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Article

Cytotoxic and Antioxidant Potential of Launaea mucronata Forssk Essential Oil Growing in Northern Saudi Arabia

by
Ehab M. Mostafa
1,2,
Ahmed H. El-Ghorab
3,4,*,
Mohammed M. Ghoneim
5,
Hasnaa Ali Ebrahim
6,
Moaz Abulfaraj
7,
Mohamed A. Abdelgawad
8,
Amr Farouk
4 and
Arafa Musa
1,2,*
1
Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia
2
Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
3
Chemistry Department, College of Science, Jouf University, Sakaka 72341, Saudi Arabia
4
Flavour and Aroma Chemistry Department, National Research Centre, Dokki, Giza 12622, Egypt
5
Department of Pharmacy, College of Pharmacy, AlMaarefa University, Riyadh 13713, Saudi Arabia
6
Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
7
Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
8
Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(20), 7025; https://doi.org/10.3390/molecules28207025
Submission received: 5 September 2023 / Revised: 26 September 2023 / Accepted: 6 October 2023 / Published: 11 October 2023
(This article belongs to the Section Food Chemistry)
Browse Figures
Versions Notes

Abstract

:
Essential oils are naturally occurring multicomponent combinations of isoprenoids with distinctive odors that are produced by aromatic plants from mevalonic acid. They are extensively applied in aromatherapy for the treatment of various ailments. To investigate the potential therapeutic value of the ingredients in Launaea mucronata essential oil (EO), gas chromatography–mass spectrometry (GC-MS) analysis was used for essential oil characterization. Then, 2,2-diphenyl-1-picrylhydrazyl (DPPH), β-carotene/linoleic acid, and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays were used to evaluate the antioxidants. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to estimate the cytotoxicity. Following a thorough analysis of the GC-MS chromatogram, 87 components representing 97.98% of the entire EO mixture were identified. N-eicosane (10.92%), 2E,6Z-farnesol (10.74%), and 2Z,6E-farnesyl acetone (46.35%) were determined to be the major components of the oil. When the produced EO was evaluated for its antioxidant properties, it showed a strong inhibitory effect (%) of 65.34 at a concentration of 80 μg/mL. The results (g/mL) showed a positive response against the tested cell lines for HCT-116, MCF-7, and HepG2 (8.45, 10.24, and 6.78 g/mL, respectively). A high-concentration mixture of deadly components consisting of farnesol, bisabolol, eicosane, and farnesyl acetone may be responsible for this significant cytotoxic action, which was especially noticeable in the HepG2 cell line. Molecular docking occurred between farnesol and farnesyl acetone with the target residues of topoisomerases I and II, CDK4/cyclD1, and Aurora B kinases; these showed binding free energies ranging from −4.5 to −7.4 kcal/mol, thus demonstrating their antiproliferative action. In addition, farnesol and farnesyl acetone fulfilled most of the ADME and drug-likeness properties, indicating their activity.

