Synthesis and Anticancer Activity of Novel Derivatives of α,ß-Unsaturated Ketones Based on Oleanolic Acid: in Vitro and in Silico Studies against Prostate Cancer Cells.

Herein, new derivatives of α,ß-unsaturated ketones based on oleanolic acid (4 a-i) were designed, synthesized, characterized, and tested against human prostate cancer (PC3). According to the in vitro cytotoxic study, title compounds (4 a-i) showed significantly lower toxicity toward healthy cells (HUVEC) in comparison with the reference drug doxorubicin. The compounds with the lowest IC50 values on PC3 cell lines were 4 b (7.785 µM), 4 c (8.869 µM), and 4 e (8.765 µM). The results of the ADME calculations showed that the drug-likeness parameters were within the defined ranges according to Lipinski's and Jorgensen's rules. For the most potent compounds 4 b, 4 c, and 4 e, a molecular docking analysis using the induced fit docking (IFD) protocol was performed against three protein targets (PARP, PI3K, and mTOR). Based on the IFD scores, compound 4 b had the highest calculated affinity for PARP1, while compound 4 c had higher affinities for mTOR and PI3K. The MM-GBSA calculations showed that the most potent compounds had high binding affinities and formed stable complexes with the protein targets. Finally, a 50 ns molecular dynamics simulation was performed to study the behavior of protein target complexes under in silico physiological conditions.

Emodin and aloe-emodin, two potential molecules in regulating cell migration of skin cells through the MAP kinase pathway and affecting Caenorhabditis elegans thermotolerance.

BACKGROUND: Emodin and aloe-emodin are two anthraquinones having positive effects in wound healing. However, their mechanism of action of wound healing is not fully understood. The MAP kinase family, which plays an active role in wound healing, is a well-characterized large family of serine/threonine kinases and regulates processes such as proliferation, oncogenesis, differentiation, and inflammation in the cell. The aim of this study is to comparatively elucidate the mechanisms of action of emodin and aloe-emodin, which are potential agents in wound healing. METHODS: The mechanism of the effects of emodin and aloe-emodin on cell viability and cell migration was examined using the human skin fibroblast (CCD-1079Sk) cell line. The gene expression levels of the MAP kinases (JNK, P38, ERK) in the skin fibroblast cells along with a molecular docking study analyzing their interaction potential were evaluated. Furthermore, the molecules' effects on the lifespan of Caenorhabditis elegans were studied. RESULTS: Emodin and aloe-emodin inhibited the ATP content of the cells in a concentration dependent manner and accelerated cell migration at the lower concentrations while inhibiting cell migration in the higher concentration treatment groups. The expressions of JNK and P38 were upregulated at the low concentrations and downregulated at the higher concentrations. The molecular docking studies of the molecules gave high docking scores indicating their interaction potential with JNK and P38. C. elegans lifespan under heat stress was observed longer after 75 µM emodin and was significantly reduced after 150 µM aloe-emodin treatment. CONCLUSION: Aloe-emodin was found to be more potent on cell viability, cell migration, gene expression levels of the MAP kinases in healthy fibroblastic skin cells, and on the lifespan of C. elegans. This study reveals the functional effects and the biological factors that interact in the wound healing process of emodin and aloe-emodin, and give a possible treatment alternative to shorten the duration of wound care.

Anti-SARS-CoV-2 and cytotoxic activity of two marine alkaloids from green alga Caulerpa cylindracea Sonder in the Dardanelles.

Caulerpa cylindracea Sonder is a green alga belonging to the Caulerpaceae family. This is the first chemical investigation of C. cylindracea in the Dardanelles which resulted in the isolation of four compounds, caulerpin (1), monomethyl caulerpinate (2), beta-sitosterol (3), and palmitic acid (4). Their structures were elucidated by spectroscopic analyses including 1D- and 2D NMR and mass. The isolated compounds 1 and 2 were tested against the SARS-CoV-2 viral targets spike protein and main protease (3CL) enzyme, and both compounds significantly inhibit the interaction of spike protein and ACE2, while the main protease activity was not significantly reduced. Docking studies suggested that compounds 1 and 2 may bind to the ACE2 binding pocket on spike, and compound 2 may also bind to an allosteric site on spike. As such, these compounds may inhibit the spike-ACE2 complex formation competitively and/or allosterically and have the potential to be used against SARS-CoV-2 virus infection. In addition, compounds 1 and 2 showed at least two-fold higher cytotoxicity against breast cancer cell lines MCF7 and MDA-MB-231 compared to the CCD fibroblast control cell line.

