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.

Identifying phenolics by UPLC-MS/MS in some Prangos Lindl. species and α-glucosidase inhibitory activities.

Diabetes mellitus is a chronic metabolic disorder associated with biochemical, physiological, and pathological changes in the liver and characterized by some deficiencies in insulin secretion or insulin action. Prangos Lindl. species are important plants used as spice and medicine in Asian countries, including Türkiye. This study first aimed to evaluate the antidiabetic potential of the aerial parts of the 5 different Prangos species (Apiaceae) collected from various locations to discover and identify bioactive phenolic components. The results revealed that the methanolic extract of P. heyniae exhibited the highest activity against α-glucosidase inhibition compared to the other Prangos species (IC50 = 458.54 ± 5.62 µg/mL). For this reason, the active species P. heyniae (an endemic species) was subjected to UPLC-MS/MS to evaluate the possible active phenolic components. The results showed that 53 phenolic compounds were correctly screened, 21 were precisely determined by UPLC-MS/MS in P. heyniae. Therefore, it was concluded that the aerial parts of P. heyniae might have therapeutic potential for hyperglycemia due to its phenolic compounds. Moreover, quinic acid (3.66%), chlorogenic acid (2.35%), rutin (2.96%), and hesperidin (0.79%) might be potential markers of the methanolic extract of P. heyniae. In the end, this study provides comprehensive knowledge regarding the phenolic profile of P. heyniae related to antidiabetic activity for the first time in this study.

In Vitro and in Silico Investigation of DNA Interaction, Topoisomerase I and II Inhibitory Properties of Polydatin.

Polydatin or piceid, is the 3-O-glucoside of resveratrol and is found abundantly in grapes, peanuts, wine, beer, and cacao products. Although anticancer activity of polydatin was reported before, and potential antiproliferative mechanisms of polydatin have been proposed, its direct effects on DNA and inhibitory potential against topoisomerase enzymes have remained unknown. In this study we aimed to reveal the link between polydatin's effects on DNA and DNA-topoisomerases and its antiproliferative promise. For this purpose, we evaluated the effects of polydatin on DNA and DNA topoisomerase using in vitro and in silico techniques. Polydatin was found to protect DNA against Fenton reaction-induced damage while not showing any hydrolytic nuclease effect. Further, polydatin inhibited topoisomerase II but not topoisomerase I. According to molecular docking studies, polydatin preferably showed minor groove binding to DNA where the stilbene moiety was important for binding to the DNA-topoisomerase II complex. As a result, topoisomerase II inhibition might be another anticancer mechanism of polydatin.

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.

Cytotoxic naphthoquinones from Arnebia densiflora (Nordm.) Ledeb and determining new apoptosis inducers.

In this study, phytochemical composition of Arnebia densiflora (AD) was determined and cytotoxic effects of the n-hexane extract and compounds isolated from this species on various cell lines were investigated. By means of serial chromatographic studies, 6 naphthoquinone derivatives were yielded, which are isovalerylalkannin, α-methyl-n-butyl alkannin, acetylalkannin, ß-acetoxy isovalerylalkannin, alkannin and a new compound: 4-hydroxy 4-methyl valeryl alkannin. Structures of the isolated compounds were elucidated using UV, IR, 1D-2D NMR, MS and CD methods. Cytotoxic effects of the extract and isolated alkannins were investigated on L929, HeLa, HEp-2 cells. AD and the isolated compounds demonstrated moderate to strong cytotoxic effects (IC50 range: 4.92-172.35 µg/ml). The results of DNA fragmentation and caspase-3 activity studies on HeLa cells exhibited that AD and the naphthoquinones isolated from it caused cytotoxicity through induction of apoptosis.[Formula: see text].

Tyrosinase and α-glucosidase inhibitory potential of compounds isolated from Quercus coccifera bark: In vitro and in silico perspectives.

Bark of Quercus coccifera is widely used in folk medicine. We tested tyrosinase and α-glucosidase inhibitory effects of Q. coccifera bark extract and isolated compounds from it. The extract inhibited tyrosinase with an IC50 value of 75.13 ±â€¯0.44 µg/mL. Among the isolated compounds, polydatin (6) showed potent tyrosinase inhibition compared to the positive control, kojic acid, with an IC50 value of 4.05 ±â€¯0.30 µg/mL. The Q. coccifera extract also inhibited α-glucosidase significantly with an IC50 value of 3.26 ±â€¯0.08 µg/mL. (-)-8-Chlorocatechin (5) was the most potent isolate, also more potent than the positive control, acarbose, with an IC50 value of 43.60 ±â€¯0.67 µg/mL. According to the kinetic analysis, 6 was a noncompetitive and 5 was a competitive inhibitor of tyrosinase, and 5 was a noncompetitive α-glucosidase inhibitor. In the light of these findings, we performed in silico molecular docking studies for 5 and 6 with QM/MM optimizations to predict their tyrosinase inhibition mechanisms at molecular level and search for correlations with the in vitro results. We found that the ionized form of 5 (5i) showed higher affinity and more stable binding to tyrosinase catalytic site than its neutral form, while 6 bound to the predicted allosteric sites of the enzyme better than the catalytic site.

