Fusaristerol A: A new cytotoxic and antifungal ergosterol fatty acid ester from the endophytic fungus Fusarium sp. associated with Mentha longifolia roots
Sabrin Ragab Mohamed Ibrahim1, Gamal Abdallah Mohamed2, Rwaida Adel Al Haidari3, Amal Abd-Elmoneim Soliman El-Kholy4, Hani Zakaria Asfour5, Mohamed Fathalla Zayed6
1 Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah Al Munawwarah 30078, Saudi Arabia; Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
2 Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
3 Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah Al Munawwarah 30078, Medina, Saudi Arabia
4 Department of Clinical and Hospital Pharmacy, College of Pharmacy, Taibah University, Al Madinah Al Munawwarah 30078, Saudi Arabia; Department of Clinical Pharmacy, Faculty of Pharmacy, Ain-Shams University, Cairo 11566, Egypt
5 Department of Medical Microbiology and Parasitology, Faculty of Medicine, Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia
6 Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah Al Munawwarah 30078, Saudi Arabia; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
|Date of Submission||15-Mar-2018|
|Date of Acceptance||16-Apr-2018|
|Date of Web Publication||14-Aug-2018|
Sabrin Ragab Mohamed Ibrahim
Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah Al Munawwarah 30078, Saudi Arabia. Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Endophytic fungi are of a growing interest as prominent sources of structurally unique bioactive natural products. Objective: This study aims to isolate and characterize bio-metabolites from the endophytic fungus Fusarium sp. isolated from Mentha longifolia L. roots as well as to assess the antimicrobial and cytotoxic potential of these metabolites. Materials and Methods: The endophytic fungi Fusarium sp. was cultured on a rice medium. The rice cultures' ethyl acetate extract was separated using various chromatographic techniques (SiO2, RP-18, and sephadex LH-20) to afford four metabolites. Their structural characterization was achieved by various spectroscopic analyses, as well as comparing with the published data. Results: A new ergosterol derivative namely, fusaristerol A (22E,24R-5β,8β-epidioxyergosta-22-en-3β-yl decanoate) (1), along with ergosta-7,22-diene-3β,5α,6β-triol (2), ergosta-5,7,22-triene-3β-ol (3), and (22E,24R)-ergosta-7,22-dien-3β-ol (4), was separated. Fusaristerol A (1) possessed a significant antifungal activity toward Candida albicans with minimum inhibitory concentration (MIC) value of 8.3 μg/disc compared to clotrimazole (MIC 5.1 μg/disc). Moreover, it displayed a potent cytotoxic potential toward HCT-116 cell line with an half maximal inhibitory concentration (IC50) value of 0.21 μM, compared to doxorubicin (IC50 0.06 μM). Conclusion: This is the first report for separation of a 5,8-epidioxy ergostane derivative from Fusarium sp. Fusaristerol A may provide a new promising candidate for the development of a potential anti-candida and cytotoxic agent.
Abbreviations used: BT-549: Ductal carcinoma; CC: Column chromatography; COSY: Correlations spectroscopy; CDCl3: Deuterated chloroform; EtOAc: Ethyl acetate; DMSO: Dimethyl sulfoxide; EIMS; Electron-impact mass spectrometry; EP: Ergosterol peroxide; GCMS; Gas chromatography mass spectrometry; HCl: Hydrochloric acid; H2O: Water; H2SO4: Sulfuric acid; HMBC: Heteronuclear multiple bond correlation experiment; HRMS: High-resolution mass spectrometry; HRESIMS: High-resolution electrospray ionization mass spectrometry; HCT-116: Colorectal adenocarcinoma; HSQC: Heteronuclear single-quantum correlation; IC50: Half maximal inhibitory concentration; IR: Infrared; KBr: Potassium bromide; KOH; Potassium hydroxide; LTQ: Linear trap quadruple; MeOH; Methanol; MIC: Minimum inhibitory concentration; MCF-7: Human breast adenocarcinoma; NMR: Nuclear magnetic resonance; PDA: Potato dextrose agar; RP: Reversed phase; SiO2: Silica gel; TLC: Thin-layer chromatography; VLC: Vacuum liquid chromatography.