Investigation of cytotoxic and apoptotic effects of 63 compounds obtained from Salvia species: Promising anticancer agents.

Since ancient time, Salvia L. species have been commonly used to treat colds, bronchitis, tuberculosis, heart diseases, and menstrual and digestive disorders in traditional medicine all around the world. They have been also used as tea and spice. Studies indicated that diterpenes and triterpenes isolated from Salvia species possess various pharmacological and biological effects such as anti-inflammatory, antiviral, cytotoxic, antioxidant, and hepatotoxic activities. Flavones were also shown to have antimicrobial, antioxidant, and cytotoxic potentials. Salvia extracts also exhibit anti-Alzheimer, antiseptic, cardiovascular, antihypertensive, and antituberculous effects. To investigate the effects of 63 secondary metabolites from Salvia species on cell viability and apoptosis, Salvia secondary metabolites including 25 phenolics, 4 fatty acids, 19 abietane diterpenoids, 12 triterpenoids, and three steroids were examined on healthy cell line (PDF), breast cancer (MCF-7), and colon cancer (HT-29) cell lines using MTT method. In addition, the effects of rosmarinic acid, 6,7-dehydroroyleanone, acetyl royleanone, ferruginol, carnosic acid, carnosol, cryptotanshinone, ß-sitosterol, and ursolic acid on pro-apoptotic Bax and antiapoptotic Bcl-2 protein expression levels were investigated by Western Blot method. PRACTICAL APPLICATIONS: Phenolic compounds (apigenin, chrysin, and luteolin) and diterpenes (especially dihydrotanshinone I, carnosic acid, and carnosol), and almost all of the triterpenes exhibited high toxic effects on healthy cell line. Cytotoxic effects of cryptotanshinone, 12-hydroxy abieta-1,3,5(10),8,11,13-hexaene, 12-demethylmulticauline, 6,7-dehydroroyleanone, acetyl royleanone, ferruginol, ursolic acid, and 3-acetyl lupeol were relatively higher than their toxic effects. Acetyl royleanone, 6,7-dehydroroyleanone, carnosic acid, and cryptotanshinone were found to have anticancer potential based on their modulating effects on the expression levels of Bax and Bcl-2 proteins which play important roles in the regulation of apoptosis. The results of the present study showed that acetyl royleanone, cryptotanshinone, 6,7-dehydroroyleanone, carnosic acid, and cryptotanshinone have potential to be used in the pharmaceutical industry.

Identification of natural compounds of Jurinea species by LC-HRMS and GC-FID and their bioactivities.

The Jurinea Cass. is one of the most important genera within Asteraceae and it comprises about 250 species in total. This genus is known for its numerous biological activities such as antioxidant, antimicrobial, antilipid peroxidation, anticholinesterase, antileishmanial activities. The aim of this study was to determine chemical composition and biological activities of ethanol and n-hexane extracts of three different Jurinea species. For this purpose, different parts of J. mollis, J. cadmea and J. pontica were extracted and totally six n-hexane and six ethanol extracts were obtained. Fatty acid content of n-hexane extracts was determined by GC-FID whereas phenolic and flavonoid content of ethanol extracts by LC-HRMS. Palmitic acid (16:0) was detected as the most abundant fatty acid in all n-hexane extracts with the rates ranging from 42.16%-55.08%, except flowers of J. mollis (JMF) and J. cadmea (JCF). LC-HRMS analysis showed the rutin content of all extracts was higher than other flavonoids, except of J. cadmea flowers, whereas apigenin-7-glucoside was found the most abundant in JCF. Cytotoxic effects of the extracts on HeLa and HEK-293 cells were determined by MTT method, and antioxidant activities were evaluated by DPPH and CUPRAC assays. Ethanol extract of J. mollis flowers significantly inhibited cancerous HeLa cells, with the IC50 value of 9.683 µg/mL while it was more less toxic on healthy HEK-293 cells. Ethanol extracts of J. mollis flowers and J. mollis steams-leaves (JMSL) showed the highest antioxidant activity by a DPPH inhibition % of 45.516 ± 2.497 and 56.671 ± 1.496, respectively. JMF and JMSL have also the highest CUPRAC values (0.880 ± 0.067 and 1.085 ± 0.152 mmol TR/g DWE, respectively). Total flavonoid content was determined using aluminum chloride colorimetric assay while total tannin and phenolic content by Folin Chiocalteu's reagent. Results showed that JMSL has the highest total phenolic (108.359 ± 6.241 mg GAE/ G DWE) and flavonoid (32.080 ± 4.385 mg QE/ g DWE) contents whereas JMF has the highest tannin content (121.333 ± 17.889 mg TAE/ g DWE). In the light of these results, various parts of Jurinea species may be regarded as alternative sources for cytotoxic and/or antioxidant flavonoids, phenolics and unsaturated fatty acids that can arouse the interest of pharmaceutical, food and cosmetic industries.

