Next Article in Journal
Characterization of the Antiproliferative Activity of Sargassum muticum Low and High Molecular Weight Polysaccharide Fractions
Next Article in Special Issue
Inhibition Effects and Mechanisms of Marine Compound Mycophenolic Acid Methyl Ester against Influenza A Virus
Previous Article in Journal
Tissue Distribution and Metabolization of Ciguatoxins in an Herbivorous Fish following Experimental Dietary Exposure to Gambierdiscus polynesiensis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Marine Drugs
Volume 22
Issue 1
10.3390/md22010015
marinedrugs-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Pestalotiopols E–J, Six New Polyketide Derivatives from a Marine Derived Fungus Pestalotiopsis sp. SWMU-WZ04-1

by
Liyuan Jiang
1,
Baorui Teng
1,
Mengyu Zhang
1,
Siwei Chen
1,
Dan Zhang
1,
Longfei Zhai
2,
Jiafu Lin
3,* and
Hui Lei
1,*
1
School of Pharmacy, Southwest Medical University, Luzhou 646000, China
2
Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610106, China
3
School of Pharmacy, Chengdu University, Chengdu 610106, China
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2024, 22(1), 15; https://doi.org/10.3390/md22010015
Submission received: 29 November 2023 / Revised: 23 December 2023 / Accepted: 23 December 2023 / Published: 26 December 2023
(This article belongs to the Special Issue Marine Bioactive Compound Discovery by Combining Virtual with Actual Laboratory Experiments)
Browse Figures
Versions Notes

Abstract

:
Chemical epigenetic cultivation of the sponge-derived fungus Pestalotiopsis sp. SWMU-WZ04-1 contributed to the identification of twelve polyketide derivatives, including six new pestalotiopols E–J (1–6) and six known analogues (7–12). Their gross structures were deduced from 1D/2D NMR and HRESIMS spectroscopic data, and their absolute configurations were further established by circular dichroism (CD) Cotton effects and the modified Mosher’s method. In the bioassay, the cytotoxic and antibacterial activities of all compounds were evaluated. Chlorinated benzophenone derivatives 7 and 8 exhibited inhibitory effects on Staphylococcus aureus and Bacillus subtilis, with MIC values varying from 3.0 to 50 μg/mL. In addition, these two compounds were cytotoxic to four types of human cancer cells, with IC50 values of 16.2~83.6 μM. The result showed that compound 7 had the probability of being developed into a lead drug with antibacterial ability.

1. Introduction

Marine fungi provide a prospective source for the discovery of novel drug leads [1]. Traditional methods used in the investigation of marine fungi mainly focus on sample collection, the cultivation of fermentation broth, and mycelium. However, it is becoming difficult to discover novel structurally and biologically active metabolites using these traditional methods, but the development of genetic technology can assist [2]. Research findings demonstrate that a large portion of gene clusters are silenced under standard fermentation conditions [3,4,5]. To explore these potential secondary metabolites, activation of silent biosynthetic gene clusters has become an important strategy. At present, the silent gene clusters have been activated through multiple strategies, such as the OSMAC strategy [6,7,8,9,10], epigenetic modification [6,11,12], and genome mining. Of these, the chemical epigenetic strategy has proved to be an effective strategy for enhancing cryptic secondary metabolites [13].
During our ongoing efforts to discover more new and biologically active secondary metabolites from sponge-derived fungi, we applied the “epigenetic modification” strategy to the investigation of Pestalotiopsis sp., including 5-aza-2-deoxycytidine and suberoylanilide hydroxamic acid (SAHA). During this study, six new polyketide derivatives, pestalotiopols E–J (1–6), and six known analogues (7–12) (Figure 1), pestalachloride E (7) [14], (±)-pestalachloride D (8) [15], 3,4-dihydro-4, 6, 8-trihydroxy-1(2H)-naphthalenone (9) [16], isosclerone (10) [17], isobenzofuranyl derivative (11) [18], and (R)-3-hydroxy-1-[(S)-4-hydroxy-1,3-dihydroisobenzo-furan 1-yl] butan-2-one (12) [19], were obtained from sponge-derived fungi Pestalotiopsis sp. 1H and 13C assignments of the pestalotiopols E–J (1–6) were accomplished, the absolute configurations of the compounds were determined by CD techniques, and furthermore, the biological activities of the separated organic molecules were assessed.