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.

Cytotoxic compounds from endemic Arnebia purpurea.

Phytochemical studies of the roots and aerial parts of endemic Arnebia purpurea S. Erik & H. Sumbul resulted in the isolation and characterization of four naphthoquinones [isovalerylalkannin (1), α-methyl-n-butanoyl alkannin (2), acetylalkannin (3), and alkannin (4)], a triterpene derivative [3-O-acetyl-oleanolic acid (5)], a steroid [ß-sitosterol (6)], three flavonoid glycosides [isorhamnetin-3-O-rutinoside (7), kaempferol-3-O-rutinoside (8), kaempferol 3-O-(5"-acetyl) apiofuranoside 7-O-rhamnopyranoside (9)] and a phenolic acid [rosmarinic acid (10)]. 3-O-Acetyl-oleanolic acid, isorhamnetin-3-O-rutinoside, kaempferol-3-O-mrutinoside, and kaempferol 3-O-(5"-acetyl) apiofuranoside 7-O-rhamnopyranoside are reported from an Arnebia species for the first time. Cytotoxic activities on L929 murine fibrosarcoma cell line of the isolated compounds were investigated using MTT assay. Naphthoquinones (1-4) showed intermediate cytotoxic activity in comparison with the standard, doxorubicin.

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.

Two antigenotoxic chalcone glycosides from Mentha longifolia subsp. longifolia.

CONTEXT: Mentha L. (Labiatae) species (mint) with their flavoring properties have been used in food industries for centuries. Besides they have a great importance in drug development and medicinal applications due to various bioactive compounds of several members of the genus. OBJECTIVE: The aim of this study was to isolate bioactive compounds with antimutagenic potential by bio-guided fractionation and determine their structures by spectroscopic methods. MATERIALS AND METHODS: The structural elucidation of the isolated compounds was done based on spectroscopic methods, including MALDI-MS, UV, IR, and 2D NMR experiments, and the bio-guided fractionation process was done by using the Ames/Salmonella test system. Henceforth, solely genotoxic and antigenotoxic potential of the new compounds were also confirmed up to 2 µM/plate by using the same test system. RESULTS: Two new chalcone glycosides: (ßR)-ß,3,2',6'-tetrahydroxy-4-methoxy-4'-O-rutinosyldihydrochalcone and (ßR)-ß,4,2',6'-tetrahydroxy-4'-O-rutinosyldihydrochalcone, were isolated from Mentha longifolia (L.) Hudson subsp. longifolia, together with known six flavonoid glycosides and one phenolic acid: apigenin-7-O-glucoside, luteolin-7-O-glucoside, apigenin-7-O-rutinoside, luteolin-7-O-rutinoside, apigenin-7-O-glucuronide, luteolin-7-O-glucuronide, rosmarinic acid. According to the antimutagenicity results, both new test compounds significantly inhibited the mutagenic activity of 9-aminoacridine in a dose-dependent manner at the tested concentrations from 0.8 to 2 µM/plate. (ßR)-ß,4,2',6'-Tetrahydroxy-4'-O-rutinosyldihydrochalcone showed the maximum inhibition rate as 75.94% at 2 µM/plate concentration. CONCLUSIONS: This is the first report that two new chalcone glycosides were isolated from Mentha longifolia subsp. longifolia and their antimutagenic potentials by using mutant bacterial tester strains. In conclusion, the two new chalcone glycosides showed a significant antigenotoxic effect on 9-aminoacridine-induced mutagenesis at tested concentrations.

Investigation on anti-inflammatory and antiulcer activities of Anchusa azurea extracts and their major constituent rosmarinic acid.

This study investigated the anti-inflammatory and antiulcer activities of different extracts from the aerial parts and the roots of Anchusa azurea Miller var. azurea (Boraginaceae), as well as their major constituent, rosmarinic acid. The extracts were water (AWa, RWa) and methanol (AMe, RMe) extracts prepared from the aerial parts and the roots of A. azurea, respectively. The AMe extract was found to exert anti-inflammatory effects; so it was evaporated to dryness and the residue was dissolved in distilled water (AMeWa) and then further fractionated with n-hexane (AMeHe) and n-butanol (AMeBu). Anti-inflammatory activity was investigated in rats using carrageenan-induced acute inflammation, and antiulcer activity was investigated using indomethacin-induced gastric damage. The methanolic extract from the aerial parts, its n-butanol fraction, and rosmarinic acid, which was isolated from the n-butanol fraction of the AMe extract, showed significant dose-dependent antiinflammatory activity. During the acute phase of inflammation, the anti-inflammatory activity of rosmarinic acid was comparable to that of ibuprofen. No antiulcer activity was observed. The experimental data demonstrate that A. azurea Miller var. azurea and rosmarinic acid display significant anti-inflammatory activity.