Graphical Abstract

1. Introduction

Aromatherapy is a well-known kind of complementary medicine that can be used through inhalation to treat a variety of conditions, including headache, nasal congestion, anxiety, and sleep disturbances [1,2,3]. To reduce tension, one can massage aromatherapeutic substances topically into the skin. Due to its total reliance on the use of essential oils (EOs), aromatherapy has been given the label “essential oil therapy”. Naturally occurring volatile distillates are dispersed throughout nature and are frequently responsible for the distinctive flavors and fragrances of various plants [2]. They are found in almost all plant organs, including fruits (citrus), flowers, leaves, roots, and stems [2].
Essential oils are applied for a variety of functions, such as attracting insects to help with flower pollination and seed dissemination or repelling unwelcome insects [4,5]. These substances are also significant parts of defense strategies due to their antibacterial and insecticidal activities. The volatile constituents are naturally occurring multicomponent combinations of isoprenoids with distinctive odors that are produced by aromatic plants as secondary metabolites. For several cellular processes, including cell division, photosynthesis, growth regulation, and mitochondrial respiration, isoprenoids are physiologically necessary. They are produced from mevalonic acid (MVA), which is the primary source of the active isoprene unit isopentenyl diphosphate, which is a unit of isoprene. The variety of volatile components in this structure has drawn researchers and experts to investigate their significance in relation to industrial and biological activities [6,7]. Throughout history and in all cultures, aromatic herbal plants have been extensively medicinally used to prevent, treat, and control a wide range of ailments [5,8,9,10].
Like other natural products that possess wide varieties of biological activities—for example, pomegranate possesses promising antioxidant, antifungal, and hypoglycemic activities [11]—essential oils are known to have a wide range of biological effects, including antiseptic, antifungal, anti-inflammatory, testicle-protective, antibacterial, antioxidant, analgesic, sedative, and anticancer properties [12,13,14,15].
EOs are also used to preserve food; eugenol, pinene, limonene, thymol, linalool, farnesyl acetone, and carvone have antimicrobial impacts [16]. Other phenolic elements, such as thymol, have antioxidant properties, and cedrelanol and aromadendrene have an anti-inflammatory effect [16]. Some components of essential oils, such as farnesyl acetone, farnesol, hexadecane, caryophyllene, eicosane, β-elemene, farnesyl acetate, β-elemene, and α-humulene, have been described as cytotoxic substances and have shown promising chemotherapeutic efficacy [17]. Farnesyl acetone has been shown in certain studies to exert cytotoxic and antiproliferative effects on cells, as well as other biological effects, such as insecticidal, sedative, spasmolytic, and antibacterial effects [18,19].
Protein kinases (PKs) are a class of enzymes that phosphorylate other proteins involved in signal transmission during cell division [20]. Diseases such as cancer and autoimmune, diabetic, and cardiovascular conditions are caused by mutations and dysregulation of PKs during cell division [21]. Most of the PK inhibitors that have been given approval can interact with the ATP-binding site kinases’ hinge regions. Over the last 40 years, enormous resources have been used by both commercial and academic institutions to assess and define the pathological and physiological roles of PKs in transduction pathways [20].
A minor genus in the Asteraceae (Compositae) family, Launaea, has roughly fifty-four species and is found all over the world, but it is most prevalent in Africa, Asia, and the Mediterranean region. The majority of these species are used as insect repellents, lactagogues, hypoglycemics, anti-inflammatory treatments, stomachic treatments, and soporifics in traditional medicines across the globe [22,23,24]. Some Launaea species have also been reported to treat a variety of conditions, including diarrhea, gastric disorders, infected wounds, fever, and hepatic pains. The existence of different metabolites, such as sesquiterpene lactones, flavonoids, triterpenoid saponin, steroids, and coumarins, in addition to essential oils, was discovered through phytochemical analysis of these plants [14,23,25].
The phytochemical makeup of EOs from several Launaea species has been the subject of numerous investigations, but the EO from L. mucronata has received little attention. The content and cytotoxic potential of the EO produced by L. mucronata, which grows in the northern KSA, have also not been investigated. The goal of this investigation was to examine the chemical makeup of the EO produced by L. mucronata in relation to the northern KSA region, as well as its bioactivity; this was supported by an in silico analysis of the main elements.

2. Results

2.1. Essential Oil Compositions

The hydro-distilled volatile components of L. mucronata flowers produced a 0.27% weight-per-weight pale yellow fragrant product in the current investigation. The volatile content of a total of 87 individuals (97.98%) was described. The highest percentages of ingredients were 77 light oxygenated compounds (83.83%), 2 monoterpenes (0.04%), and 8 sesquiterpenes (14.81%). First, the majority of the components were determined in the light oxygenated compounds (LOCs), such as 2Z,6E-farnesyl acetone (46.35%), farnesol (10.74%), α-cadinol (2.52%), 5E,9Z-farnesyl acetone (2.22%), 2Z,6Z-farnesal (1.47%), and cedr-8(15)-en-9-ol (1.44%). The next main classes included n-eicosane (10.92%) and cedrane (1.05%), which are sesquiterpenes. Dihydro citronellol acetate (2.35%), which is a light oxygenated compound (LOC), made up the final majority of the compounds. Additionally, included in Table 1 [4,26,27,28,29] is tetrahydro-lavandulol acetate (1.61%).

2.2. Antioxidant Assay

DPPH, ABTS, and β-carotene assays were used to evaluate the L. mucronata EO’s antioxidant properties. Since this EO exhibited significant antioxidant activity, it may be used as an antioxidant agent in medicine (Table 2). According to the DPPH, ABTS, and β-carotene assays, respectively, the scavenging power of the L. mucronata EO ranged from 30.13 to 65.34, 31.75 to 64.78, and 30.78 to 63.71%. According to the β-carotene, ABTS, and DPPH assays, respectively, the values of the standard antioxidant medication t-butyl hydroquinone (TBHQ) varied from 43.35 to 79.11, 42.12 to 78.41, and 42.85 to 78.79% at the same sample concentrations.

2.3. Antiproliferative Activity

The cytotoxic potential of the L. mucronata EO was evaluated using an MTT assay in triplicate. The assays were conducted on three cell lines (MCF-7, HepG2, and HCT-116). The results are expressed in μg/mL, and strong cytotoxic effects were shown against all the tested cell lines (6.78, 8.45, and 10.24 μg/mL for HepG2, HCT-116, and MCF-7, respectively), in Table 3. In particular, the strong cytotoxic effect against HepG2 may be attributed to the high percentages of farnesol (10.74%), bisabolol (0.84%), calamenene (0.85%), eicosane (10.92%), and farnesyl acetone (46.35%), which have been reported to have cytotoxic effects [30,31,32].

