Structure-activity relationship of anticancer drug candidate quinones.

Breast cancer is one of the most prevalent cancer types worldwide. Chemotherapy is a substantial approach in the management of breast cancer despite the occurrence of chemotherapy-associated side effects and the development of multidrug resistance in cancer cells. At this point, a variety of quinone derivatives may represent potential as possible anticancer drug candidates due to possessing structural similarity towards clinically used anticancer drugs like doxorubicin. Therefore, we investigated the cytotoxic effects of various quinone derivatives with structural diversity towards a variety of breast cancer cells. We further determined their toxicity in healthy cells to evaluate their drug capability potential. Eighteen quinone derivatives (arbutin, hydroquinone, alkannin, lapachol, lawsone, juglone, aloe-emodin, aloin, cascaroside A (8-O-ß-D-glucoside of 10-C-ß-D-glucosyl aloe-emodin anthrone), chrysophanol, chrysophanol-8-O-ß-D-glucoside, emodin, emodin-8-O-ß-D-glucoside, frangulin A (emodin-6-O-a-L-rhamnoside), physcion, rhein, sennoside A, sennoside B (sennoside A and sennoside B are stereoisomers and rhein-dianthrone diglycosides in which ß-D-glucose units are bound to the OH groups of rhein anthrones at their 8th positions) were tested on MCF-7, SK-BR-3, MDA-MB-468, and MDA-MB-231 breast cancer cells and on H9c2 healthy rat cardiac myoblast cells in terms of their cytotoxicity and toxicity, respectively. The resazurin reduction assay was used to determine the cytotoxicity. Among the tested compounds, two naphthoquinone derivatives alkannin and juglone exhibited remarkable cytotoxicity on breast cancer cells and exhibited alleviated toxicity profiles on healthy cells deserving further investigation as possible drug candidates against breast cancer. Structure-activity relationships of these compounds were also evaluated and discussed. Alkannin and juglone, which are naphthoquinone derivatives isolated from natural sources, may be promising agents in the development of drug-candidate molecules with increased efficacy and safety for breast cancer.

trans-Tiliroside: A potent α-glucosidase inhibitor from the leaves of Elaeagnus angustifolia L.

Elaeagnus angustifolia L. (Elaeagnaceae) is an important medicinal plant associated with numerous pharmacological activities. Its leaves are used as a therapeutic agent in traditional medicinal systems to treat diabetes. However, the active compounds responsible for the beneficial effects of E. angustifolia remain unclear. In this study, we determined the bioactive profile of E. angustifolia leaves using open column chromatography and semi-preparative HPLC. Further, we sought to determine its α-glucosidase and α-amylase inhibitory activities, and its DPPH and ABTS radical-scavenging activities. Four undescribed flavonol glycosides, igdoside A-D, and four known glucosides were isolated from the ethyl acetate and n-butanol extracts of E. angustifolia leaves. Thereafter, the compound structures were identified using spectroscopic methods, including NMR and mass spectrometry. Of the compounds extracted, kaempferol-3-O-(6″-trans-p-coumaroyl)-ß-D-glucopyranoside (trans-tiliroside), exhibited the highest α-glucosidase inhibitory activity with an IC50 value of 2128 ±â€¯63 µM compared to the positive control, acarbose (IC50 = 6561 ±â€¯207 µM). trans-Tiliroside was also found to exhibit potent scavenging activity against the ABTS radical, with an IC50 value of 5 ±â€¯0 µM, compared to the positive controls, trolox (31 ±â€¯1 µM) and α-tocopherol (50 ±â€¯1 µM). In addition, isorhamnetin-3-O-ß-D-galactopyranoside (IC50 = 6 ±â€¯0 µM) and astragalin (IC50 = 6 ±â€¯0 µM) showed similar ABTS radical-scavenging activity as trans-tiliroside. Based on HPLC, the content of trans-tiliroside was 9.69% in the ethyl acetate extract, 1.04% in decoction, 0.34% in 70% methanol extract, and 0.23% in infusion. None of the extracts and compounds showed α-amylase inhibition or DPPH-scavenging activity.

Inhibitory potential on key enzymes relevant to type II diabetes mellitus and antioxidant properties of the various extracts and phytochemical constituents from Rumex acetosella L.