2. Results

Compound 1 appeared as a white solid, and its molecular formula was C19H26O6, whose quasi-molecular ion peak was located at m/z 373.1635 [M + Na]+ by HRESIMS. The 1H NMR spectrum (Table 1) showed two aromatic proton signals [δH 6.60 (d, J = 8.1 Hz, H-4), 6.87 (d, J = 8.1 Hz, H-5)], which belong to a 1,2,3,4-tetrasubstituent benzene, and one olefinic proton signal [δH 5.57 (brt, J = 7.2 Hz, H-2’)]. The 13C NMR spectrum of compound 1 showed 19 carbon resonances (Table 1), involving three CH3, four CH2, three sp2-CH carbons, and five not-containing proton carbons. One carbonyl carbon was proposed based on resonances at δC 172.8, and five oxygenated carbon signals at δC 71.0, 71.0, 71.7, 73.3, 82.3. The 1H NMR data was initially analyzed, and it was found that 1 had similar structural characteristics to heterocornol L [20]. The major difference was that a carbonyl signal was missing and an oxygenated methine was present in 1. This was proved by the HMBC correlations between H-10 (δH 3.71) and C-11 (δC 71.7), C-9 (δC 39.1), and C-12 (δC 18.9). The location of the vicinal diol side chain was confirmed by HMBC correlations from H-8 (δH 5.53) to C-7 (δC 143.4.), C-6 (δC 125.9), C-10 (δC 73.3), C-1 (δC 71.0), and 1H–1H COSY correlations of H-8/H-9/H-10/H-11/H-12 (Figure 2). Furthermore, HMBC correlations found H-1’(δH 3.27) to C-5’ (δC 71.0), C-2’ (δC 128.8), C-3’ (δC 132.3), and C-7 (δC 143.4), together with 1H–1H COSY correlations located connections from H-1’/H-2’ suggested the existence of 5’-O-acetyl isoamylene group located at C-6 in 1 (Figure 2). Therefore, the planar structure of 1 was established.
To establish its relative configuration, the NOESY spectrum of 1 was performed; unfortunately, the NOESY spectrum of 1 was not useful for the assignment of the relative configuration at C-10 and C-11. According to the previously reported [21,22,23,24], in rythron vicinal diols (J > 4.0 Hz), the value of the coupling constant of the methine hydrogens was larger than 4 Hz, while in threo ones (J < 2.0 Hz), it is smaller than 2 Hz. On this account, consistent with the known pyriculin A and B [25] (J = 3.7/3.8 Hz), heterocornol I [20], indicating that the configurations of C-10 and C-11 in 1 (J = 4.7 Hz) were suggested as erythro. The absolute configuration of 1 (8S,10R,11S) was elucidated from the observed positive Cotton effect at 210 nm and positive Cotton effect at 313 nm in the CD and Mo2(AcO)4-induced CD spectra of 1, respectively (Figure 3) [19].
Compound 2 was purified as a white solid with the molecular formula C19H26O6, determined from the HRESIMS data. The NMR data of 2 were very similar to those of 1, which manifests that both of them had the same planar structures. Compared with compound 1, the configuration at C-10 and C-11 in the vicinal diol side chain was discrepant, which was proved by the chemical shifts of C-8 (ΔδC 1.1 ppm), C-9 (ΔδC −1.8 ppm), C-10 (ΔδC 1.1 ppm), and C-11 (ΔδC −1.8 ppm). According to the chemical shift of C-10 (δC 74.4) and C-11 (δC 69.9) [26], and the coupling constant between H-10 and H-11 (1.6 Hz), the configuration of C-10 and C-11 was inferred to be threo. We speculated that 2 had the same configuration at C-8 (8S) as 1 according to their closely similar CD spectrum. The absolute configuration of C-10,11-diols in 2 was determined by Mo2(AcO)4-induced CD (Figure 3).
In order to further confirm the absolute configuration of 2, the modified Mosher’s method was performed (2a and 2b) [27,28,29,30] (Figures S36 and S37). Treatment of 2 with [(S)-MTPA] and (R)-MTPA gave (S)-MTPA ester (2a) and (R)-MTPA ester (2b), respectively. The Δδ (δS–δR) values of 2a and 2b established the absolute configuration of C-10 and C-11 in 2. Thus, compound 2 was assigned and named pestalotiopol F.
Compound 3 appeared as a white solid, and the molecular formula was determined to be C17H22O5. Analyses of the 1D/2D NMR data of 3 suggested that compound 3 was similar to vaccinol H [31]. One additional hydroxymethyl group (δC 61.4) was observed, which was established by HMBC correlations from H-2’ (δH 5.30) to C-7 (δC 142.8), C-1’ (δC 31.2), C-5’ (δC 61.4), and C-6 (δC 126.5), from H-5’ (δH 4.19/4.20) to C-4’ (δC 21.5), C-3’ (δC 136.6), and C-2’ (δC 127.1). In terms of the positive Cotton effect at 212 nm and the biosynthetic pathway, along with the similar NMR data between vaccinol H and 3, the configuration of 3 was confirmed to be 8R, 10R. The CD spectrum of (8R, 10R)-3 helped reconfirm the configuration of 3 (Figure 3).
Compound 4 is presented as a white solid with a molecular formula of C17H22O5, with its excimer ion peak located at m/z 307.1532 [M + H]+. The NMR data indicated the same planar structure as 3 (Table 2). The differences between them were due to the variations in chemical shifts of C-8 (δC 81.5 in 3 vs. δC 81.2 in 4) and C-9 (δC 39.7 in 3 vs. δC 44.3 in 4). These results indicated both compounds differed in the relative configuration at C-8, which was similar to that of vaccinols H and I. After contrasting the similarities in chemical shifts between 3 and 4, and between vaccinol H and vaccinol I, together with biogenetic considerations, we suggested that the absolute configuration of 4 was the 8S, 10R configuration. These assignments were further confirmed by the CD spectrum of 4 (Figure 3). Thus, we determined the structure of 4 and named it pestalotiopol H.
Compounds 5 and 6 were acquired as a mixture in a nearly 1:1 ratio, which was established by their HRESIMS and the 13C NMR data. The NMR data of 5 and 6 resembled those of 3 and 4, except for a carbonyl group at C-10 (δC 211.8/211.5) in 5/6 and C-11 (δC 213.5/212.7) in 3/4. Compared with 5, the difference was that the chemical shift of C-8 (δC 79.4), C-9 (δC 38.6), and C-10 (δC 211.5) of 6 shifted to upfield (Δ0.5 ppm, Δ4.5 ppm, Δ0.3 ppm), respectively. The conclusions mentioned above were confirmed by the HMBC correlations between H-8 and C-2/C-7/C-6/C-10, between H-5’ and C-4’/C-3’/C-2’, between H-1’ and C-2’/C-3’/C-5/C-6, and the COSY cross peak of H-1’/H-2’, H-8/H-9, and H-11/H-12. The absolute configurations of C-8 and C-11 in 5 and 6 were assigned 8R, 10R, and 8S, 10R, respectively, which were consistent with other analogs from the marine fungus Pestalotiopsis vaccinii [31]. Considering that two strains belong to the same genus, Pestalotiopsis, we proposed that they arose from the same biosynthetic pathway and shared the chiral center.
Biosynthetically, a precursor polyketide substance is commonly produced by microorganisms in the synthesis of aromatics and macrolides. Compounds (1–6, 11, 12) originated from malonyl-CoA by reduction, dehydration, cyclization, and oxidation to form the different polyketide precursors and subsequently formed compounds (1–6, 11, 12) after diverse transformations (Scheme 1).
In the present study, polyketide derivatives 1–12 were evaluated for their cytotoxic activities via MTT assay (Table 3). The cytotoxicity results demonstrated that compound 7 was mildly cytotoxic to HepG2, with IC50 values of 16.2 μM; the IC50 values of 8, which was weakly cytotoxic to human cancer cells, ranged from 34.8 to 63.1 μM; unfortunately, compounds 1–6, at concentrations of 100 μM, did not show cytotoxicity against these tumor cell lines. Bacteriostatic effects 1–12 were performed (Table 3). Compounds 7 and 8 showed antibacterial effects on Staphylococcus aureus and Bacillus subtilis, with MIC values varying from 3 to 50 mg/mL. No obvious bioactivities were found in the other compounds at 100 μM or 100 mg/mL. The results showed that there was considerable potential to develop compound 7 as a lead drug with antimicrobial activity.
In order to further verify the activity of compounds 7 and 8 against HepG2, the anti-apoptotic protein Bcl-2 (PDB ID: 4LVT) was used as a target for molecular docking. Compounds 7 and 8 bound to ASN9, TRP192, ILE186, TRP141, PHE195, TRP141, LEU198, TYR199, and GLN187 residues and formed hydrogen bonds and non-polar interactions, respectively. Noticeably, the docking results showed that compounds 7 and 8 were well matched in the docking body of 4LVT and had good interaction with 4LVT. The binding free energies of systems were negative (−5.11 kcal/mol and −6.87 kcal/mol, respectively), indicating that the binding of proteins and small molecular ligands was a spontaneous process.