Selective in-vitro Enzymes' Inhibitory Activities of Fingerprints Compounds of Salvia Species and Molecular Docking Simulations.

Recently Nutrition and Food Chemistry researches have been focused on plants and their products or their secondary metabolites having anti-alzheimer, anti-cancer, anti-aging, and antioxidant properties. Among these plants Salvia L. (Lamiaceae) species come into prominence with their booster effects due to high antioxidant contents, which have over 900 species in the world and 98 in Turkey. Some Salvia species are already in use as herbal treatment of vessel stiffness, Dementia like problems and cancer. Recently some species of Salvia are of extensive research topic. In this study, inhibitory potentials of secondary metabolites, rosmarinic acid, salvigenin, salvianolic acid A and B, tanshinone I and IIA, cyrtotanshinone, dihydrotanshinone I, carnosic acid, carnosol, and danshensu sodium salt were investigated against acetylcholinesterase, butyrylcholinesterase, urease and tyrosinase enzymes both in-vitro and in slico in detail. Elevated inhibitory effects on acetyl- and butyryl-cholinesterase of dihydrotanshinone I (IC50: 1.50 ± 0.02 and 0.50 ± 0.01 µg/mL, respectively), carnasol (IC50: 11.15 ± 0.05 ve 3.92 ± 0.03 µg/mL) and carnosic acid (IC50: 31.83 ± 0.65 ve 4.12±0.04 µg/mL) were observed. Furthermore, all other secondary metabolites were active against butyrylcholinesterase. Anti-urease (42.41 ± 0.85%) and anti-tyrosinase (39.82 ± 1.16%) activities of tanshinone I were also observed. Potential inhibitory effects of these molecules on target proteins were investigated using DOCK and molecular dynamics calculations. Dock score analysis and Lipinski parameters were demonstrated that these ligands are potential inhibitors against relevant enzymes. Our findings suggest that Salvia species can be utilized as a ptential source of anti-alzheimer active compounds for designing novel products.

Composition of the essential oil of Satureja metastasiantha: a new species for the flora of Turkey.

The aerial parts of Satureja metastasiantha were hydrodistilled for 3 h using a Clevenger-type apparatus. The essential oils were analyzed by gas chromatography/flame ionization detector and gas chromatography/mass spectrometry, simultaneously, the main compounds of which were characterized as p-cymene (22.3%), thymol (21.0%), carvacrol (18.4%), and γ-terpinene (12.1%). Antioxidant capacity, acetylcholinesterase and butyrylcholinesterase inhibition effects, and antimicrobial and antifungal properties of the species were evaluated. The anticholinesterase activity of the essential oil of S. metastasiantha was observed with 30% inhibition at 200 µg/mL. The essential oil of the species showed activity against Staphylococcus aureus with 128 µg/mL minimum inhibitory concentration value.

Investigation of cell death mechanism and activity of esculetin-loaded PLGA nanoparticles on insulinoma cells in vitro.

