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Flavones Inhibit the Activity of AKR1B10, a Promising Therapeutic Target for Cancer Treatment

AKR1B10 is an NADPH-dependent reductase that plays an important function in several physiological reactions such as the conversion of retinal to retinol, reduction of isoprenyl aldehydes, and biotransformation of procarcinogens and drugs. A growing body of evidence points to the important role of the enzyme in the development of several types of cancer (e.g., breast, hepatocellular), in which it is highly overexpressed. AKR1B10 is regarded as a therapeutic target for the treatment of these diseases, and potent and specific inhibitors may be promising therapeutic agents. Several inhibitors of AKR1B10 have been described, but the area of natural plant products has been investigated sparingly. In the present study almost 40 diverse phenolic compounds and alkaloids were examined for their ability to inhibit the recombinant AKR1B10 enzyme. The most potent inhibitors-apigenin, luteolin, and 7-hydroxyflavone-were further characterized in terms of IC50, selectivity, and mode of action. Molecular docking studies were also conducted, which identified putative binding residues important for the interaction. In addition, cellular studies demonstrated a significant inhibition of the AKR1B10-mediated reduction of daunorubicin in intact cells by these inhibitors without a considerable cytotoxic effect. Although these compounds are moderately potent and selective inhibitors of AKR1B10, they constitute a new structural type of AKR1B10 inhibitor and may serve as a template for the development of better inhibitors.

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One new alkaloid from Chelidonium majus L

One new alkaloid, together with 10 known compounds were isolated from the aerial parts of Chelidonium majus L. by repeated silica gel column chromatography. Their chemical structures were elucidated on the basis of physicochemical and spectroscopic data. Among them, 6-acetonyldihydrochelerythrine (4), 6-acetonyldihydrosanguinarine (5), 6-ketenesanguinarine (6), demethylchelerythrine (7) and demethylsanguinarine (11) were isolated for the first time from this plant. Compound 6 was identified as a new compound. These compounds were screened for cytotoxicity against human non-small lung carcinoma (H1299), breast cancer (MCF-7) and liver cancer (SMMC-7721). In a series of cytotoxic tests, compounds 9 and 10 displayed potent cytotoxic activity against H1299, MCF-7 and SMMC-7721, with the IC50values of 8.16-35.25 mug/mL.

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Bioactive isoquinoline alkaloids from Glaucium arabicum

Phytochemical investigation of the aerial parts of Glaucium arabicum Fresen. (Papaveraceae) led to the isolation of two previously undescribed isoquinoline alkaloids araglaucine A, and araglaucine B, together with seven known ones 1-[(3?,4?-dimethoxy-2?-methylcarboxy)benzoyl]-6,7-methylenedioxy isoquinoline (araglaucine C), (7R,14S)-trans-N-methylcanadinium nitrate, (R,S)-trans-N-methylstylopine, 14-hydroxy-N-methyl canadine, 14-hydroxy-N-methyl stylopine, protopine, norsanguinarine, as well as beta-sitosterol, and beta-sitosterol 3-O-beta?D-glucoside. Their structural elucidation was based on the measurements of 1D, 2D NMR, HRESIMS, UV, IR and X-ray crystallography. The compounds were evaluated for their anti-melanogenesis activity using B16 melanoma cell lines. Compound (7R,14S)-trans-N-methylcanadinium nitrate exhibited a promising melanin synthesis inhibitory activity (?35%) at concentration 5 mug/ml (12.01 muM) with low cytotoxicity (?12%).

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Protopine hydrochloride

Protopine hydrochloride (5,6,14,14a-tetrahydro-14a-hydroxy-7 -methyl-8H-bis[1,3] benzodioxolo [5,6-a:4,5-g]quinolizinium chloride, C20H20 NO5 +¡¤Cl-) is the salt of the isoquinoline alkaloid protopine. It is formed by the action of dilute hydrochloric acid on the protopine free base. The N-methyl and hydroxyl groups are in a trans configuration in the quinolizine ring and the central quinolizine N-C bond is unusually long [1.579 (2) A]. The crystal is a racemate.