Keywords: Antimicrobial, cytotoxic activity, endophytic fungi, Fusarium sp., fusaristerol A
|How to cite this article:|
Mohamed Ibrahim SR, Mohamed GA, Al Haidari RA, Soliman El-Kholy AA, Asfour HZ, Zayed MF. Fusaristerol A: A new cytotoxic and antifungal ergosterol fatty acid ester from the endophytic fungus Fusarium sp. associated with Mentha longifolia roots. Phcog Mag 2018;14:308-11
|How to cite this URL:|
Mohamed Ibrahim SR, Mohamed GA, Al Haidari RA, Soliman El-Kholy AA, Asfour HZ, Zayed MF. Fusaristerol A: A new cytotoxic and antifungal ergosterol fatty acid ester from the endophytic fungus Fusarium sp. associated with Mentha longifolia roots. Phcog Mag [serial online] 2018 [cited 2021 Jun 18];14:308-11. Available from: http://www.phcog.com/text.asp?2018/14/56/308/239009
- A new ergosterol derivative (1) and three known metabolites (2–4) were separated from the endophytic fungus Fusarium sp. Their structural elucidation was achieved with the aid of extensive spectroscopic techniques. Compound 1 possessed antifungal and cytotoxic activities.
| Introduction|| |
Endophytic fungi are of a growing interest as prominent sources of structurally unique bioactive natural products. Fungal endophytes generally colonize the internal living plant tissues without resulting any external symptoms or apparent negative effects.,, They may exhibit a considerable importance to their host plants by the production of secondary metabolites that provide survival advantages and protection to the plants., They may supply the plants with antimicrobials, growth regulators, insecticides, and antivirals or even give the plants resistance to some kinds of abiotic stress. Recently, attention has been focused on them as a reliable and rich pool of significant bio-metabolites with wide pharmaceutical, agricultural, and/or industrial potentials. The genus Fusarium contains a wide number of fungal species that produce a wide range of bioactive metabolites with remarkable chemical diversity.,, Our previous phytochemical study of Fusarium sp. led to the isolation of integracide derivatives and cyclodepsipeptide.,,, In the course of our ongoing efforts to discover potential active compounds from Fusarium sp., the chemical investigation of its ethyl acetate (EtOAc) extract resulted in the separation and identification of a new natural product, fusaristerol A (1) and three known metabolites (2—4). Their structures were verified by variable spectroscopic methods. The antimicrobial and cytotoxic activities of the new compound were assessed.
| Materials and Methods|| |
General experimental procedures
Optical rotation was measured on a digital polarimeter (JASCO DIP-370) (Jasco Co., Tokyo, Japan). The infrared (IR) spectra were performed on a Shimadzu Infrared-400 spectrophotometer (Shimadzu, Kyoto, Japan). Gas chromatography mass spectrometry (GCMS) analysis was carried out on Clarus 500 GCMS (Perkin Elmer, Shelton, CT, USA). Turbo Mass 4.5.0.007 was the software controller/integrator used ((Perkin Elmer, Shelton, CT). A capillary column Elite 5MS GC (30 × 0.25 mm × 0.5 μm, Perkin Elmer) was used. Helium was the carrier gas (purity 99.9999%; 2 mL/min) (flow initial 55.8 cm/s, 32 p.s.i., split; 1:40). The 100°C—250°C was the column's temperature (5°C/min). JEOL JMS-SX/S × 102A was utilized for measuring electron-impact mass spectrometry (EIMS) (Joel, Peabody, MA, USA). A LTQ Orbitrap (ThermoFinnigan, Bremen, Germany) was used for obtaining high-resolution electrospray ionization mass spectrometry (HRESIMS). BRUKER Unity INOVA 500 was used for nuclear magnetic resonance (NMR) spectra measurement (Bruker BioSpin, Billerica, MA, USA). Sephadex LH-20 (0.25—0.1 mm), SiO2 60 (0.04—0.063 mm), and RP-18 (0.04—0.063 mm, Merck, Darmstadt, Germany) were used for chromatographic separations. Thin-layer chromatography (TLC) analysis was implemented on TLC precoated plates (SiO2 60 F254, 0.2 mm, Merck, Darmstadt, Germany). The chromatograms were developed using the following solvent systems: n-hexane: EtOAc (95:5, S1) and n-hexane: EtOAc (90:10, S2). The compounds were detected by spraying with p-anisaldehyde/H2 SO4 reagent and heating at 110°C for 1—2 min.