3. Materials and Methods

3.1. General Experimental Procedures

An MCP500 polarimeter (Anton) was used to record optical rotations in CH3OH. IR and HRESIMS were performed on a Shimadzu IR and a Bruker maXis TOF-Q mass spectrometer, respectively. Two different Bruker spectrometers (AVANCE III-400 and AV-600) were used for the NMR data collection, and the NMR data were recorded using TMS as an internal standard, d in ppm rel at 25 °C. Column chromatography involved normal-phase silica gel (100–300 mesh), Sephadex LH-20 (MeOH), and reversed-phase YMC ODS-A (50 μm) being used, while precoated silica gel GF254 plates (0.20–0.25 mm in thickness) were used for thin-layer chromatography (TLC) analyses, and the spots were visualized by UV light (254 nm) and colored by spraying heated silica gel plates with 10% H2SO4 in ethanol. Preparative HPLC was conducted on a SAIPURUISHE system equipped with a UV detector, an ODS column (YMC-5μm, ODS-A, 250 mm × 10 mm), a flow rate of 2.0 mL/min, and a column temperature of 25 °C. Circular dichroism (CD) spectra were recorded on a Chirascan circular dichroism spectrometer.

3.2. Fungal Material

The strain (SWMU-WZ04-1) was obtained from the sponge collected on Weizhou Island, China, and identified as Pestalotiopsis sp. SWMU-WZ04-1 by sequence alignment of the 18S rRNA gene. During its initial growth stage on a PDA plate, the mycelium of Pestalotiopsis sp. SWMU-WZ04-1 showed a french grey, which gradually transitioned to a brown color. As growth progressed, the mycelium produced conidia along with small oil droplets on the surface.

3.3. Fermentation, Extraction, and Isolation

The fungus SWMU-WZ04-1 was cultivated on a rice culture medium (200 g rice, 3% sea salt, 200 mL water, 10 μM of 5-aza-2-deoxycytidine and suberoylanilide hydroxamic acid (SAHA), 120 flasks) for 40 days at a temperature of 28 °C. After fermentation, the fungal culture was exhaustively extracted with EtOAc to obtain a crude extract (48.9 g).
The crude extract was fractionated on a normal-phase column using a stepped gradient elution with petroleum ether/EtOAc (30: 1 to 0: 1, v/v) to obtain 8 fractions (Fr.1–Fr.8). Fr.3 was applied to a normal-phase column (petroleum ether/EtOAc, 15:1-3:1) to obtain three subfractions (Frs. 3.1–3.3). Fr. 3.2 was purified with Sephadex LH-20 (MeOH) and further purified by HPLC eluting (MeOH/H2O 60%) to obtain compounds 3 (8.0 mg) and 4 (3.0 mg). Fr. 3.3 was further separated by an ODS column eluting with MeOH/H2O (60%) to obtain subfractions (Fr.3.3.1–Fr.3.3.4). Fr.3.3.2 was purified by Sephadex LH-20 column (MeOH) and HPLC (60%, MeOH/H2O) to obtain 11 (6.0 mg) and 12 (5.0 mg). Fr. 4 was subjected to silica gel (petroleum ether-EtOAc, 3:1-0:1) and further separated by (70%, MeOH/H2O) HPLC and Sephadex LH-20 (MeOH) to yield 1 (7.0 mg) and 2 (4.0 mg). Fr. 5 was applied by Sephadex LH-20 chromatography (MeOH) and HPLC (60% MeOH/H2O) to afford 7 (10.0 mg) and 8 (3.0 mg). Fr. 6 was further divided into seven subfractions (Frs.6.1–6.7) by silica gel cc (CH2Cl2-Acetone, 6:1-0:1). Frs.6.3 was applied by Sephadex LH-20 (MeOH) and HPLC (H2O/MeOH) to yield 5/6 (3.0 mg). Frs. 6.6 was applied by HPLC (MeOH/H2O, 45%) to afford 9 (7.0 mg) and 10 (7.0 mg).
Pestalotiopol E (1): white solid; [α ] D 25 –55 (c 0.3, MeOH); UV (MeOH) λmax (log ε) 254 (2.24), 275 (3.28) nm; 1H NMR and 13C NMR data, Table 1; HRESIMS m/z 373.1635 [M + Na]+ (calcd for C19H26NaO6, 373.1632).
Pestalotiopol F (2): white solid; [α ] D 25 –50 (c 0.4, MeOH); UV (MeOH) λmax (log ε) 246 (3.18) nm; 1H NMR and 13C NMR data, Table 1; HRESIMS m/z 373.1658 [M + Na]+ (calcd for C19H26NaO6, 373.1645).
Pestalotiopol G (3): white solid; [α ] D 25 −10 (c 0.4, MeOH); UV (MeOH) λmax (log ε) 254 (2.60), 210 (3.36) nm; 1H NMR and 13C NMR data, Table 1; HRESIMS m/z 305.1391 [M − H]− (calcd for C17H21O5, 305.1409).
Pestalotiopol H (4): white solid; [α ] D 25 +14 (c 0.2, MeOH); UV (MeOH) λmax (log ε) 246 (3.23), 210 (3.56) nm; 1H NMR and 13C NMR data, Table 2; HRESIMS m/z 307.1532 [M + H]+ (calcd for C17H23O5, 307.1525).
Pestalotiopol I and J (5/6): white solid; UV (MeOH) λmax (log ε) 254 (3.56) nm; 1H NMR and 13C NMR data, Table 2; HRESIMS m/z 307.1533 [M + H]+ (calcd for C17H23O5, 307.1526).

