyword(s):  
Wound Healing ◽  
In Silico ◽  
Binding Free Energy ◽  
Biological Properties ◽  
In Vivo Studies ◽  
Diabetic Wound ◽  
Binding Modes ◽  
Diabetic Wound Healing

Diabetes Mellitus is the most prevalent metabolic disorder that is increasing at an alarming rate worldwide. The unregulated glucose level leads to various types of health disorders, and one of the major diabetic complications is delayed wound healing. Due to the more side effects of synthetic drugs, there is a need to explore plants and their phytochemicals for medicinal purposes. It was found that Quercetin, a flavonoid, increases the rate of diabetic wound healing by enhancing the expression of SIRT1. This demands more insight towards Quercetin and its similar compounds, as it is hypothesized that similar compounds may have similar biological properties. Thus similarity searching was done to identify the most similar compounds of Quercetin, and then the molecular docking of the screened compounds was performed using AutoDock Vina. The unique ligands were docked into the active site of SIRT1 protein (PDB ID: 4ZZJ). The binding free energy of the interacting ligand with the protein was estimated. Six compounds were identified which possess the maximum structural similarity with Quercetin, and upon docking, it was found that gossypetin and herbacetin have similar binding modes and binding energy as that of Quercetin (-7.5 kcal/mol). Therefore, the hypothesis has been validated by in silico analysis. Our study identified two phytochemicals, Gossypetin, and Herbacetin which can prove beneficial for improving diabetic wound healing but needs to be validated further by in vitro and in vivo studies.

scholarly journals Albendazole solid dispersions against alveolar echinococcosis: a pharmacotechnical strategy to improve the efficacy of the drug

Parasitology ◽  
2020 ◽  
Vol 147 (9) ◽  
pp. 1026-1031
Author(s):  
Julia Fabbri ◽  
Patricia Eugenia Pensel ◽  
Clara María Albani ◽  
Lurdes Milagros Lopez ◽  
Analia Simonazzi ◽  
...  
Keyword(s):  
Alveolar Echinococcosis ◽  
Water Solubility ◽  
Solid Dispersions ◽  
Water Soluble ◽  
Poloxamer 407 ◽  
Infection Model ◽  
Efficacy Study ◽  
Dissolution Profile ◽  
Germinal Layer

AbstractAlveolar echinococcosis is a neglected parasitic zoonosis caused by Echinococcus multilocularis. The pharmacological treatment is based on albendazole (ABZ). However, the low water solubility of the drug produces a limited dissolution rate, with the consequent failure in the treatment of the disease. Solid dispersions are a successful pharmacotechnical strategy to improve the dissolution profile of poorly water-soluble drugs. The aim of this work was to determine the in vivo efficacy of ABZ solid dispersions using poloxamer 407 as a carrier (ABZ:P407 solid dispersions (SDs)) in the murine intraperitoneal infection model for secondary alveolar echinococcosis. In the chemoprophylactic efficacy study, the ABZ suspension, the ABZ:P407 SDs and the physical mixture of ABZ and poloxamer 407 showed a tendency to decrease the development of murine cysts, causing damage to the germinal layer. In the clinical efficacy study, the ABZ:P407 SDs produced a significant decrease in the weight of murine cysts. In addition, the SDs produced extensive damage to the germinal layer. The increase in the efficacy of ABZ could be due to the improvement of water solubility and wettability of the drug due to the surfactant nature of poloxamer 407. In conclusion, this study is the basis for further research. This pharmacotechnical strategy might in the future offer novel treatment alternatives for human alveolar echinococcosis.

scholarly journals Nanoparticle-Mediated Dual Targeting: An Approach for Enhanced Baicalin Delivery to the Liver

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 107 ◽  
Author(s):  
Iman Saad Ahmed ◽  
Hassan Medhat Rashed ◽  
Hend Fayez ◽  
Faten Farouk ◽  
Rehab Nabil Shamma
Keyword(s):  
Oral Administration ◽  
Water Solubility ◽  
Area Under The Curve ◽  
Oral Solution ◽  
Water Soluble ◽  
Spherical Particles ◽  
Therapeutic Molecules ◽  
Ph Dependent ◽  
Full Factorial