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Comparison of anticancer activity and hplc-dad determination of selected isoquinoline alkaloids from thalictrum foetidum, berberis sp. And chelidonium majus extracts

Background: Plants are an important origin of natural substances that The raw material for various pharmaceutical and therapeutic applications due to The presence of phytochemicals, such as alkaloids. Alkaloids, which are found in different plant species, possess numerous biological activities. Some alkaloids have strong cytotoxic effects on various cancer cells. The search for new drugs to treat various cancers is one of The most important challenges of modern scientific research. Objective: This study aimed to investigate of cytotoxic activity of extracts that were obtained from Chelidonium Majus; Berberis sp.; Thalictrum foetidum containing various alkaloids on selected cancer cell lines. The aim was also The quantification of selected alkaloids in The investigated extracts by HPLC. Methods: The analysis of alkaloids contents were performed while using HPLC in reversed phase (RP) mode using Polar RP column and mobile phase containing acetonitrile, water, and ionic liquid. The cytotoxic effect of The tested plant extracts and respective alkaloids’ standards were examined while using human pharyngeal squamous carcinoma cells (FaDu), human tongue squamous carcinoma cells (SCC-25), human breast adenocarcinoma cell line (MCF-7), and human triple-negative breast adenocarcinoma cell line (MDA-MB-231). Conclusion: All of The investigated plant extracts possess cytotoxic activity against cancer cell lines: FaDu, SCC-25, MCF-7, and MDA-MB-231. The highest cytotoxic activity against FaDu and MDA-MB-231 cells was observed for Chelidonium majus root extract, while the highest cytotoxic activity against SCC-25 and MCF-7 cells was estimated for The Thalictrum foetidum root extract. There obtained significant differences in The cytotoxic activity of extracts that were obtained from The roots and herbs of Chelidonium majus and Thalictrum foetidum. Based on these results, investigated plant extracts can be recommended for further investigations of anticancer activity.

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New anti-Alzheimer drugs from biodiversity: The role of the natural acetylcholinesterase inhibitors

Alzheimer’s disease (AD) is a progressive neurodegenerative pathology with severe economic and social impact. There is currently no cure, although cholinesterase inhibitors provide effective temporary relief of symptoms in some patients. Nowadays, drug research and development are based on the cholinergic hypothesis that supports the cognition improvement by regulation of the synthesis and release of acetylcholine in the brain. There are only four commercial medicines approved for treatment of AD, and natural products have played an important alternative role in the research for new acetylcholinesterase inhibitors, as exemplified through the discovery of galantamine. This profile conducts us to give in this paper an overview relating the several classes of natural products with anti-cholinesterasic activity as potential templates to the design of new selective and powerful anti-Alzheimer drugs.

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Identifying cancer-related molecular targets of Nandina domestica Thunb. by network pharmacology-based analysis in combination with chemical profiling and molecular docking studies

Ethnopharmacological relevance: The fruits of Nandina domestica Thunb. have served as folk medicines in Chinese and Japanese tradition for treatment of several tumors including pharynx tumor and tooth abscess for many years, yet its exact mechanism of action is not yet known. Aim of the study: The study targets the identification of the main constituents of the fruits extracts and investigation of their mode of action in cancer therapy via pharmacology-based analysis and molecular docking. Materials and methods: The different extracts of N. domestica Thunb. were analyzed via UPLC?MS/MS for identification of their active constituents. STITCH, DAVID, KEGG and STRING database were utilized for construction of compound-target and compound-target-pathway networks using Cytoscape 3.2.1. Molecular docking analysis of the top hit compounds was performed against the identified top hit molecular targets in the constructed networks. In vitro-testing of Nandina domestica Thunb. against colorectal cancer cell lines was carried out and correlated to the chemical profile of the extract to identify important biomarkers. The ADME properties of the active compounds were also evaluated. Results: 22 compounds were identified by UPLC?MS/MS analysis and were forwarded to network pharmacology-based analysis. Results showed the enrichment of 5 compounds and 4 molecular targets in the network namely; AKT1, CASP3, MAPK1 and TP53. The pathway analysis of the identified targets revealed that 15 cancer-related pathways were enriched including colorectal cancer, endometrial cancer and small-cell lung cancer. In-vitro testing of the extracts against colo-rectal cancer cell lines revealed the fractions enriched in the identified hit compounds were indeed the most active as revealed from the HCA-heat-map. ADME results showed that all compounds were drug-like candidates showing acceptable values according to Lipinski’s rule. Conclusions: Network pharmacology analysis revealed that the compounds isoquercitrin, quercitrin, berberine, chlorogenic acid and caffeic acid showed strong synergistic interactions with the cancer-related targets and pathways. It could be concluded that N. domestica Thunb. constituents affect both apoptosis and Akt-signaling pathways during the stages of early and intermediate adenoma through interaction with the targets CASP3 and MAPK1 (ErC2) while during the stages of late adenoma and carcinoma, the compounds acts through the p53 and ErbB signaling pathways.