3.4. Mo2(AcO)4-Induced CD

The Mo2(AcO)4 solution was prepared with DMSO; subsequently, compounds 1 and 2 were added to the stock solution, respectively. The CD spectra of compounds 1 and 2 were recorded immediately after every 10 min for 30 min to form stationary Mo2(AcO)4-induced CD spectra [32].

3.5. Preparation of (S)- and (R)-MTPA Esters of 2

Each of duplicate 2 (1.7 mg) in 0.3 mL unhydrous pyridine-d6 in NMR tubes was reacted with (S)- and (R)-MTPA (160 μL, for 2), respectively. The reaction was performed at 50 °C for 15 h. Then, the 1H NMR data of the (S)- and (R)-MTPA esters were obtained without purification [33,34,35,36].

3.6. Cytotoxicity Assay

The MTT method was applied to analyze the cytotoxicity of compounds 1–12 against four cancer cell lines, involving (7860), (HepG2), (H1975), and (Hela). The MTT assay was depicted as a previously used method [37]. The cells were seeded in complete medium per well within a 96-well plate. The cells were incubated at 37 °C for 12–24 h to facilitate adherent cell growth. Following this, compounds 1–12 solutions were added, and cells were cultured for 48 h. Subsequently, MTT solution was introduced into the wells and incubated for 4 h at 37 °C. DMSO was added to each well after the cell medium was discarded. The absorbance was measured at a wavelength of 570 nm.

3.7. Antimicrobial Assay

The antimicrobial assay against three bacteria (Bacillus subtilis, Staphylococcus aureus, and Escherichia coli) and one fungus (Candida albicans) was assessed for adopting the microbroth dilution reported previously [38]. The MIC was defined as the lowest concentration of the antimicrobial agent that completely inhibited the visual growth of an organism. Ciprofloxacin and amphotericin B were used as positive controls against bacteria and fungi, respectively.

3.8. Molecular Docking

The molecular docking of compounds 7 and 8 was performed (Figure 4). The initial models for Bcl-2 (PDB ID:4LVT) was gained from the Protein Data Bank (http://www.rcsb.org, accessed on 16 November 2023). The 3D structures of compounds 7 and 8 were obtained from ChemBio 3D Ultra 14.0. AutoDock Vina (Center for Computational Structural Biology, La Jolla, the US, accessed on 16 November 2023), and AutoDockTools-1.5.6 were used to generate docking input files [39]. The docking results were then analyzed for interaction patterns using PyMOL 2.3.0.

4. Conclusions

In summary, we identified six new polyketide derivatives (1–6) and six known compounds (7–12) that were produced by chemical epigenetic cultivation. The absolute configurations of 1 and 2 were further established by circular dichroism (CD) cotton effects and the modified Mosher’s method. Compounds 7 and 8 manifested antibacterial activities against Staphylococcus aureus and Bacillus subtilis, with MIC values varying from 3 to 50 mg/mL. The result of the analysis showed that the potential to develop compound 7 as a lead drug with antibacterial activity is quite high. In addition, although the cytotoxic and antibacterial activities of compounds 7 and 8 were evaluated, the detailed mechanism of action is still undefined; thus, further studies are needed.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/md22010015/s1, Figures S1–S35: 1D, 2D NMR, and HRESIMS spectra of compounds 1–6. Figures S36,S37: 1H NMR spectrum of the compounds 2a,2b; Figure S38: The Δδ (δS–δR) values from the (S)- and (R)-MTPA esters of 2.