AIM: The purpose of this study was to prepare targeted cancer therapy formulation against insulinoma INS-1 cells and to study its effect on cell death with related mechanisms in vitro. METHODS: Polylactide-co-glycolide (PLGA) nano-micelles were used for preparation of esculetin nano-formulation (nano-esculetin). The cells were treated with nano-esculetin and free esculetin. Apoptotic and necrotic cell death percentages, cell proliferation, ATP and GTP reductions and insulin levels were investigated on insulinoma INS-1 cells for both free and nano-esculetin formulations. RESULTS: About 50 mg of PLGA was able to carry 20 mg esculetin in 20 ml of formulation. The obtained optimized formulation was 150 nm, with 92% encapsulation efficiency and a slow-release behaviour was observed during release studies. Nano-esculetin bearing 25, 50 and 100 µg esculetin and free esculetin in equivalent doses successfully decreased cell viability. The prevailing cell death mechanism was necrosis. Along with cell proliferation, intracellular insulin and the ratio of ATP and GTP were decreased even with 12.5, 25 and 50 µg esculetin bearing nano-formulation and its equivalent free esculetin. CONCLUSIONS: The results revealed that esculetin is able to show its anti-tumor afficacy after loading to PLGA nano-micelles and nano-encapsulation intensifies its cytotoxic activity in vitro. Current study shows that esculetin and its nano formulations are promising agents in treatment of insulinoma.

Inhibition of Amyloid ß Aggregation Using Optimized Nano-Encapsulated Formulations of Plant Extracts with High Metal Chelator Activities.

BACKGROUND: The role of Fe+2, Cu+2 and Zn+2 in facilitating aggregation of Amyloid ß (Aß) and consequently, the progression of Alzheimer's disease (AD) is well established. OBJECTIVE: Development of non-toxic metal chelators is an emerging era in the treatment of AD, in which complete success has not been fully achieved. The purpose of this study was to determine plant extracts with high metal chelator and to encapsulate them in nano-micellar systems with the ability to pass through the Blood Brain Barrier (BBB). METHODS: Extracts of 36 different Anatolian plants were prepared, total phenolic and flavonoid contents were determined, and the extracts with high content were examined for their Fe+2, Cu+2 and Zn+2 chelating activities. Apolipoprotein E4 (Apo E) decorated nano-formulations of active extracts were prepared using Poly (Lactide-co-Glycolide) (PLGA) (final product ApoEPLGA) to provide BBB penetrating property. RESULTS: Verbascum flavidum aqueous extract was found as the most active sample, incubation of which, with Aß before and after metal-induced aggregation, resulted in successful inhibition of aggregate formation, while re-solubilization of pre-formed aggregates was not effectively achieved. The same results were obtained using ApoEPLGA. CONCLUSION: An optimized metal chelator nano-formulation with BBB penetrating ability was prepared and presented for further in-vivo studies.

A High-Performance Liquid Chromatographic Method for the Determination of Meropenem in Serum.

In this study, a new, sensitive and selective high-performance liquid chromatographic method was developed for the determination of meropenem (MEM) in human serum. In the developed method, C18 column (3.9 × 150 mm, 5 µm) was selected as stationary phase at 30°C, and methanol: acetic acid solution mixture was used as mobile phase with gradient program. Chromatographic separation was carried out at a flow rate of 1 mL/min, and detection was performed at 300 nm with diode array detector. Doripenem was selected as an internal standard, and the analytes were extracted from serum using protein precipitation method with ortho-phosphoric acid: methanol. Detection wavelength was selected as 300 nm. The developed method was validated according to International Council for Harmonisation (ICH) guidelines. The calibration curve was linear over a concentration range of 4-240 µg/mL with correlation coefficient of 0.9985. The limit of detection and limit of quantification values were found as 0.057 and 0.192 µg/mL, respectively. The validated method was successfully applied for the determination of MEM in human serum samples collected from patient volunteers at different time intervals, and therapeutic drug monitoring of MEM has been investigated.

Noscapine, a Non-addictive Opioid and Microtubule-Inhibitor in Potential Treatment of Glioblastoma.

Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks significant hypnotic and euphoric effects rendering it safe in terms of addictive potential. In 1954, Hans Lettré first described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960's, yet no effect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not affect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apoptosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-κB, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood-brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy.

Boron's neurophysiological effects and tumoricidal activity on glioblastoma cells with implications for clinical treatment.

Purpose: To define the actions of boron on normal neurophysiology and glioblastoma growth. Materials and Methods: PubMed and other relevant databases were searched. Results: Discovery of novel boron compounds in treatment of glioblastoma is being actively investigated, but the majority of such studies is focused on the synthesis of boron compounds as sensitizers to Boron Neutron Capture Therapy (BNCT). Nonetheless, the translational functionality of boron compounds is not limited to BNCT as many boron compounds possess direct tumoricidal activity and there is substantial evidence that certain boron compounds can cross the blood-brain barrier. Moreover, boron-containing compounds interfere with several tumorigenic pathways including intratumoral IGF-I levels, molybdenum Fe-S containing flavin hydroxylases, glycolysis, Transient Receptor Potential (TRP) and Store Operated Calcium Entry (SOCE) channels. Conclusions: Boron compounds deserve to be studied further in treatment of systemic cancers and glioblastoma due to their versatile antineoplastic functions.

