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1.
Artigo em Inglês | MEDLINE | ID: mdl-32418125

RESUMO

Due to a high unresponsiveness to chemotherapy, biofilm formation is an important medical problem that frequently occurs during infection with many bacterial pathogens. In this study, the marine sponge-derived natural compounds 4,6-dibromo-2-(2',4'-dibromophenoxy)phenol and 3,4,6-tribromo-2-(2',4'-dibromophenoxy)phenol were found to exhibit broad antibacterial activity against medically relevant gram-positive and gram-negative pathogens. The compounds were not only bactericidal against both replicating and stationary phase-persistent planktonic cells of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa; they also killed biofilm-incorporated cells of both species while not affecting biofilm structural integrity. Moreover, these compounds were active against carbapenemase-producing Enterobacter sp. This simultaneous activity of compounds against different growth forms of both gram-positive and gram-negative bacteria is rare. Genome sequencing of spontaneous resistant mutants and proteome analysis suggest that resistance is mediated by downregulation of the bacterial EIIBC phosphotransferase components scrA and mtlA in MRSA likely leading to a lower uptake of the molecules. Due to their only moderate cytotoxicity against human cell lines, phenoxyphenols provide an interesting new scaffold for development of antimicrobial agents with activity against planktonic cells, persisters and biofilm-incoporated cells of ESKAPE pathogens. KEY POINTS: • Brominated phenoxyphenols kill actively replicating and biofilm-incorporated bacteria. • Phosphotransferase systems mediate uptake of brominated phenoxyphenols. • Downregulation of phosphotransferase systems mediate resistance.

2.
Bioorg Med Chem ; 28(10): 115456, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32238320

RESUMO

Six new polyketides aplojaveediins A-F (1-6) were isolated from the endophytic fungus Aplosporella javeedii associated with the host plant Orychophragmus violaceus (Brassicaceae). The structures of the new metabolites were elucidated by analysis of their NMR and MS data. Compound 1 exhibited antifungal activity against the hyphae form of Candida albicans strain ATCC 24433 in the agar plate diffusion assay and the microbroth dilution assay. The kinetic of killing of C. albicans cells for compound 1 was considerably faster than that of the positive control hygromycin B. Compounds 1 and 6 also exhibited moderate antibacterial activities against sensitive (ATCC 29213) and drug-resistant (ATCC 700699) strains of Staphylococcus aureus.

3.
Mar Drugs ; 18(4)2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290208

RESUMO

The marine-derived fungus Aspergillus falconensis, isolated from sediment collected from the Canyon at Dahab, Red Sea, yielded two new chlorinated azaphilones, falconensins O and P (1 and 2) in addition to four known azaphilone derivatives (3-6) following fermentation of the fungus on solid rice medium containing 3.5% NaCl. Replacing NaCl with 3.5% NaBr induced accumulation of three additional new azaphilones, falconensins Q-S (7-9) including two brominated derivatives (7 and 8) together with three known analogues (10-12). The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopy and HRESIMS data as well as by comparison with the literature. The absolute configuration of the azaphilone derivatives was established based on single-crystal X-ray diffraction analysis of 5, comparison of NMR data and optical rotations as well as on biogenetic considerations. Compounds 1, 3-9, and 11 showed NF-κB inhibitory activity against the triple negative breast cancer cell line MDA-MB-231 with IC50 values ranging from 11.9 to 72.0 µM.