Fungal material isolation, identification, and cultivation
Mentha longifolia was compiled from Abyar Al-Mashy, Al Madinah Al Munawwarah, in March 2014. It was authenticated by Dr. Emad Alsherif (Faculty of Science and Arts, Khulais, King Abdulaziz University). A specimen (ML-1-2014) was deposited at Natural Products and Alternative Medicine Department herbarium, Faculty of Pharmacy, King Abdulaziz University. Fusarium sp. was separated from interior tissues of M. longifolia roots. Under sterile condition, the tissues were dissected precisely and placed on potato dextrose agar plates (PDA, Difco(Becton, Dickinson and Company, Sparks, Maryland)), inclosing gentamicin and chloramphenicol to prevent the growth of bacteria as antibacterial agents. The plates were incubated for 4—6 weeks at 27°C. Then, the fungal hyphal tips were removed periodically and transported to fresh plates of PDA. The fungi were specified based on their morphological colonial trait and microscopic examination by Olympus CX31RBSF light microscopy (Olympus, Tokyo, Japan). The fungus (FS No. MAR2014) was kept at the Microbiology Department, Faculty of Pharmacy, Taibah University. The fresh fungal material was cultured over rice solid cultures in Erlenmeyer flasks (10, 1 L each) (distilled H2O [100 mL] + rice [100 g] and kept overnight prior to autoclaving) and kept under septic condition for 30 days at room temperature.
Extraction and isolation
The culture was extracted at room temperature with EtOAc and concentrated under vacuum. The total EtOAc extract (11.3 g) was subjected to vacuum liquid chromatography using CHCl3, EtOAc, and methanol (MeOH), which were concentrated separately to get FSC-1 (3.8 g), FSE-2 (2.6 g), and FSM-3 (4.1 g), respectively. Fraction FSC-1 (3.8 g) was subjected to sephadex LH-20 column chromatography (CC, CHCl3:MeOH [70:30]); fractions (100 mL) were gathered and checked by TLC to afford six subfractions as follows: FSC1-1—FSC1-6. Subfraction FSC1-2 (289 mg) was separated on silica gel (SiO2) CC (30 g x 50 cm x 2 cm) using n-hexane: EtOAc (98:2—70:30) as an eluent to give impure 1, which was purified on RP-18 CC (40 g, 50 cm × 2 cm, 0.04—0.063 mm), using H2O: MeOH gradient to get 1 (11.7 mg). SiO2 CC (50 g, 50 cm × 3 cm, n-hexane: EtOAc, 95:5—70:30) of subfraction FSC1-3 (495 mg) afforded impure 2 that was further submitted by repeated SiO2 CC (n-hexane: EtOAc gradient) to obtain 2 (10.3 mg). Subfraction FSC1-4 (911 mg) was chromatographed on a SiO2 CC (70 g, 50 cm × 3 cm, n-hexane: EtOAc 97:3—80:20) to get impure 3 and 4. LiChrolut RP-18 solid-phase extraction tube (H2O: acetonitrile gradient) was used for their purification to yield 3 (17.4 mg) and 4 (8.7 mg).