Type II diabetes mellitus is a common and costly disease worldwide, characterized by hyperglycemia. Alpha (α)-amylase and α-glucosidase are important targets in diabetes therapy. Inhibition of these enzymes may lessen hyperglycemia, preventing diabetic complications. Oxidative stress is another factor involved in the disease's etiology. In the present study, we investigated antidiabetic profiles of the various extracts and phytochemicals of Rumex acetosella. Since the plant has been traditionally used for the antidiabetic purposes. α-amylase and α-glucosidase inhibitory studies in addition to DPPH•, ABTS•+, NO 2 - radical scavenging, and phosphomolybdate antioxidant assays were performed to evaluate the antidiabetic property. Specifically, the ethanol and ethanol-water extracts remarkably inhibited α-glucosidase than that of acarbose, unlike their slight/no inhibition on α-amylase. Convincing α-glucosidase inhibitory and antioxidant potential of alcohol-including extracts verified the ethnobotanical use of R. acetosella as an antidiabetic agent. PRACTICAL APPLICATIONS: The incidence of Type II DM is rising globally. Reducing hyperglycemia holds great importance to prevent devastating outcomes of diabetic complications. Ethnobotanical use of natural sources for medical purposes provides a basis for their potential activity against various diseases. The introduction of herbal agents may lead to the development of new drug candidates with convincing activity. Rumex acetosella L. has been traditionally used for the antidiabetic purposes. The research pointed out various extracts and phytochemical constituents from R. acetosella may act as antihyperglycemic agents. Particularly, alcohol-including extracts of R. acetosella may be considered as promising alternatives in the prevention or treatment of type II DM. The study puts emphasis on the therapeutic value of the plants for antidiabetic medication.

A new perspective on evaluation of medicinal plant biological activities: The correlation between phytomics and matrix metalloproteinases activities of some medicinal plants.

Phytomics or metabolomics is analysis of large-scale primary and secondary metabolites of plant extracts and provides very meaningful data to monitor or evaluate cellular function or systems biology. The activity of plant extracts depends on the synergistic/antagonistic effect of different metabolites rather than single active metabolites. Matrix metalloproteinases (MMPs) have an active role in the formation of many diseases. To our knowledge, there is no study on the correlation between the phytomics and MMP inhibitory activity of Achillea millefolium, Achillea filipendulina (Asteraceae), Mentha piperita, and Salvia officinalis (Lamiaceae), (AAMS). Therefore, this study aimed to correlate the metabolomics profiling of AAMS extracts to identify the metabolites responsible for the MMP inhibitory activity based on phytomics data. The AAMS extracts showed a significant MMP inhibitory effect (57.73-92.73%) at different concentrations (25-500 µg/mL). In order to identify the metabolites responsible for such activities in the extract, the metabolomic profiling of the plants was investigated using gas chromatography-mass spectrometry (GC-MS). After deconvolution and aligning of the chromatograms, 284 metabolites were detected, of which 149 were annotated using retention index libraries. Multivariate analyses results indicated that A. millefolium and A. filipendulina showed similar metabolomic profiles, while M. piperita and S. officinalis differed both from each other and from Achillea species. The correlation analysis was applied to evaluate the correlation between metabolomic levels and MMP inhibitory activities, and 96 metabolites had a negative correlation (r ≤ -0.70) and 55 had a highly positive correlation (r ≥ 0.70) with MMP inhibitory activity. This is the first study which revealed that phytomics, plant metabolomics, can be used for activity evaluation and a single metabolite may not be responsible for a specific activity. In conclusion, phytomics can be a more useful tool for the evaluation of the activities than investigating a single metabolite. This new perspective can also provide a better understanding of plant metabolomics and can be easily employed for future research on plant activity.

The roles of valerenic acid on BDNF expression in the SH-SY5Y cell.

The roots of Valeriana officinalis L. (Valerianaceae) are used for treating sleep disorders and/or mild nerve tension. The effect of valerenic acid on brain-derived neurotrophic factor (BDNF) has not yet been studied, although it is known that gamma-amino butyric acid A (GABAA) receptor is regulated by BDNF, which modulates the depressive-like behavior and neurogenesis. The purpose of this study is to determine the effect of V. officinalis root extract (VO), its main constituents valerenic acid (VA) and acetoxy valerenic acid (AVA) as well as valerenic acid-free (VAF), acetoxy valerenic acid-free (AVAF) extracts and increasing amounts of valerenic acid containing extracts on the BDNF expression in SH-SY5Y cell lines. The effect of methanolic extracts of VO, VA, AVA, VAF, AVAF, and the extracts whose amount of VA were increased gradually, were tested using a Human BDNF ELISA kit with 17ß-estradiol as a positive control. The VO and VA extracts caused a significant (p < 0.001) increase in the BDNF expression in SH-SY5Y cells compared to control. This effect completely disappeared when cells were treated with VAF extract. AVA alone did not show any significant change in the BDNF levels. The extracts with increasing amount of VA led to a concentration- dependent effect on the cells. In conclusion, our findings suggest that the antidepressant-like effect of the VO extract is also related to BDNF expression, and that this is mainly due to the presence of VA in the extract. Removing VA from VO extract leads to a loss of activity. Moreover, the concentration of VA plays a role for BDNF expressions in SH-SY5Y cells, which demonstrates the importance of quality control on the commercially available products.

Aloe-emodin as drug candidate for cancer therapy.