In this study, water-soluble chitosan lactate (CL) was reacted with lactobionic acid (LA), a disaccharide with remarkable affinity to hepatic asialoglycoprotein (ASGP) receptors, to form dual liver-targeting LA-modified-CL polymer for site-specific drug delivery to the liver. The synthesized polymer was used to encapsulate baicalin (BA), a promising bioactive flavonoid with pH-dependent solubility, into ultrahigh drug-loaded nanoparticles (NPs) via the ionic gelation method. The successful chemical conjugation of LA with CL was tested and the formulated drug-loaded LA-modified-CL-NPs were assessed in terms of particle size (PS), encapsulation efficiency (EE) and zeta potential (ZP) using full factorial design. The in vivo biodistribution and pharmacokinetics of the designed NPs were assessed using 99mTc-radiolabeled BA following oral administration to mice and results were compared to 99mTc-BA-loaded-LA-free-NPs and 99mTc-BA solution as controls. Results showed that the chemical modification of CL with LA was successfully achieved and the method of preparation of the optimized NPs was very efficient in encapsulating BA into nearly spherical particles with an extremely high EE exceeding 90%. The optimized BA-loaded-LA-modified-CL-NPs showed an average PS of 490 nm, EE of 93.7% and ZP of 48.1 mV. Oral administration of 99mTc-BA-loaded-LA-modified-CL-NPs showed a remarkable increase in BA delivery to the liver over 99mTc-BA-loaded-LA-free-CL-NPs and 99mTc-BA oral solution. The mean area under the curve (AUC0–24) estimates from liver data were determined to be 11-fold and 26-fold higher from 99mTc-BA-loaded-LA-modified-CL-NPs relative to 99mTc-BA-loaded-LA-free-CL-NPs and 99mTc-BA solution respectively. In conclusion, the outcome of this study highlights the great potential of using LA-modified-CL-NPs for the ultrahigh encapsulation of therapeutic molecules with pH-dependent/poor water-solubility and for targeting the liver.

Development and Characterization of the Neuroregenerative Xanthohumol C/Hydroxypropyl-β-cyclodextrin Complex Suitable for Parenteral Administration

Planta Medica ◽  
2019 ◽  
Vol 85 (16) ◽  
pp. 1233-1241
Author(s):  
Michael Kirchinger ◽  
Lara Bieler ◽  
Julia Tevini ◽  
Michael Vogl ◽  
Elisabeth Haschke-Becher ◽  
...  
Keyword(s):  
Water Solubility ◽  
Pharmaceutical Research ◽  
Water Soluble ◽  
Complexing Agents ◽  
Cyclodextrin Complex ◽  
Scanning Calorimetry ◽  
In Vivo Experiments ◽  
Strong Candidate

AbstractThe chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-β-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-β-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-β-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i. p. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i. v., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i. p. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-β-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.

Exploration on the adsorption mechanism of aminopyrimidines and quinazoline compounds on graphene oxide: Hydrophobicity and structure-controlled release process

2019 ◽  
Vol 9 (5) ◽  
pp. 419-428
Author(s):  
Li Li ◽  
Chunjiao Pan ◽  
Zhongqiu Guo ◽  
Bingmi Liu ◽  
Hao Pan ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Computer Simulations ◽  
Water Solubility ◽  
High Water ◽  
Water Soluble ◽  
Release Process ◽  
Adsorption Mechanisms ◽  
Mechanical Stirring

In this study, graphene oxide was synthesized using the Hummers method, and stable and homogeneous graphene oxide aqueous solutions were obtained through mechanical stirring and ultrasonic stripping. In conjunction with our previous studies, graphene oxide-loaded insoluble compound delivery systems were prepared to verify the in vivo release profiles of the graphene oxide delivery system. Several insoluble compounds including imatinib, nilotinib, erlotinib, gefitinib, and afatinib were selected for loading and in vitro graphene oxide release assays to study the non-covalent adsorption mechanisms. Computer simulations were employed for validation processes. For in vivo release assays, the T1/2 values of the poorly water soluble groups were 1.104 ± 0.18 h and the Cmax was 2.600 ± 2.06 mg/L. In previous assays, compounds with high water solubility supported by graphene oxide were released and detected in vivo. The solubility of the compound and its binding force with the carrier played a crucial role in release. The results of graphene oxide loading experiments showed that the maximum loading and entrapment efficiencies of the insoluble model compounds with similar aromatic rings were comparable. Under basic conditions, the in vitro release rates and maximum release levels of amino pyrimidine were elevated. In contrast, quinazoline release declined. Combined with computer simulations, π–π stacking was identified as the dominant mechanism for adsorption onto graphene oxide. Both hydrogen bonding and cation-π bonds played an auxiliary reinforcing role, and the two were regarded as antagonistic.

In-silico Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Novel Isoxazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer

2019 ◽  
Vol 11 (2) ◽  
pp. 118-128 ◽  
Author(s):  
Rajagopal Kalirajan ◽  
Arumugasamy Pandiselvi ◽  
Byran Gowramma ◽  
Pandiyan Balachandran
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
In Silico ◽  
Therapeutic Potential ◽  
Binding Free Energy ◽  
Breast Cancers ◽  
Molecular Docking Study ◽  
In Silico Admet

Background: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. Objective: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. Methods: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. Results: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. Conclusion: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.

Water soluble multiarm-polyethylene glycol–betulinic acid prodrugs: design, synthesis, and in vivo effectiveness

2014 ◽  
Vol 5 (19) ◽  
pp. 5775-5783 ◽  
Author(s):  
Lin Dai ◽  
Dan Li ◽  
Jing Cheng ◽  
Jing Liu ◽  
Li-Hong Deng ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Betulinic Acid ◽  
Water Solubility ◽  
Drug Loading ◽  
Water Soluble ◽  
Loading Capacity ◽  
Design Synthesis ◽  
High Drug ◽  
High Drug Loading

Multiarm-polyethylene glycol–betulinic acid prodrugs were prepared by using multiarm-polyethylene glycol linkers and betulinic acid, which exhibited high drug loading capacity, good water solubility, and excellent anticancer activity.

scholarly journals Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2560 ◽  
Author(s):  
Gökçe Şeker Karatoprak ◽  
Esra Küpeli Akkol ◽  
Yasin Genç ◽  
Hilal Bardakcı ◽  
Çiğdem Yücel ◽  
...  
Keyword(s):  
South African ◽  
Water Solubility ◽  
The Body ◽  
Water Soluble ◽  
In Vivo Studies ◽  
Lead Compounds ◽  
Combretastatin A4 ◽  
Potential Applications

Combretastatins are a class of closely related stilbenes (combretastatins A), dihydrostilbenes (combretastatins B), phenanthrenes (combretastatins C) and macrocyclic lactones (combretastatins D) found in the bark of Combretum caffrum (Eckl. & Zeyh.) Kuntze, commonly known as the South African bush willow. Some of the compounds in this series have been shown to be among the most potent antitubulin agents known. Due to their structural simplicity many analogs have also been synthesized. Combretastatin A4 phosphate is the most frequently tested compounds in preclinical and clinical trials. It is a water-soluble prodrug that the body can rapidly metabolize to combretastatin A4, which exhibits anti-tumor properties. In addition, in vitro and in vivo studies on combretastatins have determined that these compounds also have antioxidant, anti-inflammatory and antimicrobial effects. Nano-based formulations of natural or synthetic active agents such as combretastatin A4 phosphate exhibit several clear advantages, including improved low water solubility, prolonged circulation, drug targeting properties, enhanced efficiency, as well as fewer side effects. In this review, a synopsis of the recent literature exploring the combretastatins, their potential effects and nanoformulations as lead compounds in clinical applications is provided.

Synthesis and studies of thiazolidinedione–isatin hybrids as α-glucosidase inhibitors for management of diabetes

2021 ◽  
Vol 13 (5) ◽  
pp. 457-485
Author(s):  
Ramandeep Kaur ◽  
Rajnish Kumar ◽  
Nilambra Dogra ◽  
Ashok Kumar ◽  
Ashok Kumar Yadav ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Free Energy ◽  
Biological Evaluation ◽  
Free Energy Calculations ◽  
Standard Drug ◽  
Glucosidase Inhibitors ◽  
Cytotoxicity Studies ◽  
Cytotoxicity Assessment

Aim: Keeping in view the side effects associated with clinically used α-glucosidase inhibitors, novel thiazolidinedione–isatin hybrids were synthesized and evaluated by in vitro, in vivo and in silico procedures. Materials & methods: Biological evaluation, cytotoxicity assessment, molecular docking, binding free energy calculations and molecular dynamics studies were performed for hybrids. Results: The most potent inhibitor A-10 (IC50 = 24.73 ± 0.93 μM) was competitive in manner and observed as non-cytotoxic. A-10 possessed higher efficacy than the standard drug (acarbose) during in vivo biological testing. Conclusion: The enzyme inhibitory potential and safety profile of synthetic molecules was recognized after in vitro, in vivo, in silico and cytotoxicity studies. Further structural optimization of A-10 can offer potential hit molecules suitable for future investigations.

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