Author Contributions

L.J. and H.L. performed experiments and writing—original draft preparation. L.Z. and J.L. contributed the isolation of the fungal strain. M.Z. and S.C. contributed to this work through bioassay experiments. B.T. performed molecular docking. D.Z. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the Department of Science and Technology of Sichuan Province (2022NSFSC0109), the Sichuan Science and Technology Program (2022YFS0624), the Open Project of Sichuan Industrial Institute of Antibiotics, Chengdu University (ARRLKF20-04), the Applied Basic Research Fund of the Second People’s Hospital of Deyang City-Southwest Medical University (2022DYEXNYD004), and the Sichuan Traditional Chinese Medicine Administration (2023zd008).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the main text and the Supplementary Materials of this article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Zhang, B.; Zhang, T.; Xu, J.; Lu, J.; Qiu, P.; Wang, T.; Ding, L. Marine sponge-associated fungi as potential novel bioactive natural product sources for drug discovery. Mini Rev. Med. Chem. 2020, 20, 1966–2010. [Google Scholar] [CrossRef] [PubMed]
  2. Pan, R.; Bai, X.L.; Chen, J.W.; Zhang, H.W.; Wang, H. Exploring structural diversity of microbe secondary metabolites using OSMAC strategy: A literature review. Front. Microbiol. 2019, 10, 294. [Google Scholar] [CrossRef] [PubMed]
  3. Zhang, X.; Hindra; Elliot, M.A. Unlocking the trove of metabolic treasures: Activating silent biosynthetic gene clusters in bacteria and fungi. Curr. Opin. Microbiol. 2019, 51, 9–15. [Google Scholar] [CrossRef] [PubMed]
  4. Jiang, P.; Fu, X.J.; Niu, H.; Chen, S.W.; Liu, F.F.; Luo, Y.; Zhang, D.; Lei, H. Recent advances on Pestalotiopsis genus: Chemistry, biological activities, structure–activity relationship, and biosynthesis. Arch. Pharmacal Res. 2023, 46, 449–499. [Google Scholar] [CrossRef] [PubMed]
  5. Wang, X.R.; Filho, J.G.S.; Hoover, A.R.; King, J.B.; Ellis, T.K.; Powell, D.R.; Cichewicz, R.H. Chemical epigenetics alters the secondary metabolite composition of guttate excreted by an atlantic-forest-soil-derived Penicillium citreonigrum. J. Nat. Prod. 2010, 73, 942–948. [Google Scholar] [CrossRef] [PubMed]
  6. Cristina, P.R.; Aleu, J.; Rosa, D.P. Cryptic metabolites from marine-derived microorganisms using OSMAC and epigenetic approaches. Mar. Drugs 2022, 20, 84. [Google Scholar]
  7. Li, W.; Ding, L.J.; Wang, N.; Xu, J.Z.; Zhang, W.Y.; Zhang, B.; He, S.; Wu, B.; Jin, H.X. Isolation and characterization of two new metabolites from the sponge-derived fungus Aspergillus sp. LS34 by OSMAC approach. Mar. Drugs 2019, 17, 283. [Google Scholar] [CrossRef]
  8. Zang, Y.; Gong, Y.H.; Gong, J.J.; Liu, J.J.; Chen, C.M.; Gu, L.H.; Zhou, Y.; Wang, J.P.; Zhu, H.C.; Zhang, Y.H. Fungal polyketides with three distinctive ring skeletons from the fungus Penicillium canescens uncovered by OSMAC and molecular networking strategies. J. Org. Chem. 2020, 85, 4973–4980. [Google Scholar] [CrossRef]
  9. Victor, R.M.A.; Monica, T.M.; Cristina, C.; Antonio Hernandez, D.; Antonio, F.M.; Jose, M.S.L. OSMAC approach and cocultivation for the induction of secondary metabolism of the fungus Pleotrichocladium opacum. ACS Omega 2023, 8, 39873–39885. [Google Scholar]
  10. Victor Rodriguez, M.A.; Francisco Romero, M.; Cristina, C.; Antonio Hernandez, D.; Antonio Fernandez, M.; Jose, M.; Sanchez, L. Induction of new aromatic polyketides from the marine actinobacterium Streptomyces griseorubiginosus through an OSMAC approach. Mar. Drugs 2023, 21, 526. [Google Scholar]
  11. Liu, S.L.; Zhou, L.; Chen, H.P.; Liu, J.K. Sesquiterpenes with diverse skeletons from histone deacetylase inhibitor modified cultures of the basidiomycete Cyathus stercoreus (Schwein.) De Toni HFG134. Phytochemistry 2022, 195, 113048. [Google Scholar] [CrossRef] [PubMed]
  12. Zhang, W.F.; Li, J.Y.; Wei, C.W.; Deng, X.L.; Xu, J. Chemical epigenetic modifiers enhance the production of immunosuppressants from the endophytic fungus Aspergillus fumigatus isolated from Cynodon dactylon. Nat. Prod. Res. 2022, 36, 4481–4485. [Google Scholar] [CrossRef] [PubMed]