2.4. Molecular Docking Study

Figure 1 displays the ability of the ligands to bind to various topoisomerases: topoisomerase I (PDB IDs: 1T8I, 1K4T, and 1RR8), topoisomerase II (PDB IDs: 3QX3 and 1ZXM), aurora B kinases (PDB ID: 4C2V), and CDK4 kinase (PDB ID: 2W96). The binding energies for the ligands on topoisomerase I enzymes were very similar, ranging from −4.5 to −6.3 kcal/mol. The greatest scores for receptors in this range were between −6.3 and −6.4 kcal/mol for farnesyl acetone. An identical pattern was seen when farnesyl acetone docked with CDK4 kinases, recording −7 kcal/mol. Farnesol, on the other hand, displayed a greater affinity for topoisomerase II enzymes (−6.1 and −7.4 kcal/mol) and aurora B kinases (−6.7 kcal/mol).
Farnesyl acetone had a higher affinity for attaching to 1RR8 due to the critical conventional hydrogen bonds generated with GLY C:363, ARG C:362, and SER C:361, whereas 1T8I had a higher affinity due to its similarly special bond with GLN A:421 (Figure 2a–c). All the ligands and topoisomerase I enzymes shared alkyl interactions and pi-alkyl bonds; however, they were less effective in terms of binding energy than traditional H-bonds or C-H bonds. In the same scenario, the increased affinity of farnesyl acetone for CDK4 kinases (2W96) (Figure 2d) and topoisomerase II enzymes (1ZXM) (Figure 2e) was due to the strong pi-sigma bond with PHE B:93. Otherwise, farnesol exhibited higher binding energy compared with that of the other ligands when docking with topoisomerase II enzymes (3QX3 and 1ZXM) due to the conventional H-bond and C-H bonds with the ASN B:882, GLY B:368, and GLU B:870 residues for the former enzyme and the conventional H-bond and the unique donor–donor bond with LYS B:168 and ALA B:167 for the latter enzyme (Figure 2f,g). Farnesol and aurora B kinases only displayed one conventional H-bond (4C2V), whereas all the other ligand-to-previous-enzyme connections were created through alkyl and pi-alkyl interactions (Figure 2h). Because of its simple structure and absence of aromaticity, hydroxyl groups, and other functional groups, n-eicosane had a lower binding energy than the other molecules. This may also explain why it had a lower binding affinity. As a result, eicosane had a limited ability to bind to the target enzymes and form a complex (Figure 2i,j).

2.5. In Silico ADME Profile

The drug-likeness of farnesol and farnesyl acetone is shown in Table 4 in comparison with that of eicosane. Eicosane had lower lipophilicity, solubility, and TPSA parameters, in addition to a low TPSA value. Farnesol and farnesyl acetone, however, showed better ADME profiles with higher TPSA values (Table 4). The results showed that the investigated compounds were moderately metabolized in the liver, as they only inhibited specific CYP isoforms, as shown in Table 4. Additionally, all the compounds tested were identified as non-Pgp substrates.

3. Discussion

3.1. Essential Oil Compositions

The yield of L. mucronata EOs under investigation was 0.27% w/w, while that of the Egyptian version of the plant was 0.019 w/w [4]. The analysis of the Saudi EO resulted in the characterization of 87 components (Table 1), whereas only 50 components were identified in the Egyptian L. mucronata EOs [4]. The total content of oxygenated compounds identified in the tested oil sample was 83.5%, while that in the Egyptian plant was 75%.
The main identified components were 2E,6Z-farnesol, α-cadinol, dihydro citronellol acetate, 5E,9Z-farnesyl acetone, n-hexadecane, tetrahydro lavandulol acetate, 2Z,6Z-farnesal, n-tridecanol, n-hexadecanol, and cedrane.
It was found that the concentrations of Z,Z-farnesyl acetone, n-eicosane, and Cedr-8(15)-en-9-α-ol were significantly different (46.53, 10.92, and 1.44%, respectively) from those in the Egyptian plant (3.95, 1.38, and 2.23%, respectively). The significant variation between the Saudi and Egyptian plants regarding their yield and chemical composition might be attributable to the different localities and environmental conditions.

3.2. Antioxidant Assay

The ability of a medication or phytochemical to shield from or even stop the oxidation of the human body by dangerous radicals is known as antioxidant activity [33,34]. When the EO of L. mucronata was compared with that of TBHQ as a reference, the EO showed significant antioxidant activity in all three assays. According to the DPPH, ABTS, and β-carotene assays, the evaluated EO sample’s scavenging power ranged from 30.13 to 65.34, 31.75 to 64.78, and 30.78 to 63.71%, respectively. According to the β-carotene, ABTS, and DPPH assays, respectively, the results for TBHQ ranged from 43.35 to 79.11, 42.12 to 78.41, and 42.85 to 78.79% (Table 2). The results of all the assays were consistent with each other. The complex blend of the L. mucronata EO’s contents, which were mostly light oxygenated components (farnesol, farnesyl acetone, 1-terpineol, and ocimenone), may be responsible for its potent antioxidant activity [35]. Our results were found to be in good agreement with those of Thejanuo et al. [36]. Additionally, the antioxidant activity of the investigated sample was greater than that reported in various Launaea species growing in Egypt [4]. Moreover, the inhibition percentage of the EO’s scavenging activity (64–79) at a concentration of 80 mg/mL was greater than that obtained from a methanolic extract of the same plant collected from ArAr, Saudi Arabia (50%) [37]. Therefore, rather than using its extract, L. mucronata EO might be introduced as a food preservative.

