Home Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
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Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity

  • Lucia Pirvu EMAIL logo , Georgeta Neagu , Iulian Terchescu , Bujor Albu and Amalia Stefaniu
Published/Copyright: June 2, 2020
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Open Chemistry
From the journal Open Chemistry Volume 18 Issue 1

Abstract

In this study, two ethanolic extracts, from Stokesia aster (Slae26) and Geranium pratense (Gpre36) respectively, were evaluated in order to assess the cytotoxic activity and potential antiproliferative activity upon the nontumorigenic human epithelial cell line derived from the mammary gland (MCF-12A) and the human breast tumor cell line (BT-20). The selection of the plant species was done on the basis of their chemical composition, specifically combinations of luteolin derivatives with caffeic and gallic acid derivatives. Therefore, the S. laevis ethanolic extract proved its capacity to inhibit the viability of both normal and tumor breast cell lines (i.e., up to 90% cell viability inhibition, IC50 = 42 µg/mL). On the contrary, the G. pratense ethanolic extract proved weak stimulatory effects on the viability of the two human breast cell lines studied. The obtained results were discussed in the contexts of computational studies and drug-likeness bioactivity of seven common luteolin derivatives: luteolin, luteolin-7-O-glucoside/cynaroside, luteolin-5-O-glucoside/galuteolin, luteolin-6-C-glucoside/isoorientin, luteolin-8-C-glucoside/orientin, luteolin-3′,4′-di-O-glucoside and luteolin-7,3′-di-O-glucoside. Computational studies have revealed that the hydrophilic behavior of luteolin derivatives (log P values) does not follow other tested parameters (e.g., polar surface area values), possibly explaining different efficacy concerning the biological properties in vitro. These predictions could be a starting point for studies on the biochemical mechanism by which luteolin derivatives induce biological effects.

Graphical Abstract

The localization of frontier molecular orbitals (FMOs) for LUTEOLIN: HOMO (the highest occupied molecular orbital) and LUMO (the lowest unoccupied molecular orbital).

Keywords: Stokes’ aster; meadow cranesbill; cytotoxicity and antiproliferative effects; drug-likeness; bioactivity

1 Introduction

Scientific data of recent years indicate a greater attention to luteolin derivatives, especially as a result of in vitro evidence attesting their inhibitory potential upon breast (cancer) cell line development.

In this context, two ethanolic extracts found to contain luteolin derivatives aside caffeic and gallic/ellagic acid derivatives, from Stokesia laevis and Geranium pratense plant species, were studied concerning their in vitro cytotoxic activity and potential antiproliferative activity of two cell lines: a nontumorigenic epithelial cell line derived from mammary gland (MCF-12A) and a human breast tumor cell line (BT-20). The results were discussed in the context of computational studies and drug-likeness bioactivity of some of the most common luteolin derivatives usually found in plant species.

Regarding the two plant species selected, S. laevis (J. Hill; family Asteraceae), commonly known as “Stokes’ aster”, is a perennial species native to the United States (southeastern region) and mainly used as a decorative plant [1]. In the 1980s, there was an increased economical interest on this plant species as a result of Stokes’ aster achenes content in vernolic acid, which is used in the chemical industry [2,3]; vernolic acid is an epoxide-type structured compound acting as a nonvolatile solvent useful for manufacturing oil-based paints, varnishes, adhesives and other industrial coatings. Data on the phytochemical composition and potential biological effects of S. laevis are scarce; the only data found argue the way in which the copigment luteolin and the pigments petunidin, pelargonidin and cyanidin result in the final coloration of Stokesia aster flower heads [1]. Aster species are reported to be nontoxic to dogs, except for the woody aster, Xylorhiza orcuttii [4].

Geranium species (over 280 species are found worldwide) are particularly known for their geraniol (a volatile oil) and geraniin (a gallic/ellagic acid derivative) contents. The former has been shown to have antimicrobial [5,6,7,8] and antitumor potencies [9,10,11], while the latter shows augmented antioxidant and anti-inflammatory activities [12,13] and antitumor potency [14]. Geraniin compound also demonstrated antiviral properties on herpes simplex virus types 1 and 2 [15] and human enterovirus 71 [16] in vitro and the capacity to reduce the development of Alzheimer’s disease by inhibiting β-secretase activity [17]. Geraniol has been proved to be an effective insecticidal and antimosquito compound [18]. Owing to their specific phytochemical content, the extracts from Geranium species proved to have numerous biological effects and health benefits on human. For example, G. schiedeanum extracts demonstrated hepatoprotective properties against ethanol-induced hepatic injuries [19]; G. robertianum and G. molle extracts showed toxicity against breast, lung, cervical and hepatocellular carcinomas [20,21]; G. robertianum demonstrated strong antioxidant and anti-inflammatory properties [22]; and G. ayavacense indicated antidiabetic activity [23]; while G. carolinianum demonstrated antiviral properties on hepatitis B virus [24].

G. pratense L. plant species (commonly known as “meadow cranesbill”) are proved to be effective against free radical-induced impairment of endothelium-dependent relaxation in isolated rat aorta [25]. The methanol extract from the roots of G. pratense decreased the area with scab lesions on potato tubers; its impact against the pathogen Streptomyces scabies has been attributed to the antimicrobial activity of the geraniin compound [26]. The aqueous extract from the aerial part of G. pratense subsp. finitimum (Woronow) Knuth significantly inhibited the formation of carrageenan-induced hind paw edema (dose of 100 mg/kg) and also proved to have antinociceptive activity [27]. Finally, the Encyclopedia of Traditional Chinese Medicine recommends the utilization of the aerial parts of G. pratense in order to dispel wind damp, free channels and network vessels and treat dysentery and diarrhea [28].

2 Experimental procedure

2.1 Materials

2.1.1 Plant material description

S. laevis plant material was purchased from an authorized distributor in Romania, while G. pratense plant material was collected from Romanian Moldavian Carpathians. Taxonomic identification of the two plant species was done by the botanist’s team at the National Institute of Chemical-Pharmaceutical R&D (ICCF), Bucharest, Romania. Voucher specimens (codified Sla26 and Gpr36) were deposited in the ICCF Plant Material Storing Room.

The two plant materials (the aerial part, herba et flores) were shade dried, ground to medium-size powder and then used in technological studies.

2.1.2 Vegetal extract preparation

S. laevis plant powder of 50 g was extracted with 1,000 mL of 70% (v/v) ethanol, after 1 h at the reflux temperature. After paper filtering, 750 mL of the whole ethanolic extract with a content of 0.70 mg gallic acid equivalent (GAE) per 1 mL extract was obtained. Furthermore, 300 mL of the whole ethanolic extract was concentrated at the residue, which was dissolved into 42 mL of 40% (v/v) ethanol, and then filtered on a glass fiber filter. The resultant extract, codified as Slae26, presents as a homogeneous brown liquid having a content of 5 mg GAE per 1 mL sample.

Similarly, 50 g of G. pratense plant powder was extracted with 500 mL of 70% (v/v) ethanol solvent after 1 h at reflux temperature. The whole ethanolic extract of 330 mL with a content of 3.50 mg GAE per 1 mL extract was obtained. The whole ethanolic extract of 100 mL was further concentrated as the residue, which was dissolved into 70 mL of 40% (v/v) ethanol and then filtered on the glass fiber filter. The resultant extract, codified as Gpre36, presents as a homogeneous light brown liquid with the exact content of 5 mg GAE per 1 mL sample.