Chemical constituents of two sages with free radical scavenging activity.

From the aerial parts of Salvia trichoclada Bentham and S. verticillata L. one new and two known phenolic acids, 3-(3',4'-dihydroxyphenyl)-2-hydroxymethyl propionic acid (1), 3-(3',4'-dihydroxyphenyl) lactic acid (2), and rosmarinic acid (3); two flavonoids, apigenin 4'-methyl ether 7-O-glucuronide (4), and luteolin 7-O-beta glucuronide (5); two lupan type triterpene aglycones, lupeol (6), and 30-hydroxylup-20 (29)-en-3-on (7); an oleanane-type triterpene acid, oleanolic acid (8); and an ursan-type triterpene acid, ursolic acid (9) were isolated. The structures of the compounds were elucidated by spectroscopic analysis. Different extracts of the plants were examined for their free radical scavenging activities by DPPH (2,2-Diphenyl-1-picrylhydrazyl) assay. Some of the polar extracts showed high free radical scavenging activity.

In vitro effects of rosmarinic acid on glutathione reductase and glucose 6-phosphate dehydrogenase.

CONTEXT: Glutathione reductase (GR, NADPH:oxidized glutathione oxidoreductase, E.C 1.6.4.2) is a flavoprotein that catalyzes the NADPH-dependent reduction of oxidized glutathione (GSSG). GR is a crucial enzyme in the antioxidant system by maintaining reduced glutathione (GSH). Glucose 6-phosphate dehydrogenase (G6PD, glucose 6-phosphate (G6P):NADP(+) oxidoreductase, EC 1.1.1.49) is the key regulatory enzyme of the pentose phosphate pathway and maintains NADPH for reductive reactions. OBJECTIVE: Rosmarinic acid (RA; α-O-caffeoyl-3,4-dihydroxyphenyl lactic acid) is an ester of caffeic acid (CA) and 3,4-dihydroxyphenyllactic acid. It has a number of interesting biological activities. The inhibiting activities of the RA on GR and G6PD are investigated here for the first time. MATERIALS AND METHODS: GR and G6PD were purified from tissues, then the effects of RA are investigated. RESULTS: This study reports that RA, which was isolated from Echium vulgare L. (Boraginaceae), inhibits purified GR and G6PD in a concentration-dependent manner. Kinetic characterizations and inhibition constants are investigated. DISCUSSION AND CONCLUSION: Because of their importance in the antioxidative defense system, investigation of the inhibitors of these enzymes is important for drug development.

Glucosides from Vitex agnus-castus.

The methanolic extract of the flowering stems of Vitex agnus-castus yielded three new iridoids: 6'-O-foliamenthoylmussaenosidic acid (agnucastoside A), 6'-O-(6,7-dihydrofoliamenthoyl)mussaenosidic acid (agnucastoside B) and 7-O-trans-p-coumaroyl-6'-O-trans-caffeoyl-8-epiloganic acid (agnucastoside C) in addition to four known iridoids (aucubin, agnuside, mussaenosidic acid and 6'-O-p-hydroxybenzoylmussaenosidic acid) and one known phenylbutanone glucoside (myzodendrone). The structure elucidations were mainly done by spectroscopic methods (1D and 2D NMR spectra) and MS data interpretation. The purified compounds were tested for biological activities against various microorganisms and cancer cell lines.

4'-deoxy iridoid glycosides from Centranthus longiflorus.

The new iridoid glycosides, 4'-deoxykanokoside A and 4'-deoxykanokoside C, were isolated from the methanolic root extract of Centranthus longiflorus ssp. longiflorus. They were accompanied by the three known iridoid glycosides, kanokoside A, kanokoside C and valerosidatum, and two known phenylpropanoid glycosides, coniferin and isoconiferinoside. The structures were elucidated mainly by spectroscopic methods. The presence of 4-deoxy glucose as a part of plant glycosides is rather unusual. Cytotoxic effects of the isolated compounds were also investigated.

(6S)-Hydroxy-3-oxo-alpha-ionol glucosides from Capparis spinosa fruits.

Two new (6S)-hydroxy-3-oxo-alpha-ionol glucosides, together with corchoionoside C ((6S,9S)-roseoside) and a prenyl glucoside, were isolated from mature fruits of Capparis spinosa. The structures were established on the basis of spectroscopic, chiroptic and chemical evidence. In addition, the 13C-resonance of C-9 was found to be of particular diagnostic value in assigning the absolute configuration at that center in ionol glycosides. The alpha-ionol derivatives are metabolites of (+)-(S)-abscisic acid.