3.3. Antiproliferative Activity

An MTT assay was used to assess the cytotoxic capabilities of the L. mucronata EO against several cell lines (MCF-7, HepG2, and HCT-116). For HepG2, HCT-116, and MCF-7, respectively, the results showed substantial cytotoxic potential (6.78, 8.45, and 10.24 g/mL) (Table 3), which might be attributable to the presence of high concentrations of farnesyl acetone (46.35%), eicosane (10.92%), farnesol (10.74%), calamenene (0.85%), and bisabolol (0.84%), which have been reported to have cytotoxic effects [30,31,32]. Our results were found to be in good agreement with those of Palanisamy et al. [38,39].

3.4. Molecular Docking

The primary bioactive components of the EO (farnesol, farnesyl acetone, and n-eicosane) were subjected to docking studies for topoisomerase I, topoisomerase II, aurora B kinases, and CDK4 kinase. Certain compounds had a greater affinity than others for binding to the residues of the target enzymes due to the crucial conventional bonds that formed with the target residues (Figure 1 and Figure 2). Farnesyl acetone had the highest binding energies with topoisomerase I enzyme receptors (−6.3 to −6.4 kcal/mol) and CDK4 kinases (−7 kcal/mol). Farnesol was shown to have the highest affinity (−6.1 to −7.4 kcal/mol) for topoisomerase II enzymes and aurora B kinases. On the other hand, when farnesol docked with the topoisomerase II enzymes 3QX3 and 1ZXM, it showed higher binding energy than that of the other ligands. Due to its straightforward structure and lack of functional groups, which may favor its interactions with target enzymes, n-eicosane displayed the lowest binding energy. As a result, eicosane had a limited ability to bind to the target enzymes (Figure 1 and Figure 2). The molecular docking analysis validated the L. mucronata EO’s promising antiproliferative action, which may be explained by the compound’s farnesyl acetone and farnesol content, as these demonstrated increased binding affinity for the target enzymes [40,41,42].

3.5. In Silico ADME

SwissADME was used to evaluate the drug-likeness of the compounds based on guidelines considering various descriptors, such as molecular weight, lipophilicity, solubility, flexibility, and topological surface area. Lipophilicity and solubility are essential parameters for drug absorption, while the number of rotatable bonds should be less than 10 for drug-likeness, according to Veber’s rule [40,41,42]. Unsaturation in compounds can improve receptor–ligand complementarity. The results of the comparison of the drug-likeness of farnesol and farnesyl acetone with that of eicosane agreed with previous findings (Table 4). Eicosane had lower binding energies than those of farnesol and farnesyl acetone, which was in agreement with the violations of the lipophilicity, solubility, and TPSA parameters, as shown in Table 4. This was due to its nonpolar structure, which increased its hydrophobicity in relation to that of the other compounds studied. In addition, its low TPSA value indicated its low polarity, leading to poor oral absorption and membrane permeation. Farnesol and farnesyl acetone, on the other hand, showed better ADME profiles by incorporating polar moieties, such as hydroxyl and carbonyl groups, which increased their TPSA values (Table 4). Therefore, adding polar functional groups is crucial for increasing bioavailability [40,41].
It was necessary to perform further analyses to predict the metabolic rates of the compounds under investigation—specifically, as cytochrome P450 (CYP) enzyme inhibitors and as Pgp substrates. The cytochrome P450 (CYP) enzyme superfamily plays a crucial role in hepatic drug metabolism, while the Pgp substrate is a type of drug efflux transporter that helps limit cellular uptake and increase the elimination of drugs through excretion organs.

4. Materials and Methods

4.1. Plant Material

Launaea mucronata (Forssk.) Muschl. flowers were collected in April 2019 on the campus of Jouf University in Al-Jouf, Saudi Arabia. Mr. Hamidan Hasan, M.Sc. (Camel and Range Research Center, Al-Jouf, KSA) successfully verified the authenticity of the plant sample. The College of Pharmacy at Jouf University in Saudi Arabia has a voucher sample (71-CPJU) that is archived and kept there.

4.2. Extraction of the Volatile Constituents

In April 2019, 350 g of fresh flowers were obtained from L. mucronata and cleaned with ordinary water; then, the volatile oil was hydro-distilled with a Clevenger apparatus using the conventional extraction method. The distillate was separated from the aqueous phase using a separating funnel with a volume of 500 mL. By adding NaCl (salting out), the complete amount of oil was exhausted. Dichloromethane was then used to extract the remaining soluble ingredients from the aqueous phase. After being dehydrated with anhydrous Na2SO4, the mixed extracts were filtered with Whatman filter paper (WHA1001025, Zhejiang, China). The hydro-distilled extract that was produced (0.27% w/w) was a yellowish oily liquid with a pleasant smell. Until further investigation, it was kept in airtight, dry, sealed vials at a temperature of 2–4 °C [43,44].