As a leading cause of global mortality, cancer frequently cannot be cured due to the development of drug resistance. Therefore, novel drugs are required. Naturally occurring anthraquinones are mostly present in Rumex and Rhamnus species and are of interest because of their structural similarity to anthracyclines as well established anticancer drugs. In the present study, we focused on the structural elucidation of phytochemicals from R. acetosella as well as the investigation of cytotoxicity and modes of action of the main anthraquinone aglycons (emodin, Aloe-emodin, physcion, rhein). Resazurin reduction and protease viability marker assays were conducted to test their cytotoxicity. Microarray-based gene expression profiling was performed to identify cellular pathways affected by the compounds, which was validated by qPCR analyses and functional assays. Flow cytometry was used to measure cell cycle distribution, apoptosis and necrosis, induction of reactive oxygen species (ROS) and disruption of mitochondrial membrane potential (MMP). The comet assay was used to detect DNA damage. Aloe-emodin as the most cytotoxic compound revealed IC50 values from 9.872 µM to 22.3 µM in drug-sensitive wild-type cell lines and from 11.19 µM to 33.76 µM in drug-resistant sublines, was selected to investigate its mechanism against cancer. Aloe-emodin-induced S phase arrest, ROS generation, DNA damage and apoptosis. Microarray hybridization revealed a profile of deregulated genes in Aloe-emodin-treated CCRF-CEM cells with diverse functions such as cell death and survival, cellular growth and proliferation, cellular development, gene expression, cellular function and maintenance. Aloe-emodin as well as R. acetosella deserve further investigations as possible antineoplastic drug candidates.

Phenylacylated-flavonoids from Peucedanum chryseum

ABSTRACT Phytochemical investigation of the methanol extract of the aerial parts of Peucedanum chryseum (Boiss. & Heldr.) D.F.Chamb., Apiaceae, led to the isolation of a dihydrofuranochromone, cimifugin (1); a phloroacetophenone glucoside, myrciaphenone A (2); and a flavonoid glycoside, afzelin (3) along with two phenylacylated-flavonoid glycosides: rugosaflavonoid C (4), and isoquercitrin 6"-O-p-hydroxybenzoate (5). The structures of compounds 1-5 were elucidated by extensive 1D- and 2D-NMR spectroscopic analysis in combination with MS experiments and comparison with the relevant literature. All compounds are reported for the first time from this species and compounds 2, 4, and 5 from the genus Peucedanum and from Apiaceae.

Molecular docking and ex vivo and in vitro anticholinesterase activity studies of Salvia sp. and highlighted rosmarinic acid.

BACKGROUND/AIM: To evaluate acetylcholinesterase (AChE) inhibitory activity and antioxidant capacity of the major molecule from Salvia sp., rosmarinic acid, as a drug candidate molecule for treatment of Alzheimer disease (AD). MATERIALS AND METHODS: The AChE inhibitory activity of different extracts from Salvia trichoclada, Salvia verticillata, and Salvia fruticosa was determined by the Ellman and isolated guinea pig ileum methods, and the antioxidant capacity was determined with DPPH. The AChE inhibitory activity of the major molecule rosmarinic acid was determined by in silico docking and isolated guinea pig ileum methods. RESULTS: The methanol extract of Salvia trichoclada showed the highest inhibition on AChE. The same extract and rosmarinic acid showed significant contraction responses on isolated guinea pig ileum. All the extracts and rosmarinic acid showed high radical scavenging capacities. Docking results of rosmarinic acid showed high affinity to the selected target, AChE. CONCLUSION: In this study in vitro and ex vivo studies and in silico docking research of rosmarinic acid were used simultaneously for the first time. Rosmarinic acid showed promising results in all the methods tested.

Isolation of a flavonoid, apigenin 7-O-glucoside, from Mentha longifolia (L.) Hudson subspecies longifolia and its genotoxic potency.

Mentha is a medicinal and aromatic plant belonging to the Lamiaceae family, which is widely used in food, flavor, cosmetic and pharmaceutical industries. Recently, it has been found that the use of Mentha as a pharmaceutical source is based on its phytochemical constituents that have far been identified as tannins, saponins, phenolic acids and flavonoids. This study was designed to evaluate the mutagenic and antimutagenic activities of apigenin 7-O-glucoside (A7G), a flavonoid isolated from Mentha longifolia (L.) Hudson subspecies longifolia (ML). The possible antimutagenic potential of A7G was examined against mutagens ethyl methanesulfonate and acridine in an eukaryotic cell system Saccharomyces cerevisiae and sodium azide in Salmonella typhimurium TA1535 and 9-aminoacridine in S. typhimurium TA1537. According to our findings, any concentrations of the A7G used did not show mutagenic activity but exerted strong antimutagenic activities at tested concentrations. The inhibition rates for the Ames test ranged from 27.2% (S. typhimurium TA1535: 0.4 µM/plate) to 91.1% (S. typhimurium TA1537: 0.2 µM/plate) and for the yeast deletion assay from 4% to 57.7%. This genotoxicological study suggests that a flavonoid from ML owing to antimutagenic properties is of great pharmacological importance and might be beneficial to industries producing food additives, cosmetics and pharmaceuticals products.