  13. Xue, M.Y.; Hou, X.W.; Fu, J.J.; Zhang, J.Y.; Wang, J.C.; Zhao, Z.T.; Xu, D.; Lai, D.E.; Zhou, L.G. Recent advances in search of bioactive secondary metabolites from fungi triggered by chemical epigenetic modifiers. J. Fungi 2023, 9, 172. [Google Scholar] [CrossRef] [PubMed]
  14. Xing, Q.; Gan, L.S.; Mou, X.F.; Wang, W.; Wang, C.Y.; Wei, M.Y.; Shao, C.L. Isolation, resolution and biological evaluation of pestalachlorides E and F containing both point and axial chirality. RSC Adv. 2016, 6, 22653–22658. [Google Scholar] [CrossRef]
  15. Wei, M.Y.; Li, D.; Shao, C.L.; Deng, D.S.; Wang, C.Y. (±)-Pestalachloride D, an antibacterial racemate of chlorinated benzophenone derivative from a soft coral-derived fungus Pestalotiopsis sp. Mar. Drugs 2013, 11, 1050–1060. [Google Scholar] [CrossRef] [PubMed]
  16. Iwasaki, S.; Muro, H.; Sasaki, K.; Nozoe, S.; Okuda, S.; Sato, Z.J. Isolations of phytotoxic substances produced by pyricularia oryzae cavara. Tetrahedron Lett. 1973, 37, 3537–3542. [Google Scholar] [CrossRef]
  17. Venkatasubbaiah, P.; Chilton, W.S. Toxins produced by the dogwood anthracnose fungus Discula sp. J. Nat. Prod. 1991, 54, 1293–1297. [Google Scholar] [CrossRef]
  18. Bouillant, M.L.; Bernilion, J.; Favre-Bonvin, J.; Salin, N. New hexaketides related to sordariol in Sordaria macrospora. Z. Naturforschung C 1989, 44, 719. [Google Scholar] [CrossRef]
  19. Kesting, J.R.; Olsen, L.; Staerk, D.; Tejesvi, M.V.; Kini, K.R.; Prakash, H.S.; Jaroszewski, J.W. Production of unusual dispiro metabolites in Pestalotiopsis virgatula endophyte cultures: HPLC-SPE-NMR, electronic circular dichroism, and time-dependent density-functional computation study. J. Nat. Prod. 2011, 74, 2206–2215. [Google Scholar] [CrossRef]
  20. Lei, H.; Lin, X.P.; Han, L.; Ma, J.; Dong, K.L.; Wang, X.B.; Zhong, J.L.; Mu, Y.; Liu, Y.H.; Huang, X.S. Polyketide derivatives from a marine-sponge-associated fungus Pestalotiopsis heterocornis. Phytochemistry 2017, 142, 51–59. [Google Scholar] [CrossRef]
  21. Jarvis, B.B.; Comezoglu, S.N.; Rao, M.M.; Pena, N.B. Isolation of macrocyclic trichothecenes from a large-scale extract of Baccharis megapotamica. J. Org. Chem. 1987, 52, 45–56. [Google Scholar]
  22. Chen, X.W.; Li, C.W.; Cui, C.B.; Hua, W.; Zhu, T.J.; Gu, Q.Q. Nine new and five known polyketides derived from a deep sea-sourced Aspergillus sp. 16-02-1. Mar. Drugs 2014, 12, 3116–3137. [Google Scholar] [CrossRef] [PubMed]
  23. Ayer, W.A.; Trifonov, L.S. Metabolites of Peniophora polygonia, part 2. Some aromatic compounds. J. Nat. Prod. 1993, 56, 85–89. [Google Scholar] [CrossRef]
  24. Jarvis, B.B.; Wang, S.; Ammon, H.L. Trichoverroid stereoisomers. J. Nat. Prod. 1996, 59, 254–261. [Google Scholar] [CrossRef] [PubMed]
  25. Masi, M.; Meyer, S.; Górecki, M.; Mandoli, A.; Bari, L.D.; Pescitelli, G.; Cimmino, A.; Cristofaro, M.; Clement, S. Pyriculins A and B, two monosubstituted hex-4-ene-2,3-diols and other phytotoxic metabolites produced by Pyricularia grisea isolated from buffelgrass (Cenchrus ciliaris). Chirality 2017, 29, 726–736. [Google Scholar] [CrossRef] [PubMed]
  26. Andolfi, A.; Cimmino, A.; Vurro, M.; Berestetskiy, A.; Troise, C.; Zonno, M.C.; Motta, A.; Evidente, A. Agropyrenol and agropyrenal, phytotoxins from Ascochyta agropyrina var. nana, a fungal pathogen of Elitrigia repens. Phytochemistry 2012, 79, 102–108. [Google Scholar] [CrossRef] [PubMed]
  27. Hoye, T.R.; Jeffrey, C.S.; Shao, F. Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons. Nat. Protoc. 2007, 2, 2451–2458. [Google Scholar] [CrossRef] [PubMed]
  28. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. High-field FT NMR application of Mosher’s method. The absolute configurations of marine terpenoids. J. Am. Chem. Soc. 1991, 113, 4092–4096. [Google Scholar] [CrossRef]
  29. Kang, C.Q.; Guo, H.Q.; Qiu, X.P.; Bai, X.L.; Yao, H.B.; Gao, L.X. Assignment of absolute configuration of cyclic secondary amines by NMR techniques using Mosher’s method: A general procedure exemplified with (-)-isoanabasine. Magn. Reson. Chem. 2006, 44, 20–24. [Google Scholar] [CrossRef]
  30. Kusumi, T.; Ooi, T.; Ohkubo, Y.; Yabuuchi, T. The modified Mosher’s method and the sulfoximine method. Bull. Chem. Soc. Jpn. 2006, 79, 965–980. [Google Scholar] [CrossRef]