4.
Prog Chem Org Nat Prod ; 111: 81-153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32114663

RESUMO

Marine-derived fungi play an important role in the search for structurally unique secondary metabolites, some of which show promising pharmacological activities that make them useful leads for drug discovery. Marine natural product research in China in general has made enormous progress in the last two decades as described in this chapter on fungal metabolites. This contribution covers 613 new natural products reported from 2001 to 2017 from marine-derived fungi obtained from algae, sponges, corals, and other marine organisms from Chinese waters. The genera Aspergillus (170 new natural products, 28%) and Penicillium (70 new natural products, 11%) were the main fungal producers of new natural products during the time period covered, whereas sponges (184 new natural products, 30%) were the most abundant source of new natural products, followed by corals (154 new natural products, 25%) and algae (130 new natural products, 21%). Close to 40% of all natural products covered in this contribution displayed various bioactivities. The major bioactivities reported were cytotoxicity against different cancer cell lines, antimicrobial (mainly antibacterial) activity, and antiviral activity, which accounted for 13%, 9%, and 3% of all natural products reported. In terms of structural classes, polyketides (188 new natural products, 31%) play a dominant role, and if prenylated polyketides and nitrogen-containing polyketides (included in meroterpenes and alkaloids in this contribution) are taken into account, their total number even exceeds 50%. Nitrogen-containing compounds including peptides (65 new natural products, 10%) and alkaloids (103 new natural products, 17%) are the second largest group.


Assuntos
Produtos Biológicos/farmacologia , Fungos/química , Policetídeos/farmacologia , Animais , Antozoários/microbiologia , Anti-Infecciosos , Antineoplásicos , Organismos Aquáticos/microbiologia , Aspergillus/química , Produtos Biológicos/química , China , Penicillium/química , Policetídeos/química , Poríferos/microbiologia , Metabolismo Secundário
5.
Chirality ; 32(5): 605-610, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32115775

RESUMO

The endophytic fungus Coniothyrium sp. was isolated from leaves of Quercus robur. Fermentation of this fungus on solid rice medium yielded two new furoic acid derivatives (1 and 2) and two additional known compounds. The structures of the new compounds were determined by extensive analysis of 1D and 2D nuclear magnetic resonance spectra as well as high-resolution mass spectrometry data. Compound 1, containing three aromatic chromophores attached by rotatable sigma bonds and a chirality center in benzylic position, was found to be a scalemic mixture with an excess of the (S) enantiomer, the absolute configuration of which was elucidated as by the solution time-dependent density functional theory-electronic circular dichroism approach. The ωB97X/TZVP PCM/MeCN and SOGGA11-X/TZVP SMD/MeCN methods were used for geometry reoptimization to reproduce the solution conformational ensemble. All isolated compounds were tested for their cytotoxicity but proved to be inactive.

6.
Eur J Med Chem ; 191: 112159, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101782

RESUMO

The endophytic fungus Cladosporium sphaerospermum WBS017 was obtained from healthy bulbs of Fritillaria unibracteata var. wabuensis. Fermentation of C. sphaerospermum on solid rice medium yielded three new hybrid polyketides, cladosins L-N (1-3), and a known derivative cladodionen (4). Further cultivation of this fungus on white bean medium afforded an additional new hybrid polyketide, cladosin O (5) along with three known analogues (6-8). The structures of the new compounds were elucidated using a combination of NMR and HRESIMS data. The absolute configurations of compounds 2 and 3 were determined by Mosher's method and TDDFT-ECD calculations. All isolated compounds were evaluated for their cytotoxic and antimicrobial activities. Cladodionen (4) exhibited cytotoxicity against the mouse lymphoma cell line L5178Y with an IC50 value of 3.7 µM, and also exhibited antifungal activity against Ustilago maydis and Saccharomyces cerevisiae, while cladosin L (1) displayed week antibacterial activity against Staphylococcus aureus ATCC 29213 and S. aureus ATCC 700699 with MIC values of 50 and 25 µM, respectively.

7.
Mar Drugs ; 18(2)2020 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-32102178

RESUMO

Chemical investigation of secondary metabolites from the endophytic fungus Pseudopestalotiopsis theae led to the isolation of eighteen new polyketide derivatives, pestalotheols I-Q (1-9) and cytosporins O-W (15-23), together with eight known analogs (10-14 and 24-26). The structures of the new compounds were elucidated by HRMS and 1D and 2D NMR data, as well as by comparison with literature data. Modified Mosher's method was applied to determine the absolute configuration of some compounds. Compound 23 showed significant cytotoxicity against the mouse lymphoma cell line L5178Y with an IC50 value of 3.0 µM. Furthermore, compounds 22 and 23 showed moderate antibacterial activity against drug-resistant Acinetobacter baumannii (ATCC BAA-1605) in combination with sublethal colistin concentrations.

8.
Bioorg Med Chem ; 28(4): 115279, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31980363

RESUMO

Natural compounds (NC) are an important source of anticancer drugs. The genomic DNA of tumor cells is a major target of conventional anticancer therapeutics (cAT). DNA damage elicits a complex stress response programme termed DNA damage response (DDR), with the PI3-like kinase ATM and ATR being the key regulators. Since the DDR coordinates mechanisms of DNA repair and apoptosis, hence regulating the balance between death and survival, it is an attractive target of novel anticancer strategies. The aim of the study was to identify natural compounds derived from endophytic fungi, lichens, marine sponges or plants that interfere with mechanisms of the DDR. To this end, the cytotoxic and DDR modulating potency of 296 natural compounds, used alone or in combination with the cAT cisplatin (Cis) and doxorubicin (Doxo) was investigated by fluorescence-based analysis of the ATM/ATR-catalyzed S139 phosphorylation of histone 2AX (γH2AX), a surrogate marker of DNA damage-triggered DDR. After initial screening, a total of ten natural compounds were identified that were toxic in pancreatic carcinoma cells and activated the DDR on their own and/or promoted the DDR if used in combination with cAT. Their mode of action was shown to be independent of drug transport mechanisms. Based on their chemical structures, DDR modulatory activity and published data we suggest the marine NC 5-epi-nakijiquinone Q and 5-epi-ilimaquinone as well as the fungal compound secalonic acid F as most promising NC-based drug candidates for future synthesis of DDR-modulating chemical derivatives and their preclinical in vitro and in vivo testing.

9.
Nat Prod Res ; : 1-6, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31971016

RESUMO

A new tetronic acid derivative (1) together with terrestric acid (2), a known metabolite of Penicillium species, was isolated from the soil fungus, FG9RK following fermentation on solid rice medium. The structure of 1 was elucidated by one- and two-dimensional NMR and MS measurements. The absolute configuration of the oxygenated carbon in the side chain of 1 was identified as S by converting the compound into its Mosher ester whereas the absolute configuration of the lactone ring was deduced based on biogenetic considerations and comparison with 2.

10.
Inflammopharmacology ; 28(1): 321-331, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31482260

RESUMO

Bioactivity-guided investigation of the methanol extract of Crepis sancta aerial parts, collected off Al-Tafilah, South Jordan, was applied, and in this study, the extract was explored for its phytochemical components and in vivo antiulcer activity. In addition, a docking study involving the purified compounds with the newly crystalized gastric proton pump (PDB # 5YLU) was performed. In-depth phytochemical investigation using the state-of-the-art chromatographic and analytical techniques was implemented resulting in the identification of two eudesmane-type sesquiterpenoids, 3-oxo-γ-costic acid (1) and its methyl ester (2) together with seven different methoxylated flavonols (3-9) as the extract's major components. The in vivo antiulcer study at three different doses (50, 100, and 200 mg/kg) against ethanol-induced gastric ulcer in male albino rats, compared to omeprazole (20 mg/kg) as a standard proton pump inhibitor antiulcer drug, revealed that the tested extract, at the middle and the highest doses, featured comparable or even superior activities relative to omeprazole as deduced from histopathological examination, in particular with regard to reducing inflammatory cell infiltration and ceasing mucosal haemorrhage. The tested extract revealed also a dose-dependent reduction in the volume and titrable acidity of the gastric juice together with a dose-dependent increase in the protective gastric mucin content which may explain the noticeable gastroprotective effect. Molecular modelling study of the isolated compounds showed a binding mode similar to the co-crystallized substrate vonoprazan in 5YLU which strengthens the importance of the tested extract as a potential natural remedy for treating gastric ulcer.

11.
Nat Prod Res ; : 1-5, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31782665

RESUMO

Five chromone derivatives, including 2,6-dimethyl-5-methoxyl-7-hydroxylchromone (1), 6-hydroxymethyleugenin (2), 6-methoxymethyleugenin (3), chaetoquadrin D (4), and isoeugenitol (5), and three isocoumarin congeners, namely diaporthin (6), 8-hydroxy-6-methoxy-3-methylisocoumarin (7), and 6-methoxymellein (8), were isolated from the culture of the endophytic fungus Xylomelasma sp. Samif07 derived from the medicinal plant Salvia miltiorrhiza Bunge. Among them, compound 1 was a new natural product. Their structures were determined by spectroscopic methods and comparison with the literature. The isolated compounds were evaluated for their antibacterial and antioxidant activities. Compound 5 showed notable antitubercular activity against Mycobacterium tuberculosis with MIC value of 10.31 µg/mL, while compounds 1-3, and 5-7 displayed inhibitory activities against the other bacteria with MIC range of 25 ∼ 100 µg/mL. Meanwhile, compound 6 showed potent hydroxyl radical-scavenging activity with EC50 value of 15.1 µg/mL, while compounds 5-7 showed certain ferric reducing ability.

12.
Bioorg Med Chem ; 27(23): 115145, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648874

RESUMO

The therapy of cancer continues to be a challenge aggravated by the evolution of resistance against current medications. As an alternative for the traditional tripartite treatment options of surgery, radiation and chemotherapy, immunotherapy is gaining increasing attention due to the opportunity of more targeted approaches. Promising targets are antigen-presenting cells which drive innate and adaptive immune responses. The discovery and emergence of new drugs and lead structures can be inspired by natural products which comprise many highly bioactive molecules. The development of new drugs based on natural products is hampered by the current lack of guidelines for screening these structures for immune activating compounds. In this work, we describe a phenotypic preclinical screening pipeline for first-line identification of promising natural products using the mouse as a model system. Favorable compounds are defined to be non-toxic to immune target cells, to show direct anti-tumor effects and to be immunostimulatory at the same time. The presented screening pipeline constitutes a useful tool and aims to integrate immune activation in experimental approaches early on in drug discovery. It supports the selection of natural products for later chemical optimization, direct application in in vivo mouse models and clinical trials and promotes the emergence of new innovative drugs for cancer treatment.

13.
Bioorg Med Chem ; 27(23): 115151, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648878

RESUMO

Xanthoangelol is a geranylated chalcone isolated from fruits of Amorpha fructicosa that exhibits antibacterial effects at low micromolar concentration against Gram-positive bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium and Enterococcus faecalis. We demonstrate that Xanthoangelol treatment of Gram-positive bacteria affects bacterial membrane integrity and leads to a leakage of intracellular metabolites. This correlates with a rapid collapse of the membrane potential and results in a fast and strong bactericidal effect. Proteomic profiling of Xanthoangelol-treated cells revealed signatures of cell wall and/or membrane damage and oxidative stress. Xanthoangelol specifically disturbs the membrane of Gram-positive bacteria potentially by forming pores resulting in cell lysis. In contrast, Xanthoangelol treatment of human cells showed only mildly hemolytic and cytotoxic effects at higher concentrations. Therefore, geranylated chalcones such as Xanthoangelol are promising lead structures for new antimicrobials against drug-resistant gram-positive pathogens.

14.
Mar Drugs ; 17(9)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491907

RESUMO

There is a variety of antineoplastic drugs that are based on natural compounds from ecological niches with high evolutionary pressure. We used two cell lines (Jurkat J16 and Ramos) in a screening to assess 300 different naturally occurring compounds with regard to their antineoplastic activity. The results of the compounds 4,6-dibromo-2-(2',4'-dibromophenoxy)phenol (P01F03), 4,5,6-tribromo-2-(2',4'-dibromophenoxy)phenol (P01F08), and 5-epi-nakijinone Q (P03F03) prompted us to perform further research. Using viability and apoptosis assays on the cell lines of primary human leukemic and normal hematopoietic cells, we found that P01F08 induced apoptosis in the cell lines at IC50 values between 1.61 and 2.95 µM after 72 h. IC50 values of peripheral blood mononuclear cells (PBMNCs) from healthy donors were higher, demonstrating that the cytotoxicity in the cell lines reached 50%, while normal PBMNCs were hardly affected. The colony-forming unit assay showed that the hematopoietic progenitor cells were not significantly affected in their growth by P01F08 at a concentration of 3 µM. P01F08 showed a 3.2-fold lower IC50 value in primary leukemic cells [acute myeloid leukemia (AML)] compared to the PBMNC of healthy donors. We could confirm the antineoplastic effect of 5-epi-nakijinone Q (P03F03) on the cell lines via the induction of apoptosis but noted a similarly strong cytotoxic effect on normal PBMNCs.


Assuntos
Antineoplásicos/uso terapêutico , Fenol/uso terapêutico , Adulto , Idoso , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células HL-60 , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Células Jurkat , Leucemia Mieloide Aguda/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Células THP-1
15.
Curr Med Chem ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31526342

RESUMO

BACKGROUND: Endophytes represent a complex community of microorganisms colonizing asymptomatically internal tissues of higher plants. Several reports have shown that endophytes enhance fitness of their host plants by direct production of bioactive secondary metabolites, which are involved in protecting the host against herbivores and pathogenic microbes. In addition, it is increasingly apparent that endophytes are able to biosynthesize medicinally important "phytochemicals", originally believed to be produced only by their host plants. OBJECTIVE: The present review provides an overview of secondary metabolites from endophytic fungi with pronounced biological activities covering the literature between 2010 and 2017. Special focus is given on studies aiming at exploration of the mode of action of these metabolites towards the discovery of leads from endophytic fungi. Moreover, this review critically evaluates the potential of endophytic fungi as alternative sources of bioactive "plant metabolites". RESULTS: Over the past few years, several promising lead structures from endophytic fungi have been described in the literature. In this review, 65 metabolites are outlined with pronounced biological activities, primarily as antimicrobial and anticancer agents. Some of these metabolites have shown to be highly selective (non-toxic) or to possess novel mechanisms of action, which hold great promises as potential drug candidates. CONCLUSION: Endophytes represent an inexhaustible reservoir of pharmacologically important compounds. Moreover, endophytic fungi could be exploited for sustainable production of bioactive "plant metabolites" in the future. Towards this aim, further insights into the dynamic endophyte - host plant interactions and origin of endophytic fungal genes would be of utmost importance.

16.
Bioorg Med Chem ; 27(20): 115042, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31420258

RESUMO

In order to overcome therapy resistance in cancer, scientists search in nature for novel lead structures for the development of improved chemotherapeutics. Anthraquinones belong to a class of tricyclic organic natural compounds with promising anti-cancer effects. Anthraquinone derivatives are rich in structural diversity, and exhibit pleiotropic properties, among which the modulation of autophagy seems promising in the context of overcoming cancer-therapy resistance. Among the most promising derivatives in this regard are emodin, aloe emodin, rhein, physcion, chrysophanol and altersolanol A. On the molecular level, these compounds target autophagy via different upstream pathways including the AKT/mTOR-axis and transcription of autophagy-related proteins. The role of autophagy is pro-survival as well as cell death-promoting, depending on derivatives and their cell type specificity. This review summarizes observed effects of anthraquinone derivatives on autophagy and discusses targeted pathways and crosstalks. A cumulative knowledge about this topic paves the way for further research on modes of action, and aids to find a therapeutic window of anthraquinones in cancer-therapy.

17.
Fitoterapia ; 138: 104294, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31398449

RESUMO

Two new eremophilane-type sesquiterpenes, carperemophilanes A and B (1-2), three new maleimide-bearing compounds, carpesiumaleimides A-C (3-5), along with a known sesquiterpene, carabrol (6), were isolated from the ethanol extract of Carpesium abrotanoides L. Their structures were elucidated by analysis of their NMR and MS data as well as by comparison with the literature. The absolute configuration of carperemophilane A (1) was determined by single-crystal X-ray diffraction analysis. All isolated compounds (1-6) were evaluated in vitro for cytotoxicity against two human cancer cell lines MDA-MB-231 and HGC-27 using the MTT method. Compounds 1, 2 and 6 showed cytotoxic activities with IC50 values ranging from 7.45 to 37.35 µM.