4.3. Gas Chromatography and Gas Chromatography–Mass Spectrometry (GC-FID and GC-MS)

For the measurement of the volatile components, an Agilent gas chromatograph apparatus (model 6890, Folsom, CA, USA) equipped with an FID (flame ionization detector) at 70 eV and an HP-5ms capillary column (120 m × 0.25 mm) was used. The feed ratio for the carrier gas (He) was set to 20 cm/sec, the injector and detector temperatures were set to 250 °C, and the oven temperature was varied from 60 to 240 °C and maintained for 10 min.
Agilent Technologies’ model 7890B GC (Folsom, CA, USA) in conjunction with a 7000D GC/TQ, GC/MS, and 7693A autosampler was utilized to analyze the volatiles and identify them. Ionization occurred at 70 eV with a 120 m × 0.25 mm i.d. HP-5ms column. The injector and detector were kept at a constant temperature of 250 °C during the entire experiment, which was run at a constant velocity of 30 cm/s for the carrier gas (He). The run continued for 50 min at the preset temperature (60–240 °C) with a 3 °C/min temperature increase that was maintained until the end of the run. By injecting the sample with a solution series of homologous n-hydrocarbons (C8–C26) under identical pre-existing conditions, values of Kovat’s index were determined. By comparing the fragmentation patterns with those from NIST data, published data, and Kovat’s retention indices of authentic components, the hydro-distilled constituents were determined. This study reports the composition of volatile components as a comparative percentage of the entire peak region.

4.4. Antioxidant Activity

4.4.1. DPPH Radical Scavenging Assay

DPPH, a stable radical that has a dark purple color and can absorb UV radiation of up to 518 nm in wavelength, was used. When antioxidants are present, DPPH takes an electron, stabilizing the radical. After that, the solution is decolored, and the absorbance at the maximum wavelength of 518 nm decreases [37]. By measuring the decrease in absorbance and comparing the IC50 with that of recognized antioxidants, such as tert-butylhydroquinone (TBHQ), the antioxidant capabilities can be determined. The absorbance was measured using a UV spectrophotometer (HP 8452, UV-VIS, Bothell, WA, USA) [35]. The following calculation was used to calculate the antioxidants’ ability to scavenge the radical as a percentage of inhibition:
% inhibition = [(A control − A sample or standard)]/(A control) × 100

4.4.2. β-Carotene/Linoleic acid Bleaching Assay

A previously discussed linoleic acid/β-carotene scheme was used to determine the antioxidant capacity of the hydro-distilled extract of L. mucronata flowers. Utilizing TBHQ as a positive control, the absorbance was measured at a maximum wavelength of 471 nm. The following equation was used to compute the inhibition percentage of bleaching (I bleaching percentage) [45]:
[Absorbance (after 2 h of experiment)/Initial absorbance] × 100 = I bleaching%

4.4.3. ABTS Free Radical Assay

Following the Witayapan method with a few minor modifications, a stock solution of ABTS was diluted in methanol, and a substance called 2,2’-azino-bis [3-ethylbenzothiazoline-6-sulfonic acid] was used to determine the scavenging capabilities of the hydro-distilled components of L. mucronata flowers. Then, 2.45 mM K2S2O8 was used to oxidize the solution, resulting in the formation of pre-formed ABTS radical monocation. The mixture was held at 25 °C for 12 h in a dark environment, and the absorbance was measured at a maximum of 733 nm. The equation specified in the description of the DPPH assay was used to determine the antioxidant inhibition percentage in the ABTS assay [35].

4.5. Antiproliferative Activity

The MCF-7 (Michigan Cancer Foundation-7), HepG2 (human hepatocellular carcinoma), and HCT-116 (human colorectal carcinoma) cell lines were used in this investigation. Fetal bovine serum (10%) (FBS-Gibco, Sigma Aldrich, St. Louis, MI, USA) was added to the cell lines, which were purchased from the Regional Center for Mycology and Biotechnology at Al-Azhar University in Cairo, Egypt [46,47]. Humidified CO2 (5%) was used to maintain the cells at 36 °C. Using the MTT assay in accordance with the Lang and Denizot method, the in vitro antiproliferative capabilities of the volatile contents of L. mucronata flowers were assessed. A maximum of 598 nm was used to measure the decrease in the level of MTT with respect to formazan blue within the cells.

4.6. Docking Study

The Protein Data Bank (PDB) (https://www.rcsb.org/, accessed on 17 December 2021) was used to obtain the crystal structures of topoisomerase I enzymes (PDB IDs: 1T8I, 1K4T, and 1RR8), topoisomerase II enzymes (PDB IDs: 3QX3 and 1ZXM), aurora B kinases (PDB ID: 4C2V), and CDK4 kinases (PDB ID: 2W96) [48]. Avogadro software (Version 1.2.0) was used to optimize the 3D structures of the ligands (farnesol, farnesyl acetone, and eicosane), and these were retrieved from the PubChem database (http://pubchem.ncbi.nlm.nih.gov/, accessed on 17 December 2021) [48]. On 17–18 December 2021, the web-based program CB-DOCK (http://clab.labshare.cn/cb-dock/php/, accessed on 17 December 2021) was used to execute blind docking. The input files were reviewed by CB-Dock after submission, and OpenBabel and MGLTools translated them into pdbqt format. The protein cavities were then predicted using CB-Dock, which also determined the locations and dimensions of the top N (n = 5 by default) cavities. The docking of all the centers, sizes, and pdbqt files was performed using AutoDock Vina. The findings were presented following the computation of N rounds [36]. Using the Discovery Studio program (Version 21.1.0.20298), interaction and visualization profiles were created for the best-docked complexes [36].