  31. Wang, J.F.; Wei, X.Y.; Qin, X.C.; Chen, H.; Lin, X.P.; Zhang, T.Y.; Yang, X.W.; Liao, S.R.; Yang, B.; Liu, J.; et al. Two new prenylated phenols from endogenous fungus Pestalotiopsis vaccinii of mangrove plant Kandelia candel (L.) Druce. Phytochem. Lett. 2015, 12, 59–62. [Google Scholar] [CrossRef]
  32. Gu, C.Z.; Lv, J.J.; Zhang, X.X.; Qiao, Y.J.; Yan, H.; Li, Y.; Wang, D.; Zhu, H.T.; Luo, H.R.; Yang, C.R.; et al. Triterpenoids with promoting effects on the differentiation of PC12 cells from the steamed roots of Panax notoginseng. J. Nat. Prod. 2015, 78, 1829–1840. [Google Scholar] [CrossRef] [PubMed]
  33. Jin, Y.; Aobulikasimu, N.; Zhang, Z.G.; Liu, C.B.; Cao, B.X.; Lin, B.; Guan, P.P.; Mu, Y.; Jiang, Y.; Han, L. Amycolasporins and dibenzoyls from lichen-associated Amycolatopsis hippodromi and their antibacterial and antiinflammatory activities. J. Nat. Prod. 2020, 83, 3545–3553. [Google Scholar] [CrossRef] [PubMed]
  34. Ding, N.; Jiang, Y.; Han, L.; Chen, X.; Ma, J.; Qu, X.; Mu, Y.; Liu, J.; Li, L.; Jiang, C.; et al. Bafilomycins and odoriferous sesquiterpenoids from Streptomyces albolongus isolated from Elephas maximus feces. J. Nat. Prod. 2016, 79, 799–805. [Google Scholar] [CrossRef] [PubMed]
  35. Burley, S.K.; Bhikadiya, C.; Bi, C.; Bittrich, S.; Chen, L.; Crichlow, G.V.; Christie, C.H.; Dalenberg, K.; Di Costanzo, L.; Duarte, J.M.; et al. RCSB Protein Data Bank: Powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences. Nucleic Acids Res. 2021, 49, D437–D451. [Google Scholar] [CrossRef] [PubMed]
  36. Saito, T.; Itabashi, T.; Wakana, D.; Takeda, H.; Yaguchi, T.; Kawai, K.; Hosoe, T. Isolation and structure elucidation of new phthalide and phthalane derivatives, isolated as antimicrobial agents from Emericella sp. IFM57991. J. Antibiot. 2015, 69, 89–96. [Google Scholar] [CrossRef]
  37. Su, B.N.; Park, E.J.; Mbwambo, Z.H.; Santarsiero, B.D.; Mesecar, A.D.; Fong, H.H.S.; Pezzuto, J.M.; Kinghorn, A.D. New chemical constituents of euphorbia quinquecostata and absolute configuration assignment by a convenient Mosher ester procedure carried out in NMR tubes. J. Nat. Prod. 2002, 65, 1278–1282. [Google Scholar] [CrossRef]
  38. Rieser, M.J.; Hui, Y.H.; Rupprecht, J.K.; Kozlowski, J.F.; Wood, K.V.; McLaughlin, J.L.; Hanson, P.R.; Zhuang, Z.P.; Hoye, T.R. Determination of absolute configuration of stereogenic carbinol centers in annonaceous acetogenins by 1H- and 19F-NMR analysis of Mosher ester derivatives. J. Am. Chem. Soc. 1992, 114, 10203–10213. [Google Scholar] [CrossRef]
  39. Kouda, K.; Ooi, T.; Kusumi, T. Application of the modified Mosher’s method to linear 1,3-diols. Tetrahedron Lett. 1999, 40, 3005–3008. [Google Scholar] [CrossRef]
Marinedrugs 22 00015 g001
Figure 1. Chemical structures of compounds 1–12.
Figure 1. Chemical structures of compounds 1–12.
Marinedrugs 22 00015 g001
Marinedrugs 22 00015 g002
Figure 2. COSY and key HMBC correlations of 1, 3, 5.
Figure 2. COSY and key HMBC correlations of 1, 3, 5.
Marinedrugs 22 00015 g002
Marinedrugs 22 00015 g003
Figure 3. CD spectra of 1–4 as well as Mo2(AcO)4-induced CD spectra 1–2.
Figure 3. CD spectra of 1–4 as well as Mo2(AcO)4-induced CD spectra 1–2.
Marinedrugs 22 00015 g003
Marinedrugs 22 00015 sch001
Scheme 1. Plausible biosynthetic pathway of compounds 1–6, 11, 12.
Scheme 1. Plausible biosynthetic pathway of compounds 1–6, 11, 12.
Marinedrugs 22 00015 sch001
Marinedrugs 22 00015 g004
Figure 4. Representative docking poses of compounds 7 and 8 bound to Bcl-2 (PDB ID: 4LVT). The intermolecular interactions between Bcl-2 (PDB ID: 4LVT) and compounds 7 and 8 are as depicted in the maps (a,c) and the maps (b,d).
Figure 4. Representative docking poses of compounds 7 and 8 bound to Bcl-2 (PDB ID: 4LVT). The intermolecular interactions between Bcl-2 (PDB ID: 4LVT) and compounds 7 and 8 are as depicted in the maps (a,c) and the maps (b,d).
Marinedrugs 22 00015 g004
Table 1. 1H and 13C NMR data of compounds 1–3 in CD3OD.
Table 1. 1H and 13C NMR data of compounds 1–3 in CD3OD.
123
No.δC, TypeδH (J in Hz)δC, TypeδH (J in Hz)δC, TypeδH (J in Hz)
171.0, CH5.04, dd (12.3, 2.7)69.6, CH5.08, dd (12.2, 2.6)71.2, CH5.06, dd (12.2, 2.7)
4.95, d (12.3) 4.99, d (12.2) 4.96, d (12.2)
2126.0, C 124.5, C 126.1, C
3151.1, C 149.9, C 151.2, C