The standardized extracts, Slae26 and Gpre36, were used in pharmacological studies.

Figure 1 shows the general method for obtaining the two standardized extracts.

Figure 1 General method for the preparation of vegetal extracts.
Figure 1

General method for the preparation of vegetal extracts.

2.1.3 Chemicals, reagents and references

Chemicals (aluminum chloride, sodium carbonate and sodium acetate), reagents (Folin–Ciocalteu, Natural Product-NP/PEG), solvents (ethanol, ethyl acetate, formic acid and glacial acetic acid) as well as the reference (ref.) compounds (rutin of min. 95%, quercitrin-3-O-rhamnoside >90%, luteolin >98%, luteolin-7-O-glucoside >98%, luteolin-8-C-glucoside >97%, caffeic acid 99%, chlorogenic acid >95% and gallic acid 95%) were purchased from Sigma-Aldrich, Romania. Cell culture reagents, Dulbecco’s Modified Essential Medium, fetal bovine serum and antibiotics were also purchased from Sigma-Aldrich, Romania.

2.2 Experimental design

2.2.1 Estimation of total phenol content in the test vegetal extracts

The total phenol content was estimated by the Folin–Ciocalteu reagent, the standard method described in Romanian Pharmacopoeia [29], and the results were expressed as milligram GAEs per 1 mL sample (R2 = 0.970).

2.2.2 Qualitative high-performance thin-layer chromatography [(HP)TLC] analysis of test vegetal extracts

Chemical qualitative analyses were performed according to Wagner and Bladt [30] and Reich and Schibli [31] chromatography atlases using two solvent systems: system A (ethyl acetate–glacial acetic acid–formic acid–water/100:12:12:26) recommended for polyphenol assessment and system B (chloroform–glacial acetic acid–methanol–water/64:32:12:8) used for saponin assessment, as described in the work of Pirvu et al. (first author of this study) [32].

2.2.3 In vitro pharmacological studies

The cell lines selected for in vitro pharmacological studies consisted of the nontumorigenic epithelial cell line derived from mammary gland MCF-12A (ATCC CRL-10782) and the human breast tumor cell line BT-20 (ATCC HTB-19).

The evaluation of in vitro cell cytotoxicity and antiproliferative effects was done by the MTS test (also known as the viability test), according to the Technical Bulletin of Promega Corporation CellTiter 96 AQueous One Solution Cell Proliferation Assay [33], as described in the work of Pirvu et al. (first author of this study) [34]. The MTS test allows evaluation of either the cytotoxic effect or the antiproliferative effect. For the (anti)proliferation assay, the application of the modulating factor (in this case the two vegetal extracts, Slae26 and Gpre36) is done on “sub-confluent” cell cultures (about 30%), and the determination of the cell population is performed after at least one division cycle (population doubling interval); for the cytotoxicity assay, the cells are exposed to “semi-confluent” cultures (about 70%) and the activity is measured for a shorter time period, rather than a doubling time (usually 6–12 h). Briefly, each test vegetal extract and dilution point series were prepared as triplicates and compared to a control sample with identical concentration of test vegetal solvent sample, at 40% (v/v) ethanol solution. After 20 h (cytotoxicity test) and 20 and 44 h (antiproliferative test) of exposure, the culture medium was removed. After another 2 h of incubation with the MTS solution, the viability of the adherent cells was determined via CellTiter 96 AQueous One Solution Cell Proliferation Assay (Promega, USA). The absorbance of the treated and control samples was measured at 490 nm with a Microplate Reader (Chameleon V Plate Reader; LKB Instruments, Australia) and the recorded values were used for cell viability estimation (see formula below). The results are calculated as mean ± SD, n = 3:

%cellviability=A490oftreatedcellsA490ofcontrolcells×100.

2.2.4 Computational studies

Computational studies have been done on luteolin aglycone and several common luteolin derivatives/glucosides, namely, luteolin-7-O-glucoside/cynaroside, luteolin-5-O-glucoside/galuteolin, luteolin-6-C-glucoside/isoorientin, luteolin-8-C-glucoside/orientin, luteolin-3′,4′-di-O-glucoside and luteolin-7,3′-di-O-glucoside. Computational calculations have been carried out using Spartan ’18 software [35,36], based on the density functional theory (DFT) using Becke’s three-parameter hybrid functional with Lee, Yang, and Parr parameter (LYP) correlation functional (B3LYP) and 6.31G(d,p) basis sets [36,37]. The aims of DFT computations were to reveal site-selective and global chemical reactivity descriptors of the studied luteolin derivatives and to achieve a quantitative structure property relationship/quantitative structure-activity relationship (QSPR/QSAR) analysis of their calculated properties. The calculated properties were based on the optimized structures of molecules, thus presenting the configuration of minimum energy and an optimized geometry, in vacuum conditions; no solvent corrections were done. From their energy values, several descriptors important to assess the global chemical molecules reactivity were calculated by applying the Koopmans theorem [38,39], with the following relations: ionization potential (I = −EHOMO), electron affinity (A = −ELUMO), electronegativity (χ = (I + A)/2), global hardness (η = (I − A)/2), local softness (σ = l/η) [40,41], chemical potential (μ = (EHOMO + ELUMO)/2) and global electrophilicity index (ω = μ2/2η). Also, a drug-likeness analysis was done based on the structural features correlated with Lipinski’s rule of five [42]. The molecular descriptors included in this approach were calculated, for comparison, using the Molinspiration online platform (https://www.molinspiration.com/). In addition, the bioactivity scores toward G protein-coupled receptor (GPCR) ligand, ion channel modulators, kinase inhibitors, nuclear receptor ligands, protease inhibitors and other enzyme targets were predicted online through the Molinspiration virtual screening toolkit miscreen. The results of the seven luteolin derivatives were compared and discussed.

2.2.5 Instruments used

The instruments used for chemical analyses included the UV/Vis spectrophotometer (Hélios γ; Thermo Electron Corporation, UK) and Linomat5 TLC visualizer (CAMAG, Muttenz, Switzerland). Pharmacological in vitro cell proliferation tests were done by xCELLigence®DP Real-Time Cell Analysis (ACEA Biosciences, USA).

  1. Ethical approval: The conducted research is not related to either human or animal use.

3 Results and discussion

3.1 Polyphenol profile of the two-test vegetal extracts

In Figure 2, chromatograms A and B present the polyphenol profiles of S. aster ethanolic extract, i.e., Slae26 test sample. System A setting study of Slae26 test sample (chromatogram A, tracks T2) face to eight reference compounds (tracks T1, T3, T4, T5, T6 and T7), which indicated the occurrence of two main polyphenol classes: luteolin derivatives (yellow fluorescent/fl. spots s2, s4 and s8) and caffeic acid derivatives (blue fl. spots s1, s3, s5 and s6), mainly chlorogenic acid and several chlorogenic acid isomers, respectively. Proved to be very useful for separation and assessment of polyphenol aglycones[32]. Subsequently system B setting studies of the Slae26 test sample, before hydrolysis in 4 N HCl medium (chromatogram B, tracks T2) and after hydrolysis in 4 N HCl medium (chromatogram B, tracks T2H), both confirmed the presence of luteolin-7-O-glucoside/cynaroside (A/s4/Rf ∼ 0.68 and B/s1/Rf ∼ 0.36), luteolin (A/s8/Rf ∼ 0.94 and B/s2/Rf ∼ 0.72) and caffeic acid (A/S7Rf ∼ 0.92/and B/s3, Rf ∼ 0.76).