The spectral data were as follows: Fusaristerol A (22E,24R-5β,8β-epidioxyergosta-22-en-3β-yl decanoate) (1): white amorphous powder; Rf 0.65 (S2); [α]D25 + 65.3 (c CHCl3); IR (potassium bromide) γmax: 2946, 1693, 1452, 1385, 1035, 727 cm−1; NMR data (CDCl3, 500 MHz and 125 MHz), HRESIMS m/z 585.4879; calculated for C38H65O4, 585.4883 [M+H]+ [Table 1].
Alkaline hydrolysis of 1
A solution of 1 (5 mg, in 5 mL 3% potassium hydroxide/MeOH) was kept for 15 min at room temperature. Then, 1 N hydrochloric acid/MeOH was added drop wise for neutralization. The solution was extracted with CHCl3(10 mL × 3). The CHCl3 was evaporated and the obtained residue was separated on SiO2 CC (n-hexane: EtOAc 99:1—90:10) to furnish decanoic acid methyl ester that was characterized by EIMS and GCMS.,,
The antimicrobial effect of 1 was assessed by agar disc diffusion assay toward Staphylococcus aureus (AUMC No. B-54), Bacillus cereus (AUMC No. B-5), Escherichia coli (AUMC No. B-53), and Candida albicans (AUMC No. 418) according to the previously described procedure., All experiments were performed in triplicate, and minimal inhibitory concentrations (MICs) of 1 were assessed against all the tested strains as previously outlined.,, Clotrimazole (5 μg/disc) and ciprofloxacin (10 μg/disc) were utilized as antifungal and antibacterial standards, respectively.
The cytotoxic effect of 1 was evaluated in vitro toward human breast adenocarcinoma (MCF-7), colorectal adenocarcinoma (HCT-116), and ductal (BT-549) carcinomas. The cells (25,000 cells/well) were incubated for 24 h. The tested samples were added at different concentrations and the cells were incubated for 48 h. Neutral red dye was utilized to determine the cell viability. Doxorubicin (positive control) and DMSO (negative control) were used.,,
| Results and Discussion|| |
Purification of metabolites
The endophytic fungi Fusarium sp. was cultured on a rice medium. The rice cultures' EtOAc extract was submitted to various chromatographic techniques (SiO2, RP-18, and sephadex LH-20) to afford one new (1) and three known metabolites (2—4) [Figure 1]. Their structures were verified by spectral data analysis, including NMR and HRMS.
Structural characterization of fusaristerol A
Compound 1 was separated as white amorphous powder. It showed positive Liebermann—Burchard reaction,,,, indicating its steroidal nature. The molecular formula of 1 was assigned to be C38H64O4, relying on the 13C NMR and HRESIMS pseudo-molecular ion peak at m/z 585.4879 (calculated C38H65O4,585.4883 [M+H]+), indicating 7 DBE. That can be accounted for an olefinic double bond, a carbonyl group, an epidioxy ring, and a steroid nucleus. Its IR possessed absorptions at 2946 (C-H aliphatic) and 1693 (carbonyl) cm−1. Investigation of the 13C and HSQC revealed the existence of 38 carbon resonances: 17 methylenes, 7 methyls, 9 methines, and 5 quaternary carbons. The 1H, 13C, and HSQC spectra of 1 displayed six methyls (δH/δC 1.39/19.4 [H-18/C-8], 0.83/11.9 [H-19/C-19], 0.80/20.4 [H-21/C-21], 0.87/19.7 [H-26/C-26], 0.88/19.8 [H-27/C-27], and 0.85/17.3 [H-28/C-28]), an oxymethine (δH/δC 4.25/76.3 [H-3/C-3]), and a di-substituted olefinic bond (δH/δC 5.18/134.9 [H-22/C-22] and 5.49/130.8 [H-23/C-23]), suggesting that 1 was an ergostane derivative with a 22 (23)-double bond., This was secured by the observed COSY and HMBC cross peaks and further assured by the HRESIMS fragment at m/z 430.3439 (C28H46O3) [Figure 2]. In addition, resonances for typical decanoic acid residue were observed, which included a carbonyl (δC 171.7, C-1'), a triplet methylene (δH 2.29/δC 34.8, H-2'/C-2'), methylene cluster at δH 1.15—1.55 (H-3'-9'), and a terminal methyl (δH 0.76/δC 14.0, H-10'/C-10'). Moreover, two oxygenated quaternary carbons resonating at δC 87.1 (C-5) and 78.1 (C-8) declared the existence of an epidioxy functionality, completing the degrees of unsaturation. Its placement at C-5/C-8 was assured by HMBC experiment, through the cross peaks of H-3, H-9, and H-19 to C-5 and H-6, H-15, and H-11 to C-8 [Figure 2]. These data demonstrated that 1 was an 5,8-epidioxy ergostane derivative, similar to the known metabolite 22E,24R-5β,8β-epidioxyergosta-22-en-3β-ol isolated from Lactarium volemus, except for the presence of a decanoic acid moiety. After methanolysis, 1 gave methyl decanoate, which exhibited characteristic ion peak at m/z 186 [M]+ in the GC and EIMS. The downfield shift of H-3 (δH 4.25) and the HMBC correlation of H-3 with C-1' revealed the attachment of the fatty acid at C-3 of 1 [Figure 2]. The large J22,23 constant (15.2 Hz) indicated an E-configuration of the double bond. Comparing the 13C chemical shifts of C-26 (δC 19.7), C-27 (δC 19.8), and C-28 (δC 17.3) of 1 with those of related ergostane-type steroids unequivocally referred to a 24R of 1. The 5β,8β-configuration of the epidioxy functionality was assigned by comparison of the C-5 and C-8 chemical shifts with the related metabolites.,, In the NOESY spectrum, the cross peaks of H-9/H-14 and H-17 and H-21/H-17 and H-28 indicated the presence of these protons on the molecule at the same side. Moreover, the cross peaks of H-20/H-24, H-18, and H-19 in NOESY located these protons on the other side of the molecule. Therefore, 1 was determined to be 22E,24R-5β,8β-epidioxyergosta-22-en-3β-yl decanoate and named fusaristerol A.
|Figure 2: Some key 1H-1H correlations spectroscopy and heteronuclear multiple bond correlation experiment correlations of 1|
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The known metabolites were identified as ergosta-7,22-diene-3β,5α,6β-triol (2), ergosta-5, 7, 22-triene-3β-ol (3), and (22E,24R)-ergosta-7,22-dien-3β-ol (4) by comparison of their spectral and physical data with literature.
Activity of fusaristerol A
Ergosterol and ergosterol peroxide (EP) derivatives have been isolated from some species of fungi and marine organisms. Ergosterol is a part of the fungal cytoplasmic membrane and known as provitamin D2. Gross reported that Vitamin D2 plays an important role in the prevention of colon and prostate cancers. Moreover, EP showed significant inhibitory effects toward various cancer cell lines as well as antibacterial activity.,,, Therefore, compound 1 was evaluated for its antimicrobial and cytotoxic activities. It possessed a significant antifungal activity toward C. albicans with MIC 8.3 μg/disc, compared to clotrimazole (5.1 μg/disc), while it showed moderate activity toward S. aureus and E. coli with MIC values 29.5 and 24.1 μg/disc, respectively, in comparison to ciprofloxacin (10.4 and 8.6 μg/disc, respectively). Furthermore, it displayed a powerful cytotoxic effect toward HCT-116 cell line with an IC50 0.21 μM and moderate activity against MCF-7 (IC50 8.41 μM), compared to doxorubicin (IC50 0.06 and 0.47 μM, respectively). However, it was inactive against BT-549 cancer cell line.
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Conflicts of interest
There are no conflicts of interest.
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