4115.4, CH6.60, d (8.1)114.1, CH6.63, d (8.0)115.6, CH6.61, d (8.2)
5130.4, CH6.87, d (8.1)129.2, CH6.88, d (8.0)130.7, CH6.89, d (8.2)
6125.9, C 124.5, C 126.5, C
7143.4, C 141.6, C 142.8, C
882.3, CH5.53, brd (10.4)83.4, CH5.48, brd (10.2)81.5, CH5.51, m
939.1, CH21.83, ddd (14.3, 10.4, 2.0)37.3, CH22.11, ddd (14.8, 3.9, 2.4)39.7, CH21.87, ddd (14.5, 4.9, 2.4)
1.62, ddd (14.3, 10.4, 2.2) 1.70, dd (14.8, 6.0) 1.90, ddd (14.5, 9.8, 7.1)
1073.3, CH3.71, ddd (10.4, 4.7, 2.1)74.4, CH3.69, m76.5, CH4.35, dd (9.9, 2.9)
1171.7, CH3.61, qd (6.4, 4.7)69.9, CH3.75, qd (6.2, 1.6)213.5, C
1218.9, CH31.14, d (6.4)17.3, CH31.19, d (6.2)25.8, CH32.18, s
1’31.0, CH23.27, dd (16.0, 7.0)29.8, CH23.30, dd (16.0, 7.0)31.2, CH23.24, dd (16.0, 6.9)
3.35, dd (16.0, 7.4)
2’128.8, CH5.57, brt (7.2)127.3, CH5.54, d (7.1)127.1, CH5.30, t (7.6)
3’132.3, C 131.0, C 136.6, C
4’14.3, CH31.75, s12.6, CH31.75, s21.5, CH31.80, s
5’71.0, CH24.48, s62.8, CH24.69, s61.4, CH24.19, d (12.2),
4.20, d (12.2),
7’172.8, C 171.5, C
8’20.8, CH32.03, s20.2, CH32.05, s
Table 2. 1H and 13C NMR data of compounds 4–6 in CD3OD.
Table 2. 1H and 13C NMR data of compounds 4–6 in CD3OD.
456
No.δC, TypeδH (J in Hz)δC, TypeδH (J in Hz)δC, TypeδH (J in Hz)
171.4, CH5.05, dd (14.3, 2.2)70.1, CH5.06, dd (12.3, 2.5)69.6, CH5.03, dd (12.2, 2.3)
4.95, d (14.3) 4.96, d (12.3) 4.92, d (12.2)
2126.1, C 125.0, C 124.7, C
3151.1, C 149.7, C 149.7, C
4115.7, CH6.63, d (8.2)114.3, CH6.62, d (8.1)114.1, CH6.60, d (8.1)
5130.8, CH6.93, d (8.2)129.3, CH6.89, d (8.1)129.2, CH6.87, d (8.1)
6126.4, C 125.6, C5.31, t (7.8)125.5, CH5.31, t (7.8)
7142.0, C 141.4, C 140.6, C
881.2, CH5.76, m79.9, CH5.74, m79.4, CH25.72, m
944.3, CH22.91, d (9.6)43.1, CH22.88, m38.6, CH22.23, m
2.85, dd (16.2, 2.0)
1074.4, CH4.23, q (7.0)211.8, C 211.5, CH
11212.7, C 74.7, CH4.28, q (7.0)73.3, CH4.24, q (7.0)
1219.5, CH31.29, d (7.0)18.1, CH31.29, d (7.0)17.9, CH31.33, d (7.0)
1’31.2, CH23.21, m, 3.25, m29.6, CH23.30, d (7.1)29.6, CH23.30, d (7.1)
2’124.8, CH5.46, t (7.0)125.0, CH5.20, t (7.1)125.3, CH5.22, t (7.1)
3’137, C 135.4, C 135.2, C
4’13.9, CH31.71, s20.2, CH31.81, s20.1, CH31.83, s
5’68.6, CH23.95, s60.0, CH24.16, s60.0, CH24.16, s
Table 3. Antibacterial activities and cytotoxicity of 1–12.
Table 3. Antibacterial activities and cytotoxicity of 1–12.
Comp.Cytotoxicity (IC50 in μM)Antibacterial Activities (MIC μg/mL)
H19757860HelaHepG2B. subtilisS. aureasE. coliC. albicans
1>100>100>100>100>100>100>100>100
2>100>100>100>100>100>100>100>100
3>100>100>100>100>100>100>100>100
4>100>100>100>100>100>100>100>100
5>100>100>100>100>100>100>100>100
6>100>100>100>100>100>100>100>100
783.6>10063.516.23.03.0>100>100
8>10063.145.034.850.050.050.0>100
9>100>100>100>100>100>100>100>100
10>100>100>100>100>100>100>100>100
11>100>100>100>100>100>100>100>100
12>100>100>100>100>100>100>100>100
Adriamycin1.4822.62.2
a Ciprofloxacin 0.25 a0.13 a0.13 a
b Amphotericin 1.0 b
a, Ciprofloxacin was used as a positive control against bacteria; b, Amphotericin was used as a positive control against fungi.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Jiang, L.; Teng, B.; Zhang, M.; Chen, S.; Zhang, D.; Zhai, L.; Lin, J.; Lei, H. Pestalotiopols E–J, Six New Polyketide Derivatives from a Marine Derived Fungus Pestalotiopsis sp. SWMU-WZ04-1. Mar. Drugs 2024, 22, 15. https://doi.org/10.3390/md22010015

AMA Style

Jiang L, Teng B, Zhang M, Chen S, Zhang D, Zhai L, Lin J, Lei H. Pestalotiopols E–J, Six New Polyketide Derivatives from a Marine Derived Fungus Pestalotiopsis sp. SWMU-WZ04-1. Marine Drugs. 2024; 22(1):15. https://doi.org/10.3390/md22010015

Chicago/Turabian Style

Jiang, Liyuan, Baorui Teng, Mengyu Zhang, Siwei Chen, Dan Zhang, Longfei Zhai, Jiafu Lin, and Hui Lei. 2024. "Pestalotiopols E–J, Six New Polyketide Derivatives from a Marine Derived Fungus Pestalotiopsis sp. SWMU-WZ04-1" Marine Drugs 22, no. 1: 15. https://doi.org/10.3390/md22010015

APA Style

Jiang, L., Teng, B., Zhang, M., Chen, S., Zhang, D., Zhai, L., Lin, J., & Lei, H. (2024). Pestalotiopols E–J, Six New Polyketide Derivatives from a Marine Derived Fungus Pestalotiopsis sp. SWMU-WZ04-1. Marine Drugs, 22(1), 15. https://doi.org/10.3390/md22010015

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop