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New Antiproliferative Triflavanone from Thymelaea hirsuta-Isolation, Structure Elucidation and Molecular Docking Studies.

ABSTRACT: In this study isolates from Thymelaea hirsuta, a wild plant from the Sinai Peninsula of Egypt, were identified and their selective cytotoxicity levels were evaluated. Phytochemical examination of the ethyl acetate (EtOAc) fraction of the methanolic (MeOH) extract of the plant led to the isolation of a new triflavanone compound (1), in addition to the isolation of nine previously reported compounds. These included five dicoumarinyl ethers found in Thymelaea: daphnoretin methyl ether (2), rutamontine (3), neodaphnoretin (4), acetyldaphnoretin (5), and edgeworthin (6); two flavonoids: genkwanin (7) and trans-tiliroside (8); p-hydroxy benzoic acid (9) and ? sitosterol glucoside (10). Eight of the isolated compounds were tested for in vitro cytotoxicity against Vero and HepG2 cell lines using a sulforhodamine-B (SRB) assay. Compounds 1, 2 and 5 exhibited remarkable cytotoxic activities against HepG2 cells, with IC₅₀ values of 8.6, 12.3 and 9.4 ?M, respectively, yet these compounds exhibited non-toxic activities against the Vero cells. Additionally, compound 1 further exhibited promising cytotoxic activity against both MCF-7 and HCT-116 cells, with IC₅₀ values of 4.26 and 9.6 ?M, respectively. Compound 1 significantly stimulated apoptotic breast cancer cell death, resulting in a 14.97-fold increase and arresting 40.57% of the cell population at the Pre-G1 stage of the cell cycle. Finally, its apoptosis-inducing activity was further validated through activation of BAX and caspase-9, and inhibition of BCL2 levels. In silico molecular docking experiments revealed a good binding mode profile of the isolates towards Ras activation/pathway mitogen-activated protein kinase (Ras/MAPK); a common molecular pathway in the development and progression of liver tumors.

SUBMITTER: Elhady SS

PROVIDER: S-EPMC7867015 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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New Antiproliferative Triflavanone from Thymelaea hirsuta-Isolation, Structure Elucidation and Molecular Docking Studies.

Elhady Sameh S SS Abdelhameed Reda F A RFA El-Ayouty Mayada M MM Ibrahim Amany K AK Habib Eman S ES Elgawish Mohamed S MS Hassanean Hashim A HA Safo Martin K MK Nafie Mohamed S MS Ahmed Safwat A SA

Molecules (Basel, Switzerland) 20210131 3

In this study isolates from Thymelaea hirsuta, a wild plant from the Sinai Peninsula of Egypt, were identified and their selective cytotoxicity levels were evaluated. Phytochemical examination of the ethyl acetate (EtOAc) fraction of the methanolic (MeOH) extract of the plant led to the isolation of a new triflavanone compound (1), in addition to the isolation of nine previously reported compounds. These included five dicoumarinyl ethers found in Thymelaea: daphnoretin methy ...[more]

PMID: 33572651

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Project description:The research work presented in this study is mainly concerned with the bioactivity-directed phytochemical and biological evaluation of Persea duthiei. Persea duthiei is a typical medicinal plant used to treat a variety of ailments such as asthma, edema, and bronchitis. Ethyl acetate, n-hexane, n-butanol, and compounds that are soluble in water were used to examine the antibacterial as well as antifungal capacities of the plant. The antibacterial activity of the soluble parts of ethyl acetate and n-hexane against Escherichia coli, Staphylococcus aureus, Salmonella typhi, and Bacillus subtilis was high, even though there was no activity against Pseudomonas aeruginosa. Likewise, the n-hexane and ethyl acetate fractions were found to have substantial efficacy against several fungal strains such as Aspergillus flavus, Aspergillus fumigates, Fusarium solani, and Aspergillus niger, but not against Candida glabrata. Among the studied fractions, the ethyl acetate soluble fraction had potent antibacterial activity against all of the tested species. This fraction was submitted to phytochemical analysis utilizing various chromatographic methods for the extraction of various pure components. As a consequence, four compounds were isolated, and their structures were elucidated using various spectroscopic methods such as IR, EIMS, HR-EIMS, 1H-NMR, 13C-NMR, NOESY, COSY, HMBC, and HMQC. Urs-12-en-3β-ol (α-amyrine) (1), Urs-12-ene-2α-3β-diol (chamaedrydiol) (2), 3β-hydroxyurs-12-en-28-aldehyde (ursolic aldehyde) (3), and 12-oleanex-3β-ol (β-amyrine) (4) were extracted. Compounds 1, 2, 3, and 4 were examined for antibacterial and antifungal activity and found to have zones of inhibition ranging from 0 to 11 mm against tested bacteria strains and percent inhibition ranging from 0 to 25 percent against fungus strains. Compounds 1 and 4 showed strong efficacy against the investigated fungal species, with a 25% inhibition rate. In the case of antibacterial activity, compounds 4 and 1 showed potent activity with zones of inhibition of 11 mm and 10 mm, respectively. Compounds 2 and 3 were observed to have nonsignificant antimicrobial activity. However, docking studies reflected the complex formation of compound 1 with beta-hydroxyacyl-ACP dehydratase HadAB and S. aureus tyrosyl-tRNA synthetase and compound 2 with topoisomerase II DNA gyrase complex, and they were reported to have antibacterial properties. Similarly, compound 4 was discovered to be well compatible with the lanosterol 14-demethylase (fungal enzyme) and is thus regarded as having antifungal capabilities. Chimera software was used to identify the binding pockets of these complexes. These results indicated that Persea duthiei is a valuable source of medicinal compounds for medication development.