Assuntos
Asteraceae/química , Maleimidas/farmacologia , Sesquiterpenos/farmacologia , Linhagem Celular Tumoral , China , Humanos , Maleimidas/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Sesquiterpenos/isolamento & purificação
18.
Bioorg Med Chem ; 27(20): 115005, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31466836

RESUMO

Five new metabolites, including the xanthone derivative wentixanthone A (1), the benzophenone wentiphenone A (2), the diastereomeric mixtures of the bianthrones wentibianthrone A (3a, b) and wentibianthrone B (4a, b), as well as (10R,10'S)-wentibianthrone C (5a) and (10R,10'R)-wentibianthrone C (5b) were obtained from the fungus Aspergillus wentii, isolated from soil of the hypersaline lake El Hamra in Wadi El-Natrun, Egypt. The structures of the isolated compounds were established by one and two-dimensional NMR and MS spectroscopic analysis. The relative configuration of bianthrones (3-5) was elucidated by comparison of experimental and computed 1H NMR chemical shifts. Results of biological assays are reported.

19.
Bioorg Med Chem ; 27(19): 115044, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31443950

RESUMO

Platinum compounds are the first-line therapy for many types of cancer. However, drug resistance has frequently been reported for and is a major limitation of platinum-based chemotherapy in the clinic. In the current study, we examined the anti-tumor activity of phomoxanthone A (PXA), a tetrahydroxanthone dimer isolated from the endophytic fungus Phomopsis longicolla, in several solid cancer cell lines and their cisplatin-resistant sub-cell lines. PXA showed strong cytotoxic effects with IC50 values in the high nanomolar or low micromolar range in MTT assays. IC50 values of PXA were lower than those of cisplatin. Remarkably, equipotent anti-cancer activity was found in cisplatin-sensitive and respective cisplatin-resistant cells. Anticancer effects of PXA were studied in further detail in ovarian cancer (A2780) and bladder cancer (J82) cell pairs. PXA led to rapid depolarization of the mitochondrial membrane potential and strong activation of caspase 3 and 7, eventually resulting in strong induction of apoptosis. These effects occurred again both in sensitive and resistant cell lines. IC50 values of PXA from MTT and mitochondrial membrane depolarization assays were in good agreement. Configurational free energy computations indicate that both the neutral and singly negatively charged PXA show membrane partitioning and can penetrate the inner mitochondrial membrane. PXA treatment did not damage the plasma membranes of cancer cells, thus excluding unspecific membrane effects. Further, PXA had neither an effect on intracellular ROS nor on reduction of ROS after hydrogen peroxide treatment. In conclusion, our studies present PXA as a natural compound with strong apoptotic anticancer effects against platinum-resistant solid cancers. This may open new treatment options in clinically resistant malignancies.

20.
J Nat Prod ; 82(9): 2460-2469, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31432669

RESUMO

Three new natural products (1-3), including two butenolide derivatives (1 and 2) and one dihydroquinolone derivative (3), together with nine known natural products were isolated from a marine-derived strain of the fungus Metarhizium marquandii. The structures of the new compounds were unambiguously deduced by spectroscopic means including HRESIMS and 1D/2D NMR spectroscopy, ECD, VCD, OR measurements, and calculations. The absolute configuration of marqualide (1) was determined by a combination of modified Mosher's method with TDDFT-ECD calculations at different levels, which revealed the importance of intramolecular hydrogen bonding in determining the ECD features. The (3R,4R) absolute configuration of aflaquinolone I (3), determined by OR, ECD, and VCD calculations, was found to be opposite of the (3S,4S) absolute configuration of the related aflaquinolones A-G, suggesting that the fungus M. marquandii produces aflaquinolone I with a different configuration (chiral switching). The absolute configuration of the known natural product terrestric acid hydrate (4) was likewise determined for the first time in this study. TDDFT-ECD calculations allowed determination of the absolute configuration of its chirality center remote from the stereogenic unsaturated γ-lactone chromophore. ECD calculations aided by solvent models revealed the importance of intramolecular hydrogen bond networks in stabilizing conformers and determining relationships between ECD transitions and absolute configurations.

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