Weaam Ebrahim

Alkaloids and Polyketides from Penicillium citrinum, an Endophyte Isolated from the Moroccan Plant Ceratonia siliqua

The endophytic fungus Penicillium citrinum was isolated from a fresh stem of the Moroccan plant Ceratonia siliqua. Extracts of P. citrinum grown on rice and white bean media yielded five new compounds, namely, citriquinochroman (1), tanzawaic acids G and H (2 and 3), 6-methylcurvulinic acid (4), 8-methoxy-3,5-dimethylisoquinolin-6-ol (5), and one new natural product, 1,2,3,11b-tetrahydroquinolactacide (6), which had previously been described as a synthetic compound. In addition, 13 known compounds including seven alkaloids and six polyketides were isolated. The structures of the new compounds were unambiguously determined on the basis of one- and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. Citriquinochroman (1) features a new skeleton, consisting of quinolactacide and (3S)-6-hydroxy-8-methoxy-3,5-dimethylisochroman linked by a C-C bond. 1,2,3,11b-Tetrahydroquinolactacide (6) may be a biogenetic precursor of quinolactacide. Citriquinochroman (1) showed cytotoxicity against the murine lymphoma L5178Y cell line with an IC50 value of 6.1 μM, while the other compounds were inactive (IC50 >10 μM) in this assay.

Pullularins E and F, Two New Peptides from the Endophytic Fungus Bionectria ochroleuca Isolated from the Mangrove Plant Sonneratia caseolaris

Chemical investigation of the EtOAc extract of the endophytic fungus Bionectria ochroleuca, isolated from the inner leaf tissues of the plant Sonneratia caseolaris (Sonneratiaceae) from Hainan island (China), yielded two new peptides, pullularins E and F (1 and 2) together with three known compounds (3–5). The structures of the new compounds were unambiguously determined on the basis of one- and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. The absolute configurations of amino acids were determined by HPLC analysis of acid hydrolysates using Marfey’s method. The isolated compounds exhibited pronounced to moderate cytotoxic activity against the mouse lymphoma cells (L5178Y) with EC50 values ranging between 0.1 and 6.7 µg/mL.

Metabolites from the Fungal Endophyte Aspergillus austroafricanus in Axenic Culture and in Fungal–Bacterial Mixed Cultures

The endophytic fungus Aspergillus austroafricanus isolated from leaves of the aquatic plant Eichhornia crassipes was fermented axenically on solid rice medium as well as in mixed cultures with Bacillus subtilis or with Streptomyces lividans. Chromatographic analysis of EtOAc extract of axenic cultures afforded two new metabolites, namely, the xanthone dimer austradixanthone (1) and the sesquiterpene (+)-austrosene (2), along with five known compounds (3-7). Austradixanthone (1) represents the first highly oxygenated heterodimeric xanthone derivative. When A. austroafricanus was grown in mixed cultures with B. subtilis or with S. lividans, several diphenyl ethers (8-11) including the new austramide (8) were induced up to 29-fold. The structures of new compounds were unambiguously elucidated using 1D- and 2D-NMR spectroscopy, HRESIMS, and chemical derivatization. Compound 7 exhibited weak cytotoxicity against the murine lymphoma L5178Y cell line (EC50 is 12.6 μM). In addition, compounds 9 and 10, which were enhanced in mixed fungal/bacterial cultures, proved to be active against Staphylococcus aureus (ATCC 700699) with minimal inhibitory concentrations (MICs) of 25 μM each (6.6 μg/mL), whereas compound 11 revealed moderate antibacterial activity against B. subtilis 168 trpC2 with an MIC value of 34.8 μM (8 μg/mL).

Embellicines A and B: absolute configuration and NF-κB transcriptional inhibitory activity.

Two new metabolites, embellicines A and B (1 and 2), were isolated from the EtOAc extract of the fungus Embellisia eureka , an endophyte of the Moroccan plant Cladanthus arabicus (Asteraceae). The structures of these new compounds were determined on the basis of extensive one- and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. The absolute configuration of embellicine A (1) was determined by TDDFT ECD calculations of solution conformers, whereas that of embellicine B (2) was deduced based on ROESY correlations and on biogenetic considerations in comparison to 1. Both embellicines (1 and 2) are cytostatic, cytotoxic, and inhibit NF-κB transcriptional activity, indicating that inhibition of NF-κB may be a possible mechanism of action of these compounds. Embellicine B (2) was the most active compound encountered in this study and acts at nanomolar concentrations without affecting tumor microenvironment.

O-heterocyclic embeurekols from embellisia eureka, an endophyte of cladanthus arabicus

Three new polyketides ((-)-1, (+)-1, and 2) were isolated from the EtOAc extract of the fungus Embellisia eureka, an endophyte of the Moroccan plant Cladanthus arabicus (Asteraceae). The structures of these new compounds were determined on the basis of one- and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. The absolute configurations of (-)-1, (+)-1, and 2 were determined by TDDFT ECD calculations of solution conformers, online HPLC-ECD analysis, and the modified Mosher method.

Natural Products from Deep-Sea-Derived Fungi ̶ A New Source of Novel Bioactive Compounds?

BACKGROUND Over the last two decades, deep-sea-derived fungi are considered to be a new source of pharmacologically active secondary metabolites for drug discovery mainly based on the underlying assumption that the uniqueness of the deep sea will give rise to equally unprecedented natural products. Indeed, up to now over 200 new metabolites have been identified from deep-sea fungi, which is in support of the statement made above. RESULTS This review summarizes the new and/or bioactive compounds reported from deepsea- derived fungi in the last six years (2010 - October 2016) and critically evaluates whether the data published so far really support the notion that these fungi are a promising source of new bioactive chemical entities.

Two new triterpenoids and a new naphthoquinone derivative isolated from a hard coral-derived fungus Scopulariopsis sp.

Scopulariopsis sp. isolated from the Red Sea hard coral Stylophora sp. yielded two new triterpenoids (1-2) and a new naphthoquinone derivative (8) when cultured on white beans. In addition, fourteen known compounds including three triterpene analogues (3-5), two sesquiterpenoids (6-7), two polyketides (9-10) and seven nitrogenous compounds (11-17) were isolated. All structures were determined through extensive analysis of the NMR and MS data as well as by comparison with literature data. All isolated compounds were evaluated for their cytotoxic, antibacterial and antitubercular activities. However, none of them showed significant activity.

Induction of new metabolites from the endophytic fungus Bionectria sp. through bacterial co-culture

A new alkaloid, 1,2-dihydrophenopyrrozin (1), along with five known compounds (2-6) was isolated from an axenic culture of the endophytic fungus, Bionectria sp., obtained from seeds of the tropical plant Raphia taedigera. Co-cultivation of this fungus either with Bacillus subtilis or with Streptomyces lividans resulted in the production of two new o-aminobenzoic acid derivatives, bionectriamines A and B (7 and 8) as well as of two additional known compounds (9 and 10). None of the latter compounds (7-10) were detected in axenic cultures of the fungus or of the bacteria indicating activation of silent biogenetic gene clusters through co-cultivation with bacteria. The structures of the new compounds were unambiguously determined based on detailed NMR and MS spectroscopic analysis and by comparison with the literature. The crystal structure of agathic acid (6) is reported here for the first time. Penicolinate A (4) exhibited potent cytotoxic activity against the human ovarian cancer cell line A2780 with an IC50 value of 4.1μM.

Germacrane-Type Sesquiterpenoids with Antiproliferative Activities from Eupatorium chinense

Ten new germacrane-type sesquiterpenoids (1-10) were isolated from a whole plant extract of Eupatorium chinense. The structures were elucidated by analysis of their NMR and MS data as well as by comparison with literature values. The absolute configuration of eupachinsin A (1) was determined by single-crystal X-ray diffraction analysis. Compounds 3 and 4 exhibited cytotoxicity against a human breast cancer cell line (MDA-MB-231), with IC50 values of 0.8 and 3.4 μM, respectively. In addition, compounds 3-5 showed cytotoxicity against the human hepatocellular carcinoma cell line (HepG2), with IC50 values ranging from 3.6 to 7.6 μM.

Hydroquinone derivatives from the marine-derived fungus Gliomastix sp.

Eight new hydroquinone derivatives, gliomastins A–D (1–4), 9-O-methylgliomastin C (5), acremonin A 1-O-β-D-glucopyranoside (6), gliomastin E 1-O-β-D-glucopyranoside (7), and 6′-O-acetyl-isohomoarbutin (8), together with seven known analogues were isolated from the marine-derived fungus Gliomastix sp. Their structures were elucidated by extensive spectroscopic analysis including 1D and 2D NMR measurements aided by DFT NMR calculations as well as MS data. TDDFT-ECD and OR calculations were performed to determine the absolute configurations of 1 and the aglycones of 6 and 7. Compound 1 features a novel skeleton, biogenetically derived from a Diels–Alder reaction between derivatives of 11 and 13. Compound 2 represents a rare sulfur-containing alkaloid derived from the known hydroquinone 13. Compounds 1, 10 and 12 showed strong cytotoxicity against the L5178Y mouse lymphoma cell line with IC50 values of 1.8, 1.0 and 1.1 μM, respectively. Compound 3 exhibited moderate antitubercular activity against Mycobacterium tuberculosis with a MIC value of 12.5 μM.