4.7. In Silico ADME Properties

The SwissADME server (http://www.swissadme.ch/) (accessed on 16 September 2023) from the Swiss Institute of Bioinformatics was used to evaluate all the ligands’ in silico ADME profiles. The SMILES notations were generated and submitted to the server during ligand preparation for the ADME evaluation [35].

4.8. Statistical Analysis

The data (means ± SD) were analyzed using one-way ANOVA followed by the Tukey–Kramer test. The level of significance was set at a probability of less than 0.05. GraphPad Prism 8 software was used for statistical analysis.

5. Conclusions

An analysis of the EO from Launaea mucronata resulted in the characterization of 87 components, the majority of which were represented by 2Z,6E-farnesyl acetone (46.35%), 2E,6Z-farnesol (10.74%), and n-eicosane (10.92%). The EO showed promising antioxidant and antiproliferative activities in comparison with the standards used. The docking study supported the oil’s antiproliferative effect. The overall conclusion is in support of the safe application of the EO from L. mucronata at low concentrations in aromatherapy as a strong antioxidant agent for food preservation.

Author Contributions

Conceptualization, E.M.M. and A.F.; methodology, A.H.E.-G.; software, A.M. and A.F.; validation, A.H.E.-G.; formal analysis, A.M. and E.M.M.; investigation, H.A.E.; resources, M.A.; data curation, M.M.G.; writing—original draft preparation, A.M. and M.A.A.; writing—review and editing, A.M. and M.A.A.; visualization, M.A.A.; supervision, A.H.E.-G.; project administration, E.M.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The researchers would like to acknowledge Princess Nourah bint Abdulrahman University Researcher Supporting Project (number: PNURSP2023R171), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples are available from the authors.

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Molecules 28 07025 g001
Figure 1. Binding free energy values were calculated using the molecular docking of ligands (farnesol, farnesyl acetone, and eicosane) and receptors (3QX3, 1ZXM, 1T8I, 1K4T, 1RR8, 4C2V, and 2W96).
Figure 1. Binding free energy values were calculated using the molecular docking of ligands (farnesol, farnesyl acetone, and eicosane) and receptors (3QX3, 1ZXM, 1T8I, 1K4T, 1RR8, 4C2V, and 2W96).
Molecules 28 07025 g001
Molecules 28 07025 g002
Figure 2. Interactions of farnesyl acetone with topoisomerase I enzymes ((a) 1T8I, (b) 1K4T, and (c) 1RR8), CDK4 kinase ((d) 2W96), and topoisomerase II enzymes ((e) 1ZXM). Interactions of farnesol with topoisomerase II enzymes ((f) 3QX3 and (g) 1ZXM) and aurora B kinase ((h) 4C2V). Interactions of eicosane with topoisomerase II enzymes ((i) 1ZXM) and aurora B ((j) 4C2V).
Figure 2. Interactions of farnesyl acetone with topoisomerase I enzymes ((a) 1T8I, (b) 1K4T, and (c) 1RR8), CDK4 kinase ((d) 2W96), and topoisomerase II enzymes ((e) 1ZXM). Interactions of farnesol with topoisomerase II enzymes ((f) 3QX3 and (g) 1ZXM) and aurora B kinase ((h) 4C2V). Interactions of eicosane with topoisomerase II enzymes ((i) 1ZXM) and aurora B ((j) 4C2V).
Molecules 28 07025 g002
Table 1. Chemical composition of L. mucronata EO according to GC-MS analysis.
Table 1. Chemical composition of L. mucronata EO according to GC-MS analysis.
Peak
No.		Rel. Comp. %Calculated * KIKI DataCompound NameCompounds’ ClassIdentification Methods
10.0210241023–1027Trimethyl benzene (1,2,4)MMS&KI
20.0210291028–1034β-PhellandreneMMS&KI
30.0210351033–10382-acetyl-5-methyl-furanLOCMS&KI
40.0610381035–10415-methyl-hexanoic acidLOCMS&KI
50.1510481045–1048γ-hexalactone LOCMS&KI
60.0210681065–10692-methyl-benzaldehydeLOCMS&KI
70.0410861085–10893-methyl-1,2-cyclohexanedioneLOCMS&KI
80.0210991095–10992-nonanol LOCMS&KI
90.0611071104–11092,6-dimethyl phenolLOCMS&KI
100.0511091108–1112cis-rose oxideLOCMS&KI
110.0211151114–1118Endo-fencholLOCMS&KI
120.111211119–1123exo-fencholLOCMS&KI
130.0211241122–1125MyrcenolLOCMS&KI
140.5111301127–1131Octyl formateLOCMS&KI
150.3411321132–11361-terpineolLOCMS&KI
160.1411391138–1140trans-pinocarveolLOCMS&KI
170.0511441142–1145cis-Pinene hydrateLOCMS&KI
180.0511471144–1147CamphorLOCMS&KI
190.0211501146–1151Camphene hydrateLOCMS&KI
200.0711551153–1156Isobutyl hexanoateLOCMS&KI
210.0511561155–1159Nerol oxideLOCMS&KI
220.0211601160–1163cis-dihydro-β-terpineolLOCMS&KI
230.1511651164–11682E-nonenolLOCMS&KI
240.0211721170–1174Octanoic acidLOCMS&KI
250.0711761172–1177cis-pyranoid linalool oxideLOCMS&KI
260.111841181–1184Thuj-3-en-10-alLOCMS&KI
270.0511871185–1188neoiso-mentholLOCMS&KI
280.0411941193–1197cis-piperitolLOCMS&KI
290.0212001199–1201cis-4-caranoneLOCMS&KI
310.0512121211–1215Iso-dihydro carveolLOCMS&KI
320.0512231221–1225Methyl-2E-nonenoateLOCMS&KI
330.7112381237–1239E-ocimenoneLOCMS&KI
340.6812471246–1251Ethyl-oct-2E-enoateLOCMS&KI
350.0512641263–1266cis-chrysanthenyl acetate LOCMS&KI
361.6112711268–1272tetrahydro-lavandulol acetateLOCMS&KI
370.1512761274–1277dihydro-linalool acetateLOCMS&KI
380.2812811279–12823Z-hexenyl valerateLOCMS&KI
390.0212831280–1284cis-verbenyl acetateLOCMS&KI
400.1512881286–12892-ethyl-endo-fencholLOCMS&KI
410.0713011298–1302trans-dihydro-α-terpinyl acetateLOCMS&KI
420.3313041303–1307UndecanalLOCMS&KI
430.2513131312–1317Citronellic acidLOCMS&KI
442.3513211319–1322Dihydro citronellol acetateLOCMS&KI
450.0213541351–1355Thymol acetateLOCMS&KI
460.113601360–13632E-UndecenalLOCMS&KI
470.1513891388–13912-dodecanone-methyl decyl ketoneLOCMS&KI
480.1213911390–13923-DodecanoneLOCMS&KI
490.0213941391–1394β-elemeneSMS&KI
500.0514011398–1402β-longipineneSMS&KI
510.3514081406–1409DodecanalSMS&KI
521.0514421440–1444CedraneSMS&KI
530.3114461446–1450BakerolLOCMS&KI
540.2514551453–1456Geranyl acetoneLOCMS&KI
550.8514911490–149410,11-epoxy-calameneneLOCMS&KI
560.4515061203–1507E,E-α-FarneseneSMS&KI
570.0515541553–1557Thymohydro quinoneLOCMS&KI
580.2215681567–15692E-Tridecen-1-alLOCMS&KI
591.1515731570–1573n-TridecanolLOCMS&KI
601.8516001558–1601n-HexadecaneSMS&KI
610.0516041602–1606LedolLOCMS&KI
620.1216061605–1609Geranyl isovalerateLOCMS&KI
630.0516111608–1611Dodecyl acetateLOCMS&KI
640.1716151613–1616cis-isolongifolanoneLOCMS&KI
650.0216171615–1619Davanol D1LOCMS&KI
660.3616281627–16292-(3-oxobutyl)-isomenthone LOCMS&KI
670.0716501648–1651β-eudesmolLOCMS&KI
681.4416531650–1653Cedr-8(15)-en-9-α-olLOCMS&KI
690.2516541652–1655α-eudesmolLOCMS&KI
702.5216551654–1657α-cadinolLOCMS&KI
