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1.
Mol Divers ; 26(2): 1213-1225, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34553298

ABSTRACT

Diabetes mellitus is a main global health apprehension. Macrovascular illnesses, neuropathy, retinopathy, and nephropathy are considered some of its severe hitches. Gliptins are a group of hypoglycemic agents that inhibit dipeptidyl peptidase-IV (DPP-IV) enzyme and support blood glucose-lowering effect of incretins. In the current research, synthesis, characterization, docking, and biological evaluation of fourteen Schiff's bases 5a-f and 9a-h were carried out. Compound 9f revealed the best in vitro anti-DPP-IV activity of 35.7% inhibition at a concentration of 100 µM. Compounds 9c and 9f with the highest in vitro DPP-IV inhibition were subjected to the in vivo glucose-lowering test using vildagliptin as a positive inhibitor. Vildagliptin, 9c, and 9f showed significant reduction in the blood glucose levels of the treated mice after 30 min of glucose administration. Moreover, induced fit docking showed that these derivatives accommodated the enzyme binding site with comparable docking scores. Schiff's bases can serve as promising lead for the development of new DPP-IV inhibitors.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Animals , Blood Glucose , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypoglycemic Agents/chemistry , Mice , Vildagliptin
2.
Molecules ; 27(18)2022 Sep 12.
Article in English | MEDLINE | ID: mdl-36144646

ABSTRACT

Lavandula angustifolia is the most widely cultivated Lavandula species for medicinal use. In this study, chemical and biological evaluation of L. angustifolia aqueous, methanol (MeOH), ethanol (EtOH), ethyl acetate (EtOAc), and chloroform (CHCl3) extracts were conducted. Phytochemically, the extracts' total phenol and flavonoid contents and their antioxidant potential were evaluated. Ethanol extract was analyzed by LC-MS. All extracts were screened in vitro for their antitumor potential using human breast cancer cell lines MCF-7 and MDA-MB-23. For the first time, the antiproliferative potential of the EtOH extract was tested in vivo using mice with induced breast cancer. Ethanol extract exhibited the best cytotoxicity and safety profile of the tested extracts, with IC50 values of 104.1 µg/mL on MCF-7 and 214.5 µg/mL on MDA-MB-231 cell lines, respectively. In vivo, this extract revealed a reduction in tumor size by 43.29% in the treated group, compared to an increase in the tumor growth by 58.9% in the control group. Moreover, undetected tumor was found in 12.5% of the sample size. In conclusion, this study provides novel insight and evidence on the antiproliferative efficacy of L. angustifolia ethanol extract against breast cancer with potent anti-oxidant potential.


Subject(s)
Breast Neoplasms , Lavandula , Animals , Antioxidants/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Line, Tumor , Chloroform , Ethanol , Female , Flavonoids/pharmacology , Humans , Jordan , Lavandula/chemistry , Methanol , Mice , Phenols/pharmacology , Plant Extracts/chemistry , Plant Extracts/pharmacology
3.
Molecules ; 24(21)2019 Oct 23.
Article in English | MEDLINE | ID: mdl-31652710

ABSTRACT

Plant polyphenols have received considerable attention in recent years due to their ability to undergo oxidation-triggered self-polymerization, forming biocompatible versatile coatings and templated nanoparticles (NPs) that can be leveraged for a variety of biomedical applications. Here we show for the first time that untemplated NPs can be conveniently synthesized from the abundant plant polyphenol quercetin (QCT) simply by incubation with an oxidizing agent in a universal organic solvent, followed by self-assembly upon gradual addition of water. The process yielded NPs of around 180-200 nm in size with a range of colors that resembled light to medium-brown skin tones. The NPs were characterized by UV-Vis, FT-IR, and 1H-NMR spectroscopy and by dynamic light scattering and transmission electron microscopy to understand their physicochemical properties. Antioxidant and cell viability assays were also conducted to demonstrate the NPs' free-radical scavenging activity and biocompatibility, altogether providing valuable insights into the structure and function of this emerging class of nanomaterials to guide future biomedical applications.


Subject(s)
Antioxidants , Nanoparticles/chemistry , Polymerization , Quercetin/chemistry , Skin Pigmentation , Antioxidants/chemical synthesis , Antioxidants/chemistry , Humans , Particle Size
4.
Arch Pharm (Weinheim) ; 350(12)2017 Dec.
Article in English | MEDLINE | ID: mdl-29112287

ABSTRACT

Cardiovascular disease is the most common cause for mortality and morbidity in the developed world; its risk is inversely related to the high-density lipoprotein (HDL) cholesterol levels. Therefore, there is a great interest in developing new cholesteryl ester transfer protein (CETP) inhibitors capable of raising HDL as a novel approach for the prevention of cardiovascular disease. Herein, the synthesis and characterization of ten benzyl benzamides 8a-j that aim at CETP inhibition was performed. The in vitro CETP inhibition bioassay revealed that benzamide 8j had the best activity, with a percent inhibition of 82.2% at 10 µM concentration and an IC50 value of 1.3 µM. The docking study shows that the verified compounds accommodate the binding cleft of CETP and are enclosed by a hydrophobic lining. Furthermore, the scaffold of 8a-j matches the pharmacophoric points of CETP inhibitors, particularly in its hydrophobic and aromatic functionalities.


Subject(s)
Anticholesteremic Agents/pharmacology , Benzamides/pharmacology , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Models, Molecular , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Benzamides/chemical synthesis , Benzamides/chemistry , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Cholesterol, HDL/blood , Drug Design , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Molecular Docking Simulation , Structure-Activity Relationship
5.
Biomater Sci ; 10(19): 5504-5519, 2022 Sep 27.
Article in English | MEDLINE | ID: mdl-35920694

ABSTRACT

Rhoifolin (ROF) is a bioactive plant flavonoid with potent antioxidant and anti-inflammatory activity. However, no delivery system has yet been developed for ROF to overcome its biopharmaceutical limitations. The purpose of this study was to design a ROF-loaded polymeric nanocarrier as a potential anti-inflammatory nanomedicine. ROF was isolated from Jordanian Teucrium polium L. and entrapped into poly(lactide-co-glycolide) nanoparticles (PLGA NPs), followed by tannic acid-mediated surface modification with poly(ethylene glycol) (PEG). The optimal ROF NPs were highly monodisperse with an average diameter of 204 nm, a zeta potential of -28 mV, an entrapment efficiency of 45%, and drug loading of 9% w/w. The NPs exhibited excellent colloidal stability during storage and in the presence of serum and achieved sustained drug release for up to 96 h at physiologic (7.4) and acidic pH (5.0). In vitro cell-free antioxidant assays confirmed the potent radical scavenging activity of free ROF and ROF NPs. Moreover, ROF NPs were superior to free ROF in relieving oxidative stress in stimulated RAW 264.7 murine macrophages, which was attributed to enhanced cellular uptake of the NPs as confirmed by confocal microscopy and fluorimetry. In vivo anti-inflammatory activity was evaluated in a formalin-induced rat paw edema model. The results showed that ROF NPs were superior to free ROF in mitigating the histopathological changes in the inflamed paw tissues. Moreover, the NPs were equally potent to free ROF and the nonsteroidal anti-inflammatory drug diclofenac in terms of inhibiting the increase in paw thickness, normalizing nitric oxide levels, and modulating the gene expression of pro-inflammatory cytokines in the inflamed paw tissues. Our findings present a promising nanocarrier platform that can enhance the solubility and control the release of ROF, which will facilitate its administration in the treatment of inflammatory diseases.


Subject(s)
Biological Products , Nanoparticles , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Apigenin , Cytokines , Diclofenac , Disaccharides , Drug Carriers , Flavonoids , Formaldehyde , Glucose/analogs & derivatives , Inflammation/drug therapy , Mannose/analogs & derivatives , Mice , Nitric Oxide , Oxidative Stress , Particle Size , Polyethylene Glycols , Polyglactin 910 , Rats , Tannins
6.
ACS Omega ; 6(4): 2767-2776, 2021 Feb 02.
Article in English | MEDLINE | ID: mdl-33553895

ABSTRACT

Plant polyphenols have attracted attention in recent years due to their ability to undergo oxidative coupling reactions enabled by the presence of multiple phenolic hydroxyl groups, forming chemically versatile coatings and biocompatible nanoparticles (NPs) for various applications. The aim of this study was to investigate whether coffee bean aqueous extracts, which are known to be rich in polyphenols, could serve as a natural source of NP building blocks. Extracts were prepared by heating ground Arabica beans of varying roasting degrees in water with or without the addition of sodium metaperiodate or copper sulfate as an oxidizing agent, followed by filtration. NP formation was verified by dynamic light scattering and transmission electron microscopy, which revealed the presence of nano-sized particles with varying sizes and polydispersities as a function of the coffee type and oxidizing agent used. NP colors ranged from light to medium to dark brown, and particle sizes were between 44 and 250 nm with relatively low polydispersity indices. In vitro antioxidant assays showed that oxidizing agent-treated coffee NPs had lower antioxidant potency compared to air-oxidized NPs, but the free-radical scavenging activity was still retained. Coffee NPs exhibited no antimicrobial activity against common bacterial and fungal strains. Cell viability assays demonstrated that the NPs were biocompatible in human dermal fibroblasts, while exhibiting antiproliferative activity against MCF7 breast cancer cells, particularly copper sulfate-oxidized NPs. This study presents a facile and economical method to produce template-free antioxidant NPs that may be explored for various applications such as drug delivery and cosmetics.

7.
ACS Biomater Sci Eng ; 5(11): 6036-6045, 2019 Nov 11.
Article in English | MEDLINE | ID: mdl-33405725

ABSTRACT

Nanomedicine has had a profound impact on the treatment of many diseases, especially cancer. However, synthesis of multifunctional nanoscale drug carriers often requires multistep coupling and purification reactions, which can pose major scale-up challenges. Here, we leveraged bioinspired oxidation-triggered polymerization of catechols to synthesize nanoparticles (NPs) from the plant polyphenol quercetin (QCT) loaded with a hydrophobic anticancer drug, curcumin, and functionalized with poly(ethylene glycol) (PEG) for steric stabilization in one reaction step. NPs were formed by base-catalyzed oxidative self-polymerization of QCT in the presence of curcumin and thiol-terminated PEG upon mixing in a universal solvent (dimethyl sulfoxide), followed by self-assembly with the gradual addition of water. Dynamic light scattering and X-ray photoelectron spectroscopy were used to confirm NP PEGylation. Drug loading was verified by UV-vis spectroscopy. Curcumin-loaded NPs were efficiently internalized by CT26 murine colon cancer cells as determined by flow cytometry and confocal microscopy. NPs also demonstrated sustained release and potent cytotoxicity in vitro. Moreover, in vivo imaging of CT26 tumor-bearing Balb/c mice following tail vein injection of DiR-labeled QCT NPs showed steady tumor accumulation of the NPs up to 24 h. This was further supported by significant tumor uptake of curcumin-loaded QCT NPs as measured by flow cytometry analysis of tumor homogenates. Our findings present a greener synthetic route for the fabrication of drug-loaded surface-functionalized NPs from poorly water-soluble plant polyphenols such as QCT as promising anticancer delivery systems.

8.
Med Chem ; 15(4): 417-429, 2019.
Article in English | MEDLINE | ID: mdl-30207238

ABSTRACT

BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) has emerged as a promising target for anticancer drug design. OBJECTIVES: Target compounds were designed to investigate the effect of the p-OCH3 motifs on ligand/PI3Kα complex interaction and antiproliferative activity. METHODS: Synthesis of the proposed compounds, biological examination tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, along with Glide docking studies. RESULTS: A series of 1,2-bis(4-methoxyphenyl)-2-oxoethyl benzoates was synthesized and characterized by means of FT-IR, 1H and 13C NMR, and by elemental analysis. Biological investigation demonstrated that the newly synthesized compounds exhibit antiproliferative activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines possibly via inhibition of PI3Kα and estrogen receptor alpha (ERα). Additionally, results revealed that these compounds exert selective inhibitory activity, induce apoptosis, and suppress VEGF production. Compound 3c exhibited promising antiproliferative activity in HCT-116 interrogating that hydrogen bond-acceptor mediates ligand/PI3Kα complex formation on m- position. Compounds 3e and 3i displayed high inhibitory activity in MCF-7 and T47D implying a wide cleft discloses the o-attachment. Furthermore, compound 3g exerted selective inhibitory activity against T47D. Glide docking studies against PI3Kα and ERα demonstrated that the series accommodate binding to PI3Kα and/or ERα. CONCLUSION: The series exhibited a potential antitumor activity in human carcinoma cell lines encoding PI3Kα and/or ERα.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzoin/chemical synthesis , Benzoin/pharmacology , Drug Design , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Benzoin/chemistry , Benzoin/metabolism , Catalytic Domain , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Drug Screening Assays, Antitumor , Humans , Ligands , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Structure-Activity Relationship
9.
Biomater Sci ; 6(10): 2656-2666, 2018 Sep 25.
Article in English | MEDLINE | ID: mdl-30140818

ABSTRACT

Nanoparticle-mediated drug delivery has demonstrated great potential to treat various diseases especially cancer. However, there is an unmet need for the scalable synthesis of multifunctional nanoparticles to meet the complex challenges of drug delivery. Here we show that we can synthesize nanoparticles from the polyphenol quercetin, which can be conveniently functionalized with ligands and drug molecules by simple mixing under ambient conditions. Nanoparticles (∼30-40 nm in diameter) were formed by oxidative self-polymerization of quercetin in alkaline buffer (pH 9). The reactivity of oxidized polyphenols was exploited to immobilize amine-terminated methoxy poly(ethylene glycol) on the nanoparticles' surface for steric stability, followed by loading with doxorubicin as a model drug. Surface modification of the nanoparticles was confirmed by X-ray Photoelectron Spectroscopy. An antioxidant assay showed that the nanoparticles retained some antioxidant activity. The nanoparticles were readily internalized by KB cells via an endo-lysosomal pathway. Doxorubicin-loaded nanoparticles showed a drug loading of 35.6 ± 4.9% w/w with a loading efficiency of 88.9 ± 12.4%, sustained drug release, and potent cytotoxicity in vitro. Our findings demonstrate a promising new application for naturally occurring polyphenols as a renewable source of drug delivery nanocarriers that can be synthesized at low cost with minimal equipment.