Figure 2 (HP)TLC studies of Stokesia laevis ethanolic extract (Slae26). Chromatogram A (system a) – track T1, rutin, chlorogenic acid and caffeic acid (ref.); tracks T2 – ethanolic extract from S. laevis (Slae26) – two series; track T3, luteolin-8-C-glucoside/orientin (ref.); track T4, quercitrin-3-O-galactoside/hyperoside, quercitrin-3-O-rhamnoside/quercitrin and gallic acid (ref.); track T5, luteolin-7-O-glucoside/cynaroside and luteolin (ref.). Chromatogram B (system b) – track T1, rutin, chlorogenic acid and caffeic acid (ref.); tracks T2 – ethanolic extract from S. laevis (Slae26); track T6, luteolin (ref); track T7, luteolin-7-O-glucoside/cynaroside (ref.); track T3, luteolin-8-C-glucoside/orientin (ref.); track T2H, the hydrolyzed extract from ethanolic extract Slae26.
Figure 2

(HP)TLC studies of Stokesia laevis ethanolic extract (Slae26). Chromatogram A (system a) – track T1, rutin, chlorogenic acid and caffeic acid (ref.); tracks T2 – ethanolic extract from S. laevis (Slae26) – two series; track T3, luteolin-8-C-glucoside/orientin (ref.); track T4, quercitrin-3-O-galactoside/hyperoside, quercitrin-3-O-rhamnoside/quercitrin and gallic acid (ref.); track T5, luteolin-7-O-glucoside/cynaroside and luteolin (ref.). Chromatogram B (system b) – track T1, rutin, chlorogenic acid and caffeic acid (ref.); tracks T2 – ethanolic extract from S. laevis (Slae26); track T6, luteolin (ref); track T7, luteolin-7-O-glucoside/cynaroside (ref.); track T3, luteolin-8-C-glucoside/orientin (ref.); track T2H, the hydrolyzed extract from ethanolic extract Slae26.

In Figure 3, chromatograms A, B and C present the polyphenol profile of the G. pratense ethanolic extract i.e., Gpre36 test sample, compared to several reference compounds (tracks T1, T3, T4 and T5). System A setting study of the Gpre36 extract (chromatogram A, tracks T2) reveals an important number of polyphenol compounds, namely, luteolin (yellow fl., spots s5, s8), ellagic (light blue fl., spots s1, s2 and s4) and caffeic acid (blue fl., spots s7 and s10) derivatives and at least one kaempferol derivative (blue-green fl., spot s11).

Figure 3 (HP)TLC studies of the G. pratense ethanolic extract (Gpre36). Chromatogram A (system a) – track T1, rutin, chlorogenic acid and caffeic acid (ref.); tracks T2, ethanolic extract from G. pratense (Gpre36); track T3, quercitrin-3-O-glucoside/isoquercitrin and quercitrin-3-O-rhamnoside/quercitrin (ref.); chromatogram B (system b) – track T1, rutin, chlorogenic acid and caffeic acid (ref.); tracks T2 – ethanolic extract from G. pratense (Gpre36); track T4, luteolin-8-C-glucoside/orientin (ref.); chromatogram C (system c) – track T1, rutin, chlorogenic acid and caffeic acid (ref.); track T2H, the hydrolyzed extract from ethanolic extract Gpre36; track T5, gallic acid (ref.).
Figure 3

(HP)TLC studies of the G. pratense ethanolic extract (Gpre36). Chromatogram A (system a) – track T1, rutin, chlorogenic acid and caffeic acid (ref.); tracks T2, ethanolic extract from G. pratense (Gpre36); track T3, quercitrin-3-O-glucoside/isoquercitrin and quercitrin-3-O-rhamnoside/quercitrin (ref.); chromatogram B (system b) – track T1, rutin, chlorogenic acid and caffeic acid (ref.); tracks T2 – ethanolic extract from G. pratense (Gpre36); track T4, luteolin-8-C-glucoside/orientin (ref.); chromatogram C (system c) – track T1, rutin, chlorogenic acid and caffeic acid (ref.); track T2H, the hydrolyzed extract from ethanolic extract Gpre36; track T5, gallic acid (ref.).

System B setting study of the Gpre36 test sample, before and after hydrolysis in 4 N HCl medium (chromatogram B, tracks T2 and chromatogram C, tracks T2H) confirmed the presence of gallic acid aglycone (intense blue-indigo fl. spot s7, Rf ∼ 0.55) and condensed derivatives, ellagic acids (intense blue-indigo fl. spot s1, s2 and s4); chromatogram C also revealed augmented quantities of luteolin (yellow fl. spot s8, Rf ∼ 0.75) and kaempferol (green-blue fl. spot s9, Rf ∼ 86) aglycones as well as low quantities of caffeic acid aglycone (blue fl. spot s8′ covered by luteolin s8). Other high-performance liquid chromatography studies [25] of extracts of G. pratense indicated the presence of quercitrin-3-O-α-arabinopyranoside, quercitrin-3-O-β-glucopyranoside, quercitrin-3-O-β-galactopyranoside, quercitrin-3-O-(2-O-galloyl)-β-glucopyranoside, quercitrin-3-O-(2-O-galloyl)-β-galactopyranoside, kaempferol-3-O-β-galactopyranoside, kaempferol-3-O-β-glucopyranoside and also myricetin-3-O-(2-O-galloyl)-β-glucopyranoside and (−)-6-chloro-epicatechin polyphenols.

By comparison, qualitative (HP)TLC studies revealed that the ethanolic extract from S. aster plant species, caffeic acid/s7, chlorogenic acid/s3 and one luteolin monoglycoside (likely luteolin-7-O-glucoside/s4) were found, and the ethanolic extract from G. pratense plant species confirmed numerous gallic/ellagic acid derivatives/s1, s2, s4 and one augmented luteolin polyglycoside/s5. Concerning the quantitative aspects, the two ethanolic extracts, Slae26 and Gpra36, were made in a manner to assure the exact content of 5 mg total phenol content, GAEs per 1 mL sample.

3.2 Cytotoxic and antiproliferative potential assays in vitro

In vitro cytotoxicity and antiproliferative assessments were done on Slae26 and Gpre36 test vegetal extracts (characterized by 5 mg GAE/mL sample) by using six dilution series, that is, 1, 5, 10, 25, 50 and 100 µg GAE/mL samples. The two test vegetal dilution series and the corresponding control sample dilution series (40% ethanol solvent series) were applied on “semi-confluent” and “sub-confluent” mammary gland cell culture MCF-12A and human breast tumor cell culture BT-20, as described in Section 2.2.3. As described, the cytotoxic and antiproliferative activities essentially consist in a colorimetric test based on the selective ability of the viable cells to reduce the tetrazolium component of MTS into a purple-colored formazan crystal; the quantity of the formazan product, as measured by absorbance at 490 nm, is directly proportional to the number of living cells in culture and thus the effect of the two-test vegetal series on the cytotoxic and proliferation tests can be computed as the cell viability percentage (%).

Figures 4 and 5 show the results on the S. laevis and G. pratense test vegetal extracts, Slae26 and Gpre36 dilution series, respectively.