710.0216561655–1659Geranyl valerateLOCMS&KI
720.2216671666–166914-hydroxy-(Z)-caryophyllene LOCMS&KI
730.4116751674–1678Z-nerolidyl acetateLOCMS&KI
741.4716831682–16862Z,6Z-farnesalLOCMS&KI
750.8416861685–1689α-bisabololLOCMS&KI
7610.7417131709–17132E,6Z-farnesolLOCMS&KI
770.7517151712–171614-hydroxy-α-HumuleneLOCMS&KI
7846.3518601857–1882Z,Z-farnesyl acetoneLOCMS&KI
790.1218551853–1858CyclopentadecanolideSMS&KI
800.0218621859–1863Eudesm-7(11)-en-4-ol, acetateLOCMS&KI
810.818651864–1867HomoisobaeckeolLOCMS&KI
820.518701869–18732,7(14),10-bisabolatrien-1-ol-4-oneLOCMS&KI
830.0218801878–1882α-chenopodiolLOCMS&KI
841.1218851883–1887n-hexadecanolLOCMS&KI
852.2218911891–18965E,9Z-farnesyl acetoneLOCMS&KI
860.3719001898–1902Dihydro-columellarinLOCMS&KI
8710.9220012000–2004n-eicosaneSMS&KI
* KI: Kovat’s index; the calculated KI data were compared with those obtained from the literature, as well as documented websites dealing with the KI ranges of volatiles. Rel. comp. (relative composition) %: comparative percentage of the entire peak region. MS: tentative characterization through comparison with NIST mass spectra library data. M: monoterpenes. S: sesquiterpenes. LOC: light oxygenated compound.
Table 2. Antioxidant potential of the volatile oil of L. mucronata.
Table 2. Antioxidant potential of the volatile oil of L. mucronata.
Sample Concentration (µg/mL)% Inhibition by DPPH % Inhibition by ABTS % Inhibition by β-Carotene/Linoleic Acid
EOTBHQEOTBHQEOTBHQ
20 30.13 ± 1.842.85 ± 1.931.75 ± 1.842.12 ± 1.830.78 ± 1.943.35 ± 1.8
4042.65 ± 1.965.02 ± 1.841.26 ± 1.964.72 ± 1.943.32 ± 1.966.01 ± 2.0
60 53.71 ± 1.972.15 ± 2.151.25 ± 1.971.84 ± 2.052.16 ± 2.171.65 ± 2.1
8065.34 ± 2.178.79 ± 2.064.78 ± 2.278.41 ± 2.263.91 ± 2.179.11 ± 2.1
Values are presented as the average of experiments performed in triplicate ± the standard deviation (p < 0.005).
Table 3. Antiproliferative activity of the L. mucronata essential oil.
Table 3. Antiproliferative activity of the L. mucronata essential oil.
CompoundsIC50 ± SD (μg/mL) a
MCF-7HepG2HCT-116
EO10.24 ± 2.146.78 ± 1.828.45 ± 1.64
Doxorubicin0.81 ± 0.830.85 ± 0.480.78 ± 0.63
a Cell proliferation was determined using an MTT assay. IC50 ± SD or IC50 values in µg/mL after 48 h of incubation. The values are the average of three independent experiments. SD: standard deviation. MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. IC50: concentration that achieved 50% inhibition of the proliferation response exhibited in the specified cell lines without treatment.
Table 4. In silico ADME properties of farnesol, farnesyl acetone, and eicosane according to SwissADME.
Table 4. In silico ADME properties of farnesol, farnesyl acetone, and eicosane according to SwissADME.
ADME PropertiesIdentifierFarnesolFarnesyl AcetoneEicosane
Physicochemical PropertiesMolecular weight222.37262.43282.55
No. rotatable bonds7917
TPSA20.23Å17.07 Å0.00 Å
LipophilicityiLOGP3.713.675.64
XLOGP35.425.5610.45
WLOGP4.405.778.05
MLOGP3.864.507.38
SILICOS-IT4.215.697.98
Water SolubilityESOL−4.17−4.38−7.05
Log S−5.60−5.68−10.40
SILICOS-IT−3.15−4.47−7.94
PharmacokineticsGI absorptionHighHighLow
BBB permeantYesNoNo
P-gp substrateNoNoNo
CYP1A2 inhibitorYesYesYes
CYP2C19 inhibitorNoNoNo
CYP2C9 inhibitorYesYesNo
CYP2D6 inhibitorNoNoNo
CYP3A4 inhibitorNoNoNo
Log Kp−3.81 cm/s−3.95 cm/s−0.6 cm/s
Drug-likenessLipinskiYesYesYes
GhoseYesNoNo
VeberYesYesNo
EganYesYesNo
MueggeNoNoNo
Bioavailability score0.550.550.55
Medicinal ChemistryPAINS0 alert0 alert0 alert
Brenk1 alert1 alert0 alert
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Mostafa, E.M.; El-Ghorab, A.H.; Ghoneim, M.M.; Ebrahim, H.A.; Abulfaraj, M.; Abdelgawad, M.A.; Farouk, A.; Musa, A. Cytotoxic and Antioxidant Potential of Launaea mucronata Forssk Essential Oil Growing in Northern Saudi Arabia. Molecules 2023, 28, 7025. https://doi.org/10.3390/molecules28207025

AMA Style

Mostafa EM, El-Ghorab AH, Ghoneim MM, Ebrahim HA, Abulfaraj M, Abdelgawad MA, Farouk A, Musa A. Cytotoxic and Antioxidant Potential of Launaea mucronata Forssk Essential Oil Growing in Northern Saudi Arabia. Molecules. 2023; 28(20):7025. https://doi.org/10.3390/molecules28207025

Chicago/Turabian Style

Mostafa, Ehab M., Ahmed H. El-Ghorab, Mohammed M. Ghoneim, Hasnaa Ali Ebrahim, Moaz Abulfaraj, Mohamed A. Abdelgawad, Amr Farouk, and Arafa Musa. 2023. "Cytotoxic and Antioxidant Potential of Launaea mucronata Forssk Essential Oil Growing in Northern Saudi Arabia" Molecules 28, no. 20: 7025. https://doi.org/10.3390/molecules28207025

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