Subject(s)
Antibiotics, Antineoplastic , Antioxidants , Doxorubicin , Nanoparticles , Quercetin , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/chemistry , Antioxidants/administration & dosage , Antioxidants/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemistry , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Drug Liberation , Fluorescein-5-isothiocyanate/administration & dosage , Fluorescein-5-isothiocyanate/chemistry , Fluorescent Dyes/administration & dosage , Fluorescent Dyes/chemistry , Humans , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/chemistry , Quercetin/administration & dosage , Quercetin/chemistry
10.
Curr Comput Aided Drug Des ; 14(2): 142-151, 2018.
Article in English | MEDLINE | ID: mdl-29521244

ABSTRACT

BACKGROUND: Diabetes mellitus is a major worldwide health concern that has several serious complications including retinopathy, neuropathy, nephropathy and macrovascular diseases. OBJECTIVE: Dipeptidyl peptidase-IV (DPP-IV) inhibitors, gliptins, are a new class of antidiabetic agents that potentiate the action of incretins in decreasing the blood glucose levels. METHODS: In the present study, synthesis and characterization of a series of ten N4-sulfonamido-acrylic and phthalamic acid methyl esters (3a-e and 5a-e) were achieved. RESULTS: In vitro anti-DPP-IV activity of the synthesized compounds was evaluated, where compound 3b demonstrated the best activity with a % inhibition of 41.7 at 10 µM concentration and an IC50 of 23.9 µM. Moreover, Glide docking experiments revealed that our targeted compounds accommodate the binding site of DPP-IV and tend to form H-bonding with the backbones of R125, E206, S209, D545, K554, W629, Y631, and G632. CONCLUSION: Modeling findings recommend the attachment of bulky hydrophobic group on the ester side of the structure in addition to harboring extra aromatic rings that might be beneficial for better binding interaction and biological activity.


Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Acrylates/chemical synthesis , Acrylates/chemistry , Acrylates/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Esters/chemical synthesis , Esters/chemistry , Esters/pharmacology , Humans , Hypoglycemic Agents/chemical synthesis , Molecular Docking Simulation , Phthalimides/chemical synthesis , Phthalimides/chemistry , Phthalimides/pharmacology , Sulfonamides/chemical synthesis
11.
Med Chem ; 14(7): 695-708, 2018.
Article in English | MEDLINE | ID: mdl-29651943

ABSTRACT

BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) is an attractive target for anticancer drug design. OBJECTIVES: Target compounds were designed to probe the significance of alcohol and imine moieties tailored on a benzoin scaffold to better understand the structure activity relation (SAR) and improve their biological activity as anticancer compounds. METHODS: Chemical synthesis of the targeted compounds, biological evaluation tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, as well as Glide docking studies were employed in this investigation. RESULTS: A new series of 1,2-diphenylimino ethanol was successfully synthesized and characterized by means of FT-IR, HRMS, NMR, and by elemental analysis. Biological screening revealed that the newly synthesized compounds inhibit PI3Kα activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines. Results additionally showed that these compounds exhibit selective antiproliferative activity, induce apoptosis, and suppress the VEGF production. Compounds 2b, 2d, and 2g displayed promising inhibitory activity in HCT-116 suggesting that hydrophobic and/or hydrogen bond-acceptor mediate(s) ligand-receptor interaction on o- and mpositions. Furthermore, compounds 2g, 2i, 2j, and 2h, bearing hydrophobic moiety on m- and pposition, exerted high antiproliferative activity in T47D and MCF-7 cells, whereas compound 2e showed selectivity against T47D and MCF-7. Molecular docking studies against PI3Kα and caspase-3 demonstrated a strong correlation between the predicted binding affinity (ΔGobsd) and IC50 values of prepared compounds for the caspase-3 model, implying that the cellulous inhibitory activity was caspase-3-dependent. Moreover, Glide docking against PI3Kα identified Ser774, Lys802, E849, V851, and Asp933 as key binding residues. CONCLUSION: The series exerted a potential PI3Kα inhibitory activity in human carcinoma cell lines expressing PI3Kα.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Schiff Bases/chemical synthesis , Apoptosis/drug effects , Benzoin , Caspase 3/genetics , Caspase 3/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Design , Gene Expression Regulation, Neoplastic/drug effects , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Schiff Bases/pharmacology , Structure-Activity Relationship , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
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