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Semi-synthetic aristolactams-inhibitors of CDK2 enzyme

Several analogs of aristolochic acids were isolated and derivatized into their lactam derivatives to study their inhibition in CDK2 assay. The study helped to derive some conclusions about the structure-activity relation around the phenanthrin moiety. Semi-synthetic aristolactam 21 showed good activity with inhibition IC50 of 35 nM in CDK2 assay. The activity of this compound was comparable to some of the most potent synthetic compounds reported in the literature.

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ALKALOIDS FROM Papaver albiflorum Pacz. subsp. albiflorum AND P. cf. stevenianum A. D. Mikheev

Papaver albiflorum Pacz. subsp. albiflorum (tetraploid, 2n = 28; total alkaloid content 0.001percent) afforded corytuberine, protopine and allocryptopine as dominant alkaloids; in addition, small amounts of mecambrine, thebaine, scoulerine, rhoeadine, papaverrubines D, C, A and E, berberine and coptisine were detected.Papaver cf. stevenianum A.D.MIKHEEV (hexaploid, 2n = 42; total alkaloid content 0.066percent and 0.015percent, respectively) gave berberine as the principal alkaloid (0.065percent and 0.013percent, respectively) which was responsible for the yellow colour of latex.Corytuberine, allocryptopine, protopine and isocorydine were isolated as minor alkaloids and small amounts of corydine, mecambrine, thebaine, scoulerine, papaverrubines D, C, A and E, coptisine, cis-N-methylcanadinium hydroxide and N-methylthebainium hydroxide were detected.Alkaloid PCH 1, isolated recently as minor constituent from Papaver rhoeas var. chelidonioides O.KUNTZE, has been shown to be identical with isorhoeagenine.

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Characterization of isoquinolin alkaloids from Fumaria agraria and evaluation of their antiproliferative activity against human breast cancer cell lines

Fumaria agraria (Fumariaceae) is an annual plant used traditionally in Algeria for various medicinal purposes. Alkaloids extracts from areal parts were subjected to solvent fractionation and GCMS analysis. Rates of alkaloids recorded were respectively of 700 mg/100 g of Dry Weight of total alkaloids ?TA?, 400 mg/100 g DWof neutral fraction ?NF?, 40 mg/100 g DW of acid fraction ?AF? and 250 mg/100 g DWof the basic fraction ?BF?. Protopine was found to be the most potent alkaloid of the total extract (41.55%). Fractionation showed that Protopine was found essentially in the BF fraction (60.7%). Antiproliferative activities of total alkaloids extract and BF fraction were assessed on MCF-7 and MDAMB- 231 breast cancer and MCF10A mammary normal cell lines, by trypan blue exclusion essay. Both TA extract and BF fraction showed potent antiproliferative activities against MCF-7 breast cancer cells in varying degrees with respective IC50 of 47.8 ¡À 1.8 mug/ml and 17.6 ¡À 0.4 muM, without cell death induction but no impact was observed on normal MCF-10A cell growth. MCF7 Cell line was most sensitive (IC50 of 17,6 ¡À 0,4muM) to BF fraction effect than MDAMB-231 one (IC50 of 36,4 ¡À 0,6muM). Isoquinolein alkaloids of Fumaria agraria and specially the fraction which contain Protopine showed potent antiproliferative activity against breast cancer cells.

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