Recent Advances on 3-Hydroxyflavone Derivatives: Structures and Properties.

Flavonoids are naturally occurring phenolic compounds named as 2-phenyl-1-benzopyran- 4-one and classified into several subclasses according to their basic chemical structures such as flavones, flavonols, flavanones, flavanonols, and flavanols. Among them, flavonols (3-hydroxyflavone), containing a 3-hydroxyl group in association with its 4-keto group and double bond between 2- and 3- carbon atoms, have the best electron conjugated skeleton in flavonoid family, providing several resonance structures and chelating ability, through which various pharmacological activities such as antiviral, antitumour, anti-inflammatory, anticholinesterase, cytotoxicity and particularly high antioxidant activity are demonstrated. They prevent generation of free radicals and are used as food preservatives. Their strong electron conjugation provides them with fluorescent property, which make them used as imaging agents for therapeutic purpose.

Screening of Hallucinogenic Compounds and Genomic Characterisation of 40 Anatolian Salvia Species.

INTRODUCTION: Salvia, an important and widely available member of Lamiaceae family. Although comparative analysis on secondary metabolites in several Salvia species from Turkey has been reported, their hallucinogenic chemicals have not been screened thoroughly. OBJECTIVE: This study provides LC-MS/MS analysis of 40 Salvia species for screening their psychoactive constituents of salvinorin A and salvinorin B. 5S-rRNA gene non-coding region of Salvia plants was sequenced, aligned and compared with that sequence of Salvia divinorum plant. METHODOLOGY: Targeted molecules of salvinorin A and salvinorin B were quantified, using LC-MS/MS, from all aerial parts of 40 Salvia species, collected from different parts of Turkey. Regions of 5S-rRNA gene from different species were amplified by polymerase chain reaction and DNA sequences were aligned with Salvia divinorum DNA sequences. RESULTS: Very few of the Salvia species (S. recognita, S. cryptantha and S. glutinosa) contained relatively high levels of salvinorin A (212.86 ± 20.46 µg/g, 51.50 ± 4.95 µg/g and 38.92 ± 3.74 µg/g, respectively). Salvinorin B was also found in Salvia species of S. potentillifolia, S. adenocaulon and S. cryptantha as 2351.99 ± 232.22 µg/g, 768.78 ± 75.90 µg/g and 402.24 ± 39.71 µg/g, respectively. The sequences of 5S-rRNA gene of 40 different Salvia species were presented and it was found that none of the Salvia species in Turkey had similar DNA sequence to Salvia divinorum plant. CONCLUSION: This is the first report of screening 40 Salvia species in Turkey according to their psychoactive constituents, salvinorin A and salvinorin B and their genomic structures. It is possible that some of these Salvia species may exhibit some psycho activity. Thus, they need to be screened further. Copyright © 2017 John Wiley & Sons, Ltd.

Bioassay-guided isolation, identification of compounds from Origanum rotundifolium and investigation of their antiproliferative and antioxidant activities.

CONTEXT: Origanum (Lamiaceae) has been used in food and pharmaceutical industries. OBJECTIVE: Isolation and identification of bioactive compounds from Origanum rotundifolium Boiss. and investigation of their antiproliferative and antioxidant activities. MATERIALS AND METHODS: The aerial part of O. rotundifolium was dried and powdered (1.0 kg ±2.0 g) then extracted with hexane, ethyl acetate, methanol and water. Solvent (3 × 1 L) was used for each extraction for a week at room temperature. The aqueous extract was partitioned with ethyl acetate (3 × 1 L) to yield the water/EtOAc extract subjected to chromatography to isolate the active compounds. The structures of isolated compounds were elucidated by 1 D, 2 D NMR and LC-TOF/MS. RESULTS: Apigenin (1), ferulic acid (2), vitexin (3), caprolactam (4), rosmarinic acid (5), and globoidnan A (6) were isolated and identified. Globoidnan A (6), vitexin (3), and rosmarinic acid (5) revealed the excellent DPPH• scavenging effect with IC50 values of 22.4, 31.4, 47.2 µM, respectively. Vitexin (3) (IC50 3.6), globoidnan A (6) (IC50 4.6), apigenin (1) (IC50 8.9) and ferulic acid (2) exhibited more ABTS•+ activity than standard Trolox (IC50 13.8 µg/mL). Vitexin (3) revealed the most antiproliferative activity against HeLa, HT29, C6 and Vero cells lines with IC50 values of 35.6, 32.5, 41.6, 46.7 (µM), respectively. DISCUSSION AND CONCLUSION: Globoidnan A (6) has the most antioxidant effects on all assays. This has to do with the chemical structure of the compound bearing the acidic protons. Vitexin (3) could be a promising anticancer agent.

Cytotoxic, Apoptotic and Genotoxic Effects of Lipid-Based and Polymeric Nano Micelles, an In Vitro Evaluation.

Self-assembly systems (SAS) mainly consist of micelles, and liposomes are the classes of Nano Drug Delivery Systems with superior properties compared to traditional therapeutics in targeting cancer tumors. All commercially available nano-formulations of chemotherapeutics currently consist of SAS. According to our knowledge, a specific toxicity comparison based on material differences has not yet been performed. The purpose of this study was to evaluate and compare the toxicity of two SAS consisting of Sterically Stabilized Micelles (SSM) made of a lipid-based amphiphilic distearoyl-sn-glycero-phosphatidylethanolamine-polyethylene glycol (PEG)-2000 and a polymeric micelle (PM) consisting of Y-shape amphiphilic block copolymer, synthesized using poly ε-caprolactone and PEG. The mechanism of cytotoxicity and genotoxicity of micelles on L-929 healthy mouse fibroblast cells was assessed using Sulforhodamine-B, WST-1, Acridine Orange/Ethidium Bromide and alkaline single-cell gel electrophoresis assays. Results showed that SSM in conc. of 40 mg/mL shows very low cytotoxicity at the end of 24, 48 and 72 h. The DNA damage caused by SSM was much lower than PM while the latter one showed significant toxicity by causing apoptosis with the ED50 value of 3 mg/mL. While the DNA damage caused by SSM was ignorable, some DNA chain breaks were detected on cells treated with PM.

Antioxidant and Anticholinesterase Activities of Some Dialkylamino Substituted 3-Hydroxyflavone Derivatives.

BACKGROUND: Flavones, are a class of naturally occuring polyphenolic compounds which have 2-phenylchromen-4-one structure. Various studies showed that flavones have several pharmacological activities such as antioxidant, anti-inflammatory, antimicrobial, cytotoxic, antitumour and antiallergic. In the present study, 3-hydroxyflavones also called flavonols, posessing 4'-dialkylamino moiety were synthesized, and their antioxidant and anticholinesterase activities were investigated by comparison with unmodified 3-hydroxflavone. METHOD: For investigation of antioxidant potential, radical scavenging assays (DPPH•, ABTS+_, O2.-) were used along with CUPRAC and lipid peroxidation inhibitory assays, as well as anticholinesterase activity by Ellman method. RESULTS: The best results were obtained for 4'-N,N-dimethyl flavonol (1) in both antioxidant and anticholinesterase activity tests, possibly due to its least steric hinderance effect. It exhibited remarkable DPPH free radical scavenging activity (2.43±0,09 µg/mL) competing with a standard compound quercetin (2.10±0,10 µg/mL). Moreover, the other tested flavonols also showed high antioxidant activities. Compounds 5 and 6 exhibited close IC50 values to those of compound 1. CONCLUSION: Antioxidant activity test results were found to be well correlated with anticholinesterase activity test results indicating possible role of antioxidant compounds in the treatment of Alzheimer's disease.

A new lipid-based nano formulation of vinorelbine.

Vinorelbine (VLB) is a semi-synthetic Vinca alkaloid which is currently used in treatment of different cancer types mainly advanced breast cancer (ABC) and advanced/metastatic non-small cell lung cancer (NSCLC). However, its marketed formulation has been reported to have serious side effects, such as granulocytopenia, which is the major dose-limiting toxicity. Other unwanted effects include venous discoloration and phlebitis proximal to the site of injection, as well as localized rashes and urticaria, blistering, and skin sloughing. Our long-term aim in synthesizing a novel nanomicellar vinorelbine formulation is to reduce or even eliminate these side effects and increase drug activity by formulating the drug in a lipid-based system as a nanomedicine targeted to the site of action. To this end, the purpose of this study was to prepare, characterize, and determine the in vitro efficacy of vinorelbine-loaded sterically stabilized, biocompatible, and biodegradable phospholipid nanomicelles (SSM; size, ∼15 nm). Our results indicated that vinorelbine incorporate at high quantities and within the interface between the core and palisade sections of the micelles. Incorporation ratio of drug within sterically stabilized micelles increased as the total amount of drug in the system increased, and no drug particles were formed at the highest drug concentrations tested. The nanomicellar formulation of vinorelbine was ∼6.7-fold more potent than vinorelbine dissolved in DMSO on MCF-7 cell line. Collectively, these data indicate that vinorelbine-loaded SSM can be developed as a new, safe, stable, and effective nanomedicine for the treatment of breast and lung cancers.

Antioxidant and tyrosinase inhibitory activities of flavonoids from Trifolium nigrescens Subsp. petrisavi.

Trifolium nigrescens was researched for its chemical constituents for the first time. Bioassay-guided isolation of the EtOAc extract from the leaves of T. nigrescens resulted in the purification of a new biflavone, 4''',5,5″,7,7″-pentahydroxy-3',3'''-dimethoxy-3-O-ß-d-glucosyl-3″,4'-O-biflavone (1) along with eleven known compounds consisting of three phenolics (2-4), and eight flavonoid glycosides (5-12). Their structures were determined by extensive 1D and 2D NMR, and MS data analyses. The isolated compounds were evaluated for their antioxidant activity and inhibitory activity on mushroom tyrosinase. Highly potent inhibitions were found by compounds 7 (IC50 = 0.38 mM), 8 (IC50 = 0.19 mM), and 12 (IC50 = 0.26 mM) when compared with standard tyrosinase inhibitors kojic acid (IC50 = 0.67 mM) and l-mimosine (IC50 = 0.64 mM). The antioxidative effect of the isolated compounds and the extracts were determined by using ß-carotene-linoleic acid, DPPH(•) scavenging, ABTS(+•) scavenging, superoxide scavenging, and CUPRAC assays. The experimental findings indicated that all the compounds demonstrated activity in all antioxidant activity tests employed except for the compounds 2-6. Compounds 2-6 showed moderate activity only in ABTS(+•) scavenging assay. The new compound 1 exhibited better activity than standard α-tocopherol in DPPH(•) scavenging, and ABTS(+•) scavenging assays. The results show that T. nigrescens can be regarded as a potential source of antioxidant compounds and tyrosinase inhibitors of significance in both the pharmaceutical and food industries.

Evaluation of fruit extracts of six Turkish Juniperus species for their antioxidant, anticholinesterase and antimicrobial activities.

BACKGROUND: Juniperus L. (Cupressaceae) species are mostly spread out in the Northern Hemisphere of the world, and some of them are used as folkloric medicines. The fruits of some species are eaten. Since oxidative stress is one of the reasons for neurodegeneration and is associated with the Alzheimer's disease (AD), the extracts prepared from the fruits of six Juniperus species were screened for their antioxidant activity. Therefore, the extracts were also evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are chief enzymes in the pathogenesis of AD. In addition, antimicrobial activity was also evaluated. RESULTS: In the ß-carotene-linoleic acid assay, acetone extracts of J. oxycedrus subsp. oxycedrus, J. sabina and J. excelsa, and methanol extracts of J. phoenicea and J. sabina, effectively inhibited oxidation of linoleic acid. The hexane extracts of J. oxycedrus subsp. oxycedrus, J. foetidissima and J. phoenicea showed remarkable inhibitory effect against AChE and BChE. CONCLUSION: Because of their high antioxidant activity, J. excelsa, J. oxycedrus subsp. oxycedrus, J. sabina and J. phoenicia might be used in the food industry as preservative agents or extension of the shelf-life of raw and processed foods. Since the hexane extracts of J. oxycedrus subsp. oxycedrus and J. foetidissima demonstrated significant anticholinesterase activity they should be considered as a potential source for anticholinesterase agents.