Project description:With 19.3 million new cases and almost 10 million deaths in 2020, cancer has become a leading cause of death today. Curcumin and its analogues were found to have promising anticancer activity. Inspired by curcumin's promising anticancer activity, we prepared three semi-synthetic analogues by chemically modifying the diketone function of curcumin to its pyrazole counterpart. The curcumin analogues (3a-c) were synthesized by two different methods, followed by their DFT analyses to study the HOMO/LUMO configuration to access the stability of compounds (∆E = 3.55 to 3.35 eV). The curcumin analogues (3a-c) were tested for antiproliferative activity against a total of five dozen cancer cell lines in a single (10 µM) and five dose (0.001 to 100 µM) assays. 3,5-Bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(phenoxy)ethanone (3b) and 3,5-bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(2,4-dichlorophenoxy)ethanone (3c) demonstrated the most promising antiproliferative activity against the cancer cell lines with growth inhibitions of 92.41% and 87.28%, respectively, in a high single dose of 10 µM and exhibited good antiproliferative activity (%GIs > 68%) against 54 out of 56 cancer cell lines and 54 out of 60 cell lines, respectively. The compound 3b and 3c demonstrated the most potent antiproliferative activity in a 5-dose assay with GI50 values ranging between 0.281 and 5.59 µM and 0.39 and 0.196 and 3.07 µM, respectively. The compound 3b demonstrated moderate selectivity against a leukemia panel with a selectivity ratio of 4.59. The HOMO-LUMO energy-gap (∆E) of the compounds in the order of 3a > 3b > 3c, was found to be in harmony with the anticancer activity in the order of 3c ≥ 3b > 3a. Following that, all of the curcumin analogues were molecular docked against EGFR, one of the most appealing targets for antiproliferative activity. In a molecular docking simulation, the ligand 3b exhibited three different types of interactions: H-bond, π-π-stacking and π-cationic. The ligand 3b displayed three H-bonds with the residues Met793 (with methoxy group), Lys875 (with phenolic group) and Asp855 (with methoxy group). The π-π-stacking interaction was observed between the phenyl (of phenoxy) and the residue Phe997, while π-cationic interaction was displayed between the phenyl (of curcumin) and the residue Arg841. Similarly, the ligand 3c displayed five H-bonds with the residue Met793 (with methoxy and phenolic groups), Lys845 (methoxy group), Cys797 (phenoxy oxygen), and Asp855 (phenolic group), as well as a halogen bond with residue Cys797 (chloro group). Furthermore, all the compound 3a-c demonstrated significant binding affinity (-6.003 to -7.957 kcal/mol) against the active site of EGFR. The curcumin analogues described in the current work might offer beneficial therapeutic intervention for the treatment and prevention of cancer. Future anticancer drug discovery programs can be expedited by further modifying these analogues to create new compounds with powerful anticancer potentials.

Project description:Management of diabetes without any side effects is still a challenge to the medical system. This leads to increasing demand for natural products with antidiabetic activity with fewer side effects. Grewia hirsuta (Tiliaceae) is a traditional herbal medicinal plant and is reported to possess a variety of pharmacological actions. In the present research, a compound (4Z, 12Z)-cyclopentadeca-4, 12-dienone isolated from Grewia hirsuta was taken as ligand for molecular docking studies. Evaluation of hypoglycemic activity through an extensive in silico docking approach with molecular targets such as aldose reductase, glucokinase, pyruvate dehydrogenase kinase isoform 2, peroxisome proliferator-activated receptor-gamma, glycogen synthase kinase-3, 11?-Hydroxysteroid dehydrogenase, and glutamine: fructose-6-phosphate amidotransferase were performed.Isolation of the (4Z, 12Z)-cyclopentadeca-4,12-dienone from the methanol extract of the leaves of Grewia hirsuta was performed by the column chromatography to yield different fractions. These fractions were then subjected to purification and the structure was elucidated and confirmed by spectroscopic methods including UV, FTIR, (1)H, (13)C NMR and the accurate mass determination was carried out using the Q-TOF mass spectrometer. In-vivo experimentation was performed with evaluation of ?-glucosidase, ?-amylase and MTT assay that had been reported by the author in the earlier paper. Molecular docking study was performed with GLIDE docking software.The docking studies of the ligand (4Z, 12Z)-cyclopentadeca-4, 12-dienone with seven different target proteins showed that this is a good inhibitor, which docks well with various targets related to diabetes mellitus. Hence (4Z, 12Z)-cyclopentadeca-4,12-dienone can be considered for developing into a potent anti-diabetic drug.The results of the current study have revealed that the leaves of the selected plant Grewia hirsuta contains a potential inhibitor for diabetes (4Z, 12Z)-cyclopentadeca-4,12-dienone. Thus enabling a possibility of this plant extract as a new alternative to existing diabetic approaches.

Dataset Information

New Antiproliferative Triflavanone from Thymelaea hirsuta-Isolation, Structure Elucidation and Molecular Docking Studies.

Publications

New Antiproliferative Triflavanone from <i>Thymelaea hirsuta</i>-Isolation, Structure Elucidation and Molecular Docking Studies.

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