Figure 4 Cytotoxic and antiproliferative effects (cell viability, %) of Slae26 tested on (a) mammary gland cell line MCF-12A and (b) human breast tumor cell line BT-20, compared to the control negative cells; n = 3, ± SD(%).
Figure 4

Cytotoxic and antiproliferative effects (cell viability, %) of Slae26 tested on (a) mammary gland cell line MCF-12A and (b) human breast tumor cell line BT-20, compared to the control negative cells; n = 3, ± SD(%).

Figure 5 Cytotoxic and antiproliferative effects (cell viability, %) of Gpre36 tested on (a) mammary gland cell line MCF-12A and (b) human breast tumor cell line BT-20, compared to the control negative cells; n = 3, ± SD(%).
Figure 5

Cytotoxic and antiproliferative effects (cell viability, %) of Gpre36 tested on (a) mammary gland cell line MCF-12A and (b) human breast tumor cell line BT-20, compared to the control negative cells; n = 3, ± SD(%).

Comparison with the control negative cell series indicated the following results: during cytotoxicity test, Slae26 test sample applied on the normal epithelial mammary gland cell line MCF-12A (Figure 3a) led to the stimulation of cell viability up to 50 µg/mL concentration level (up to 33% cell viability stimulation), followed by a severe decline in the cell viability at higher concentrations (up to 75% cell viability inhibition at 100 µg/mL); during the antiproliferative test, Slae 26 induced important inhibitory effects on MCF-12A viability (up to 52% and 70% cell viability inhibition at 24 and 48 h, respectively); Slae26 tested on human breast tumor cell line BT-20 (Figure 3b) revealed either cytotoxic effects (88% cell viability inhibition at 24 h) or antiproliferative activity (87% and 89% cell viability inhibition at 24 and 48 h, respectively), concluding that Stokesia aster ethanolic extract has inhibitory potential on the growth and proliferation of normal and tumor human breast cells. The antiproliferative effect (IC50) was estimated at around values of 68 µg GAE/mL sample at 24 h and 42 µg GAE/mL sample at 48 h.

Due to the combination of luteolin derivatives with gallic or ellagic acid derivatives, which were shown to have strong antitumor, antimetastatic and antiangiogenesis activities [43,44], it is expected that the G. pratense ethanolic extract (Gpre36) has a strong antiproliferative potential. However, when applied on the normal mammary gland cell line MCF-12A (Figure 4a), it indicated a weak stimulatory activity in the cytotoxicity test (up to 15% cell viability stimulation); during the antiproliferative test, at first stimulatory effects were noticed (up to 50% cell viability stimulation at 24 h), followed by inhibitory effects (up to 8% cell viability inhibition at 48 h). Gpre36 test sample tested on human breast tumor cell line BT-20 (Figure 4b) indicated weak cytotoxic effects (up to 16% cell viability inhibition at 24 h), and no antiproliferative activity; in fact, 7% and 8% cell viability stimulatory effects were measured at 24 and 48 h, respectively. The results are available in Supplementary Tables 1s, 2s, 3s and 4s.

3.3 Computational results

Computational study of the seven luteolin derivatives, molecular descriptors and physicochemical properties was planned in order to find a possible explanation for the differences in pharmacological activity of the two-test vegetal extracts. Although the G. pratense ethanolic extract has a theoretically more efficient chemical composition, in vitro assessments indicated the lack of antiproliferative activity of Gpre36 versus certain antiproliferative activity of S. aster ethanolic extract, Slae26. Therefore, it appears that the specific chemical structure of luteolin derivatives (the position and the number of substituents) and less combination with caffeic or gallic/ellagic acid derivatives lead to the final antiproliferative potential of the two vegetal extracts.

Table 1 summarizes the quantum chemical parameters for luteolin and the six most common luteolin derivatives: luteolin-7-O-glucoside/cynaroside, luteolin-5-O-glucoside/galuteolin, luteolin-6-C-glucoside/isoorientin, luteolin-8-C-glucoside/orientin, luteolin-3′,4′-di-O-glucoside and luteolin-7,3′-di-O-glucoside.

Table 1

Calculated quantum chemical parameters of the studied compounds

Studied parameterLuteolinLuteolin-7-O-glucoside/cynarosideLuteolin-5-O-glucoside/galuteolinLuteolin-6-C-glucoside/isoorientinLuteolin-8-C-glucoside/orientinLuteolin-3′,4′-di-O-glucosideLuteolin-7,3′-di-O-glucoside
EHOMO−6.05−6.00−6.46−6.09−6.11−6.20−6.56
ELUMO−1.84−1.82−2.29−1.83−1.89−1.89−2.42
ΔEgap4.214.184.174.264.224.314.14
I6.056.006.466.096.116.206.56
A1.841.822.291.831.891.892.42
χ3.943.914.373.964.004.044.49
η2.1052.092.082.132.112.152.07
σ0.470.480.480.470.470.460.48
μ−3.94−3.91−4.37−3.96−4.00−4.04−4.49
ω3.683.664.593.683.793.794.87

EHOMO, the energy of the HOMO orbital; ELUMO, the energy of the LUMO orbital; ΔEgap, difference between frontier molecular orbitals; I(ionization potential), (−EHOMO); A (electron affinity), (−ELUMO); χ (electronegativity), (I + A)/2; H (global hardness), (I − A)/2; σ (local softness), l/η; μ (chemical potential), (EHOMO + ELUMO)/2 and ω (global electrophilicity index), μ2/2 η, expressed in eV.

First of all, it is obvious that the energy of the highest occupied molecular orbital (HOMO) orbital (EHOMO) of all studied compounds is significantly smaller than that of the energy of the lowest unoccupied molecular orbital (LUMO) orbital (ELUMO). Energetically, from the HOMO orbital, it is easiest to donate electrons to form new bonds to be involved in oxidation. The LUMO is energetically more able to receive electrons, possibly involved in reduction reactions.

Second, the ΔEgap parameter (the energy difference between HOMO and LUMO) providing information about chemical reactivity and kinetic stability of the molecules indicated close values, ranging between 4.14 and 4.26 eV.

Table 2 presents the values obtained for physicochemical properties and molecular descriptors involved when discussing the drug-likeness and matching with the statements of Lipinski’s rule of five concerning oral bioavailability. For each structure, the first line of values corresponds to Spartan computations, and on the second line are the values obtained from the Molinspiration platform. A small difference is due to the methods used for computation. Molinspiration employed the semiempirical AM1 method for the optimized 3D molecular geometries, wherein volumes and polar surface area (PSA) are approximated based on the fragment contributions.

Table 2

Drug-likeness predicted parameters for luteolin and its derivativesa

NameMolecular weight Molecular volumeNrotblog PPSAHBDHBANo. of Lipinski violations
286.239261.111−3.4697.416460
232.071.97111.12
448.380399.024−5.45168.6577112
364.190.19190.28
448.380398.714−0.83163.4637112
364.19−0.07190.28
448.380394.223−1.61164.6028112
363.220.03201.27
448.380397.093−6.39178.9888112
363.220.03201.27
610.521533.187−2.67214.90410163
610.521535.087−7.45221.72810163
496.31−1.83269.43

Nrotb, number of rotatable bonds; HBD, number of hydrogen bond donors; HBA, number of hydrogen bond acceptors; PSA, polar surface area; log P, water–octanol partition coefficient.

  1. a

    Values on the first line were calculated using Spartan software and values listed on the second line were obtained using Molinspiration tools.

  2. b
  3. c

Table 2 clearly demonstrates luteolin aglycone as the most feasible drug candidate due to zero violation of Lipinski’s rule [42]. Although not sufficient and mandatory to send a potential drug compound forward for pharmaceutical development, these limits of physicochemical parameters are used, rather than excluding from screening the compound with poor success rate. As observed from the results of computations, the correlation between the molecular weight and the PSA indicated that, generally, by increasing the molecular weight, from luteolin to luteolin diglucoside, the number of added hydroxyl groups and PSA increases. The biggest structures with the highest hydrophilicity, luteolin-3′,4′-diglucoside and luteolin-7,3′-di-glucoside, showed the most deviations from drug-likeness criteria (Lipinski’s rule), also presenting the highest number of flexible bonds (Nrotb).

Yet, even if luteolin derivatives present a more augmented lipophilic character due to the lack of one hydroxyl group in position 3, the comparison of log P values (the calculated values of octanol–water partition coefficient log P by Spartan computations) with those computed for quercitrin derivatives [34] indicates that (1) luteolin derivatives are more hydrophilic compounds capable of exhibiting greater oral bioavailability and (2) their log P values do not follow PSA values, possibly explaining their different efficacies concerning the biological properties and function of test conditions.

The correlation between PSA, molecular volume (vol) and water–octanol partition coefficient (log P) for the seven luteolin derivatives studied (Figure 6) indicated that luteolin, luteolin-5-O-glucoside, luteolin-6-C-glucoside and luteolin-3′,4′-O-diglucoside have significantly different log P values in comparison with luteolin-7-O-glucoside, luteolin-8-C-glucoside and luteolin-7,3′-O-diglucoside, which could support the differences between the pharmacological activity of the vegetal extracts.

Figure 6 The correlation between molecular volume (vol), PSA and water–octanol partition coefficient (log P) for several common luteolin derivatives.
Figure 6

The correlation between molecular volume (vol), PSA and water–octanol partition coefficient (log P) for several common luteolin derivatives.

In Table 3 are listed the bioactivity scores predicted using the Molinspiration software toward GPCR ligands, ion channel modulators, kinase inhibitors, nuclear receptor ligands, protease inhibitors and enzyme targets. It is known that if the bioactivity score is larger than 0.0, the drug candidate is classified as active; if score range is between −5 and 0, then the structure is moderately active and if the score is less than −5, then inactive. Therefore, luteolin exhibits larger score values for kinase inhibitor (0.26 – the largest of all the tested structures), nuclear receptor ligand (0.39, also the highest score, compared with its derivatives) and enzyme inhibitor (0.28), thus being considered as the most promising structure, the lead compound.

Table 3

Bioactivity scores for luteolin and its derivatives predicted with Molinspiration toolkit

Name/ChemSpider IDGPCR ligandIon channel modulatorKinase inhibitorNuclear receptor ligand bindProtease inhibitorEnzyme inhibitor
Luteolin ID 4444102−0.02−0.070.260.39−0.220.28
Luteolin 7-O-glucoside/Cynaroside 44442410.09−0.020.150.27−0.010.42
Luteolin 5-O-glucoside/Galuteolin 103060910.120.000.180.29−0.010.41
Luteolin 8-C-glucoside/Orientin 44449940.12−0.140.200.200.010.45
Luteolin 6-C-glucoside/Isoorientin 1027530.110.010.160.200.010.46
Luteolin-7,3′-di-O-glucoside 4590322−0.03−0.50−0.11−0.06−0.040.07

This conclusion is also supported by the results presented in Table 2, showing no deviation from the limiting criteria postulated by Lipinski’s rule of five. On the contrary, luteolin-7,3′-di-O-glucoside, the most flexible molecule presenting seven rotatable bonds and three violations from Lipinski’s rule (molecular weight larger than 500 Da; more than five hydrogen bond donors, more than ten hydrogen bond acceptors), shows the lowest scores for all targets. Thus, it is classified as a moderately active candidate. None of the luteolin derivatives can be considered inactive, as they all show scores larger than −5.0.

Table 3 also indicates that all compounds show greater scores for enzyme inhibition, all values being positives, acting as active drug candidates. Based on this, we can declare that the most active ligand is luteolin 6-C-glucoside with 0.46 score for enzyme inhibition. Concerning protease inhibition, the most active ones are luteolin 6-C-glucoside and luteolin 8-C-glucoside (score = 0.01). Luteolin aglycone is the most active when compared with its derivatives, because it is the ligand that is capable of binding to nuclear receptor (score = 0.39) and kinase inhibitor (score = 0.26). Luteolin 5-O-glucoside and luteolin 8-C-glucoside were found to be highly bioactive toward GPCR ligand (score = 0.12). Regarding ion channel modulator bioactivity, luteolin 6-C-glucoside shows a promising score (0.01).

Considering all the above observations of the drug-likeness parameters (Table 2) and bioactivities (Table 3), it can be concluded that all compounds show great potential in terms of bioactivity as ligands for the tested targets, starting with their lead compound, luteolin. Therefore, the interest in luteolin and luteolin derivatives in the recent years is argued. The advantages offered by luteolin derivatives as opposed to other flavonoid subclasses are drawn from their chemical structures: they are more resistant to the (auto)oxidation process explained by the lack of a hydroxyl group in position 3 of the flavan ring. They are resistant to acidic hydrolysis [32], at the same time more stable and safe and able to pass through the cell membranes more easily, while also showing great bioactivity potential.

Proving these, scientific data indicate that luteolin stimulates breast cancer cell apoptosis [45] and inhibits fatty acid synthase (FASN) activity [46,47,48,49], essential for normal and tumor breast cell growth and function. FASN is the only enzyme capable of inhibiting the novo synthesis of fatty acids with long chains (starting from acetyl-CoA, malonyl-CoA and nicotinamide adenine dinucleotide phosphate). At the same time, it is significantly activated in many types of malignant tumors, especially in the case of human mammary tumor growth and metastasis.

Moreover, due to the complex actions that compete for the final effect, luteolin aglycone was proved to be an effective inhibitor of mammary and prostate cancer metastases [50]. For instance, luteolin inhibits the angiogenesis process induced by the vascular endothelial growth factor, which reduces the chance of colonization of metastatic targets [51]; luteolin inhibits the expression of specific matrix metalloproteinases involved in basement membrane degradation, a key step in the neovascularization and tumor invasion process [52]; luteolin inhibits the secretion of interleukin (IL)-8 [53] and IL-6, acting as an amplifying signal of cancer cell growth and invasion [54]; luteolin inhibits epithelial–mesenchymal transition considered as a pinnacle step in the process of cancer cell invasion and metastasis [55]; luteolin acts as a p90 ribosomal S6 kinase inhibitor that suppresses Notch4 signaling [56]; luteolin promotes cell cycle arrest in breast cancer and inhibits the expression of human epidermal growth factor receptors HER2 [57] and EGFR/aka HER1 [58], related to the new breast cancer cases; luteolin acts as an insulin-like growth factor-mediated proliferation antagonist [59] and stimulates breast cancer cell apoptosis through extrinsic (via caspase 9) [60] and intrinsic (via caspases 8 and 10) [61] pathways, thus being the subject of numerous review articles [62,63,64].

Regarding aspects of bioavailability, luteolin derivatives appear to be generally degraded to smaller metabolites by the intestinal bacterium Eubacterium cellulosolvens within 24 h; in contrast, luteolin C-polyglycosides appear unchanged when they are absorbed in the intestine, before being distributed to the body tissues [65].

Another aspect to be mentioned is the capacity of polyphenols, especially of flavonoid subclasses, to bind iron from the medium; flavonoid C-glycosides fulfil the role of siderophores in plant tissues [66,67]. The sequestration of iron from the intestine by polyphenol-based supplements leads to several shortcomings in humans: the inhibition of heme iron absorption possibly promotes anemia [68], the intestinal inflammation and colon tumor development. Data suggest that good intestinal bacteria are significantly affected by iron depletion. This is because their metabolism is dependent on numerous iron enzymes, while pathogenic bacteria necessitate low or no levels of iron to survive and proliferate [69]. A possible way to oppose iron sequestration by polyphenol-based supplements is by the addition of Fe and EDTA in tea in a molar ratio of 1:2, to avoid iron sequestration by green tea catechins [70].

4 Conclusion

The present study aims to evaluate the antiproliferative potencies of two vegetal extracts combining luteolin derivatives with caffeic and, respectively, gallic/ellagic acid derivatives isolated from S. laevis and G. pratense plant species.

In vitro pharmacological studies indicated that the ethanolic extracts of S. laevis have the ability to inhibit the viability of both sub-confluent and semi-confluent nontumorigenic epithelial mammary gland cell line MCF-12A and sub-confluent and semi-confluent human breast tumor cell line BT-20. This suggests both potential toxic effects and potential antiproliferative activity of human breast (cancer) cell development. Also, the fact that Stokes’ aster ethanolic extract inhibited either normal or tumor breast cell line sustains the involvement of luteolin derivatives, which proved to inhibit the activity of FASN involved in both normal and tumor mammary cell metabolism.

G. pratense ethanolic extract yielded in vitro results that rather seem to suggest stimulatory effects on normal and tumor human breast cell development.

Computational studies made on luteolin and several common luteolin derivatives conducted to a reactivity analysis and to drug-likeness and bioactivity prediction approaches. For example, it was shown that luteolin, the structure that respects all limitations imposed by Lipinski’s drug-likeness criteria, is a promising drug molecule, with a potential for higher activity against several biological targets. The predictions also indicate that all of its studied derivatives could exhibit good or moderate activity toward used receptors. The fact that log P values computed for luteolin derivatives do not follow the PSA values also explains to some extent the results of in vitro pharmacological studies, and antiproliferative effectiveness of Slae26 and Gpre36.

In summary, prediction studies are key factors for developing new drugs, giving a preview of the hydrophilic–lipophilic character, absorption, transport and distribution through the physiological media of the modeled compounds; it must be noticed that the computational scores are based on experimental data collected from the medicinal chemistry literature (about 10,000 data points for every target class) [71].

Overall, for the first time in the literature, the potential antiproliferative activity of the S. aster ethanolic extract was proved on tumor human breast cell line MT-20, but further studies are required to assess the exact chemical composition and to separate more active fractions to decrease the IC50 value. This way, the S. laevis plant species turns out to be a good source of luteolin derivatives for pharmaceutical purposes, but not for alimentary or phytomedicine purposes, since in vitro studies on the normal human epithelial mammary cell line MCT-12A indicate potential toxic effects (up to 88% cell viability inhibition) of the polar extracts from the aerial part of Stokes’ aster.

Acknowledgments

This work was supported by the ANCSI program POC-A1-A1.2.3-G-2015, Project title <New technologies and natural derived products for human health use>, Contract no.60/05.09.2016, ID P_40_406, SMIS 105542.

  1. Conflict of interest: The authors declare that this paper content has no conflict of interest.

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Received: 2020-01-17
Revised: 2020-03-23
Accepted: 2020-03-24
Published Online: 2020-06-02

© 2020 Lucia Pirvu et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
  28. Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α
  29. Incorporation of silver stearate nanoparticles in methacrylate polymeric monoliths for hemeprotein isolation
  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
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  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
  33. Diorganotin(iv) benzyldithiocarbamate complexes: synthesis, characterization, and thermal and cytotoxicity study
  34. Keratin 17 is induced in prurigo nodularis lesions
  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
  40. Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
  42. Electronic structural properties of amino/hydroxyl functionalized imidazolium-based bromide ionic liquids
  43. New Schiff bases of 2-(quinolin-8-yloxy)acetohydrazide and their Cu(ii), and Zn(ii) metal complexes: their in vitro antimicrobial potentials and in silico physicochemical and pharmacokinetics properties
  44. Treatment of adhesions after Achilles tendon injury using focused ultrasound with targeted bFGF plasmid-loaded cationic microbubbles
  45. Synthesis of orotic acid derivatives and their effects on stem cell proliferation
  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
  47. Fe3O4@urea/HITh-SO3H as an efficient and reusable catalyst for the solvent-free synthesis of 7-aryl-8H-benzo[h]indeno[1,2-b]quinoline-8-one and indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine derivatives
  48. Adsorption kinetic characteristics of molybdenum in yellow-brown soil in response to pH and phosphate
  49. Enhancement of thermal properties of bio-based microcapsules intended for textile applications
  50. Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique
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  52. Cadmium (Cd) chloride affects the nutrient uptake and Cd-resistant bacterium reduces the adsorption of Cd in muskmelon plants
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  54. Structural cytotoxicity relationship of 2-phenoxy(thiomethyl)pyridotriazolopyrimidines: Quantum chemical calculations and statistical analysis
  55. A self-breaking supramolecular plugging system as lost circulation material in oilfield
  56. Synthesis, characterization, and pharmacological evaluation of thiourea derivatives
  57. Application of drug–metal ion interaction principle in conductometric determination of imatinib, sorafenib, gefitinib and bosutinib
  58. Synthesis and characterization of a novel chitosan-grafted-polyorthoethylaniline biocomposite and utilization for dye removal from water
  59. Optimisation of urine sample preparation for shotgun proteomics
  60. DFT investigations on arylsulphonyl pyrazole derivatives as potential ligands of selected kinases
  61. Treatment of Parkinson’s disease using focused ultrasound with GDNF retrovirus-loaded microbubbles to open the blood–brain barrier
  62. New derivatives of a natural nordentatin
  63. Fluorescence biomarkers of malignant melanoma detectable in urine
  64. Study of the remediation effects of passivation materials on Pb-contaminated soil
  65. Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma
  66. Withania frutescens: Chemical characterization, analgesic, anti-inflammatory, and healing activities
  67. Design, synthesis and pharmacological profile of (−)-verbenone hydrazones
  68. Synthesis of magnesium carbonate hydrate from natural talc
  69. Stability-indicating HPLC-DAD assay for simultaneous quantification of hydrocortisone 21 acetate, dexamethasone, and fluocinolone acetonide in cosmetics
  70. A novel lactose biosensor based on electrochemically synthesized 3,4-ethylenedioxythiophene/thiophene (EDOT/Th) copolymer
  71. Citrullus colocynthis (L.) Schrad: Chemical characterization, scavenging and cytotoxic activities
  72. Development and validation of a high performance liquid chromatography/diode array detection method for estrogen determination: Application to residual analysis in meat products
  73. PCSK9 concentrations in different stages of subclinical atherosclerosis and their relationship with inflammation
  74. Development of trace analysis for alkyl methanesulfonates in the delgocitinib drug substance using GC-FID and liquid–liquid extraction with ionic liquid
  75. Electrochemical evaluation of the antioxidant capacity of natural compounds on glassy carbon electrode modified with guanine-, polythionine-, and nitrogen-doped graphene
  76. A Dy(iii)–organic framework as a fluorescent probe for highly selective detection of picric acid and treatment activity on human lung cancer cells
  77. A Zn(ii)–organic cage with semirigid ligand for solvent-free cyanosilylation and inhibitory effect on ovarian cancer cell migration and invasion ability via regulating mi-RNA16 expression
  78. Polyphenol content and antioxidant activities of Prunus padus L. and Prunus serotina L. leaves: Electrochemical and spectrophotometric approach and their antimicrobial properties
  79. The combined use of GC, PDSC and FT-IR techniques to characterize fat extracted from commercial complete dry pet food for adult cats
  80. MALDI-TOF MS profiling in the discovery and identification of salivary proteomic patterns of temporomandibular joint disorders
  81. Concentrations of dioxins, furans and dioxin-like PCBs in natural animal feed additives
  82. Structure and some physicochemical and functional properties of water treated under ammonia with low-temperature low-pressure glow plasma of low frequency
  83. Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models
  84. Amine-functionalized magnetic activated carbon as an adsorbent for preconcentration and determination of acidic drugs in environmental water samples using HPLC-DAD
  85. Antioxidant activity as a response to cadmium pollution in three durum wheat genotypes differing in salt-tolerance
  86. A promising naphthoquinone [8-hydroxy-2-(2-thienylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione] exerts anti-colorectal cancer activity through ferroptosis and inhibition of MAPK signaling pathway based on RNA sequencing
  87. Synthesis and efficacy of herbicidal ionic liquids with chlorsulfuron as the anion
  88. Effect of isovalent substitution on the crystal structure and properties of two-slab indates BaLa2−xSmxIn2O7
  89. Synthesis, spectral and thermo-kinetics explorations of Schiff-base derived metal complexes
  90. An improved reduction method for phase stability testing in the single-phase region
  91. Comparative analysis of chemical composition of some commercially important fishes with an emphasis on various Malaysian diets
  92. Development of a solventless stir bar sorptive extraction/thermal desorption large volume injection capillary gas chromatographic-mass spectrometric method for ultra-trace determination of pyrethroids pesticides in river and tap water samples
  93. A turbidity sensor development based on NL-PI observers: Experimental application to the control of a Sinaloa’s River Spirulina maxima cultivation
  94. Deep desulfurization of sintering flue gas in iron and steel works based on low-temperature oxidation
  95. Investigations of metallic elements and phenolics in Chinese medicinal plants
  96. Influence of site-classification approach on geochemical background values
  97. Effects of ageing on the surface characteristics and Cu(ii) adsorption behaviour of rice husk biochar in soil
  98. Adsorption and sugarcane-bagasse-derived activated carbon-based mitigation of 1-[2-(2-chloroethoxy)phenyl]sulfonyl-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) urea-contaminated soils
  99. Antimicrobial and antifungal activities of bifunctional cooper(ii) complexes with non-steroidal anti-inflammatory drugs, flufenamic, mefenamic and tolfenamic acids and 1,10-phenanthroline
  100. Application of selenium and silicon to alleviate short-term drought stress in French marigold (Tagetes patula L.) as a model plant species
  101. Screening and analysis of xanthine oxidase inhibitors in jute leaves and their protective effects against hydrogen peroxide-induced oxidative stress in cells
  102. Synthesis and physicochemical studies of a series of mixed-ligand transition metal complexes and their molecular docking investigations against Coronavirus main protease
  103. A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses
  104. A new phenyl alkyl ester and a new combretin triterpene derivative from Combretum fragrans F. Hoffm (Combretaceae) and antiproliferative activity
  105. Erratum
  106. Erratum to: A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  107. Review Articles
  108. Sinoporphyrin sodium, a novel sensitizer for photodynamic and sonodynamic therapy
  109. Natural products isolated from Casimiroa
  110. Plant description, phytochemical constituents and bioactivities of Syzygium genus: A review
  111. Evaluation of elastomeric heat shielding materials as insulators for solid propellant rocket motors: A short review
  112. Special Issue on Applied Biochemistry and Biotechnology 2019
  113. An overview of Monascus fermentation processes for monacolin K production
  114. Study on online soft sensor method of total sugar content in chlorotetracycline fermentation tank
  115. Studies on the Anti-Gouty Arthritis and Anti-hyperuricemia Properties of Astilbin in Animal Models
  116. Effects of organic fertilizer on water use, photosynthetic characteristics, and fruit quality of pear jujube in northern Shaanxi
  117. Characteristics of the root exudate release system of typical plants in plateau lakeside wetland under phosphorus stress conditions
  118. Characterization of soil water by the means of hydrogen and oxygen isotope ratio at dry-wet season under different soil layers in the dry-hot valley of Jinsha River
  119. Composition and diurnal variation of floral scent emission in Rosa rugosa Thunb. and Tulipa gesneriana L.
  120. Preparation of a novel ginkgolide B niosomal composite drug
  121. The degradation, biodegradability and toxicity evaluation of sulfamethazine antibiotics by gamma radiation
  122. Special issue on Monitoring, Risk Assessment and Sustainable Management for the Exposure to Environmental Toxins
  123. Insight into the cadmium and zinc binding potential of humic acids derived from composts by EEM spectra combined with PARAFAC analysis
  124. Source apportionment of soil contamination based on multivariate receptor and robust geostatistics in a typical rural–urban area, Wuhan city, middle China
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  128. Topical Issue on Agriculture
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  130. The effect of silica-calcite sedimentary rock contained in the chicken broiler diet on the overall quality of chicken muscles
  131. Physicochemical properties of selected herbicidal products containing nicosulfuron as an active ingredient
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https://doi.org/10.1515/chem-2020-0098
Keywords for this article
Stokes’ aster; meadow cranesbill; cytotoxicity and antiproliferative effects; drug-likeness; bioactivity
Creative Commons
BY 4.0

Articles in the same Issue

  1. Regular Articles
  2. Electrochemical antioxidant screening and evaluation based on guanine and chitosan immobilized MoS2 nanosheet modified glassy carbon electrode (guanine/CS/MoS2/GCE)
  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
  4. On the maximum ABC index of bipartite graphs without pendent vertices
  5. Estimation of the total antioxidant potential in the meat samples using thin-layer chromatography
  6. Molecular dynamics simulation of sI methane hydrate under compression and tension
  7. Spatial distribution and potential ecological risk assessment of some trace elements in sediments and grey mangrove (Avicennia marina) along the Arabian Gulf coast, Saudi Arabia
  8. Amino-functionalized graphene oxide for Cr(VI), Cu(II), Pb(II) and Cd(II) removal from industrial wastewater
  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
  28. Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α
  29. Incorporation of silver stearate nanoparticles in methacrylate polymeric monoliths for hemeprotein isolation
  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
  31. N,N′-Bis[2-hydroxynaphthylidene]/[2-methoxybenzylidene]amino]oxamides and their divalent manganese complexes: Isolation, spectral characterization, morphology, antibacterial and cytotoxicity against leukemia cells
  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
  33. Diorganotin(iv) benzyldithiocarbamate complexes: synthesis, characterization, and thermal and cytotoxicity study
  34. Keratin 17 is induced in prurigo nodularis lesions
  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
  40. Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
  42. Electronic structural properties of amino/hydroxyl functionalized imidazolium-based bromide ionic liquids
  43. New Schiff bases of 2-(quinolin-8-yloxy)acetohydrazide and their Cu(ii), and Zn(ii) metal complexes: their in vitro antimicrobial potentials and in silico physicochemical and pharmacokinetics properties
  44. Treatment of adhesions after Achilles tendon injury using focused ultrasound with targeted bFGF plasmid-loaded cationic microbubbles
  45. Synthesis of orotic acid derivatives and their effects on stem cell proliferation
  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
  47. Fe3O4@urea/HITh-SO3H as an efficient and reusable catalyst for the solvent-free synthesis of 7-aryl-8H-benzo[h]indeno[1,2-b]quinoline-8-one and indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine derivatives
  48. Adsorption kinetic characteristics of molybdenum in yellow-brown soil in response to pH and phosphate
  49. Enhancement of thermal properties of bio-based microcapsules intended for textile applications
  50. Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique
  51. A green strategy for obtaining anthraquinones from Rheum tanguticum by subcritical water
  52. Cadmium (Cd) chloride affects the nutrient uptake and Cd-resistant bacterium reduces the adsorption of Cd in muskmelon plants
  53. Removal of H2S by vermicompost biofilter and analysis on bacterial community
  54. Structural cytotoxicity relationship of 2-phenoxy(thiomethyl)pyridotriazolopyrimidines: Quantum chemical calculations and statistical analysis
  55. A self-breaking supramolecular plugging system as lost circulation material in oilfield
  56. Synthesis, characterization, and pharmacological evaluation of thiourea derivatives
  57. Application of drug–metal ion interaction principle in conductometric determination of imatinib, sorafenib, gefitinib and bosutinib
  58. Synthesis and characterization of a novel chitosan-grafted-polyorthoethylaniline biocomposite and utilization for dye removal from water
  59. Optimisation of urine sample preparation for shotgun proteomics
  60. DFT investigations on arylsulphonyl pyrazole derivatives as potential ligands of selected kinases
  61. Treatment of Parkinson’s disease using focused ultrasound with GDNF retrovirus-loaded microbubbles to open the blood–brain barrier
  62. New derivatives of a natural nordentatin
  63. Fluorescence biomarkers of malignant melanoma detectable in urine
  64. Study of the remediation effects of passivation materials on Pb-contaminated soil
  65. Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma
  66. Withania frutescens: Chemical characterization, analgesic, anti-inflammatory, and healing activities
  67. Design, synthesis and pharmacological profile of (−)-verbenone hydrazones
  68. Synthesis of magnesium carbonate hydrate from natural talc
  69. Stability-indicating HPLC-DAD assay for simultaneous quantification of hydrocortisone 21 acetate, dexamethasone, and fluocinolone acetonide in cosmetics
  70. A novel lactose biosensor based on electrochemically synthesized 3,4-ethylenedioxythiophene/thiophene (EDOT/Th) copolymer
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  75. Electrochemical evaluation of the antioxidant capacity of natural compounds on glassy carbon electrode modified with guanine-, polythionine-, and nitrogen-doped graphene
  76. A Dy(iii)–organic framework as a fluorescent probe for highly selective detection of picric acid and treatment activity on human lung cancer cells
  77. A Zn(ii)–organic cage with semirigid ligand for solvent-free cyanosilylation and inhibitory effect on ovarian cancer cell migration and invasion ability via regulating mi-RNA16 expression
  78. Polyphenol content and antioxidant activities of Prunus padus L. and Prunus serotina L. leaves: Electrochemical and spectrophotometric approach and their antimicrobial properties
  79. The combined use of GC, PDSC and FT-IR techniques to characterize fat extracted from commercial complete dry pet food for adult cats
  80. MALDI-TOF MS profiling in the discovery and identification of salivary proteomic patterns of temporomandibular joint disorders
  81. Concentrations of dioxins, furans and dioxin-like PCBs in natural animal feed additives
  82. Structure and some physicochemical and functional properties of water treated under ammonia with low-temperature low-pressure glow plasma of low frequency
  83. Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models
  84. Amine-functionalized magnetic activated carbon as an adsorbent for preconcentration and determination of acidic drugs in environmental water samples using HPLC-DAD
  85. Antioxidant activity as a response to cadmium pollution in three durum wheat genotypes differing in salt-tolerance
  86. A promising naphthoquinone [8-hydroxy-2-(2-thienylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione] exerts anti-colorectal cancer activity through ferroptosis and inhibition of MAPK signaling pathway based on RNA sequencing
  87. Synthesis and efficacy of herbicidal ionic liquids with chlorsulfuron as the anion
  88. Effect of isovalent substitution on the crystal structure and properties of two-slab indates BaLa2−xSmxIn2O7
  89. Synthesis, spectral and thermo-kinetics explorations of Schiff-base derived metal complexes
  90. An improved reduction method for phase stability testing in the single-phase region
  91. Comparative analysis of chemical composition of some commercially important fishes with an emphasis on various Malaysian diets
  92. Development of a solventless stir bar sorptive extraction/thermal desorption large volume injection capillary gas chromatographic-mass spectrometric method for ultra-trace determination of pyrethroids pesticides in river and tap water samples
  93. A turbidity sensor development based on NL-PI observers: Experimental application to the control of a Sinaloa’s River Spirulina maxima cultivation
  94. Deep desulfurization of sintering flue gas in iron and steel works based on low-temperature oxidation
  95. Investigations of metallic elements and phenolics in Chinese medicinal plants
  96. Influence of site-classification approach on geochemical background values
  97. Effects of ageing on the surface characteristics and Cu(ii) adsorption behaviour of rice husk biochar in soil
  98. Adsorption and sugarcane-bagasse-derived activated carbon-based mitigation of 1-[2-(2-chloroethoxy)phenyl]sulfonyl-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) urea-contaminated soils
  99. Antimicrobial and antifungal activities of bifunctional cooper(ii) complexes with non-steroidal anti-inflammatory drugs, flufenamic, mefenamic and tolfenamic acids and 1,10-phenanthroline
  100. Application of selenium and silicon to alleviate short-term drought stress in French marigold (Tagetes patula L.) as a model plant species
  101. Screening and analysis of xanthine oxidase inhibitors in jute leaves and their protective effects against hydrogen peroxide-induced oxidative stress in cells
  102. Synthesis and physicochemical studies of a series of mixed-ligand transition metal complexes and their molecular docking investigations against Coronavirus main protease
  103. A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses
  104. A new phenyl alkyl ester and a new combretin triterpene derivative from Combretum fragrans F. Hoffm (Combretaceae) and antiproliferative activity
  105. Erratum
  106. Erratum to: A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  107. Review Articles
  108. Sinoporphyrin sodium, a novel sensitizer for photodynamic and sonodynamic therapy
  109. Natural products isolated from Casimiroa
  110. Plant description, phytochemical constituents and bioactivities of Syzygium genus: A review
  111. Evaluation of elastomeric heat shielding materials as insulators for solid propellant rocket motors: A short review
  112. Special Issue on Applied Biochemistry and Biotechnology 2019
  113. An overview of Monascus fermentation processes for monacolin K production
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  118. Characterization of soil water by the means of hydrogen and oxygen isotope ratio at dry-wet season under different soil layers in the dry-hot valley of Jinsha River
  119. Composition and diurnal variation of floral scent emission in Rosa rugosa Thunb. and Tulipa gesneriana L.
  120. Preparation of a novel ginkgolide B niosomal composite drug
  121. The degradation, biodegradability and toxicity evaluation of sulfamethazine antibiotics by gamma radiation
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