Investigation of iso-propylchaetominine anticancer activity on apoptosis, cell cycle and Wnt signaling pathway in different cancer models.

Dysregulation of the Wnt signaling pathway contributes to the development of many cancer types. Natural compounds produced with biotechnological systems have been the focus of research for being a new drug candidate both with unlimited resources and cost-effective production. In this study, it was aimed to reveal the effects of isopropylchaetominine on cytotoxic, cytostatic, apoptotic and Wnt signaling pathways in brain, pancreatic and prostate cancer. The IC50 values of isopropylchaetominine in U-87 MG, PANC1, PC3 and LNCaP cells were calculated as 91.94 µM, 41.68 µM, 54.54 µM and 7.86 µM in 72nd h, respectively. The metabolite arrests the cell cycle in G0/G1 phase in each cancer cells. Iso-propylchaetominine induced a 4.3-fold and 1.9-fold increase in apoptosis in PC3 and PANC1 cells, respectively. The toxicity of isopropylchaetominine in healthy fibroblast cells was assessed using the annexin V method, and no significant apoptotic activity was observed between the groups treated with the active substance and untreated. In U-87 MG, PANC1, PC3, and LNCaP cells under treatment with isopropylchaetominin, the expression levels of DKK3, TLE1, AES, DKK1, FRZB, DAB2, AXIN1/2, PPARD, SFRP4, APC and SOX17 tumor suppressor genes increased significantly. Decreases in expression of Wnt1, Wnt2, Wnt3, Wnt4, Wnt5, Wnt6, Wnt10, Wnt11, FRZ2, FRZ3, FRZ7, TCF7L1, BCL9, PYGO, CCND2, c-MYC, WISP1 and CTNNB1 oncogenic genes were detected. All these result shows that isopropylchaetominine can present promising new treatment strategy in different cancer types.

Promising anti-Helicobacter pylori and anti-inflammatory metabolites from unused parts of Phoenix dactylifera CV 'Zaghloul': in vitro and in silico study.

CONTEXT: Date palm waste is an agricultural waste that accumulates in massive amounts causing serious pollution and environmental problems. OBJECTIVES: Date palm trees, Phoenix dactylifera Linn CV 'Zaghloul' (Arecaceae) grown in Egypt, leave behind waste products that were investigated to produce compounds with anti-Helicobacter pylori and anti-inflammatory activities. MATERIALS AND METHODS: Chromatographic workup of P. dactylifera aqueous methanol extract derived from fibrous mesh and fruit bunch (without fruit) afforded a new sesquiterpene lactone derivative, phodactolide A (1), along with ten known compounds (2-11), primarily identified as polyphenols. Chemical structures were unambiguously elucidated based on mass and 1D/2D NMR spectroscopy. All isolated compounds were assessed for their activities against H. pylori using broth micro-well dilution method and clarithromycin as a positive control. The anti-inflammatory response of isolated compounds was evaluated by inhibiting cyclooxygenase-2 enzyme using TMPD Assay followed by an in silico study to validate their mechanism of action using celecoxib as a standard drug. RESULTS: Compounds 4, 6 and 8-10 exhibited potent anti-H. pylori activity with MIC values ranging from 0.48 to 1.95 µg/mL that were comparable to or more potent than clarithromycin. For COX-2 inhibitory assay, 4, 7 and 8 revealed promising activities with IC50 values of 1.04, 0.65 and 0.45 µg/mL, respectively. These results were verified by molecular docking studies, where 4, 7 and 8 showed the best interactions with key amino acid residues of COX-2 active site. CONCLUSION: The present study characterizes a new sesquiterpene lactone and recommends 4 and 8 for future in vivo studies as plausible anti-ulcer remedies.

Cytotoxic effects of extracts obtained from plants of the Oleaceae family: bio-guided isolation and molecular docking of new secoiridoids from Jasminum humile.

CONTEXT: Traditionally, Oleaceae plants are used to treat many diseases, such as rheumatism, hypercholesterolaemia, or ulcers. OBJECTIVES: To investigate the cytotoxic potential of Jasminum humile L., Jasminum grandiflorum L., and Olea europaea L. (Oleaceae) extracts against selected human cancer cells lines, followed by a phytochemical investigation of the most potent one. MATERIALS AND METHODS: The 95% ethanol extracts of aerial parts of three oleaceous plants were examined for their cytotoxicity against HepG-2, MCF-7, and THP-1 cell lines using MTT assay and doxorubicin (positive control). J. humile was bio-selected and submitted to bio-guided fractionation. Chromatographic workup of ethyl acetate and n-butanol fractions afforded two new compounds; 1-methoxyjasmigenin (1) and 1-methyl-9-aldojasmigenin (2), along with five known ones (3-7). Structures were unambiguously elucidated using 1D/2D NMR and ESI-HRMS. Isolated compounds were assessed for their anti-proliferative potential, and both selectivity index and statistical significance were determined. Molecular docking was conducted against the Mcl-1 receptor using (AZD5991) as a standard. RESULTS: Jasmoside (5) was the most potent anticancer compound showing IC50 values of 66.47, 41.32, and 27.59 µg/mL against HepG-2, MCF-7, and THP-1 cell lines, respectively. Moreover, isojasminin (4) exhibited IC50 values of 33.49, 43.12, and 51.07 µg/mL against the same cell lines, respectively. Interestingly, 5 exhibited the highest selectivity index towards MCF-7 and THP-1, even greater than doxorubicin. Molecular docking results were in full agreement with the MTT assay and the proposed SAR. CONCLUSION: In this study, two new compounds were purified. The biological activity highlighted jasmoside (5) as a lead anticancer drug for further future investigation.

In Vitro Phytobiological Investigation of Bioactive Secondary Metabolites from the Malus domestica-Derived Endophytic Fungus Aspergillus tubingensis Strain AN103.

Endophytic fungi including black aspergilli have the potential to synthesize multiple bioactive secondary metabolites. Therefore, the search for active metabolites from endophytic fungi against pathogenic microbes has become a necessity for alternative and promising strategies. In this study, 25 endophytic fungal isolates associated with Malus domestica were isolated, grown, and fermented on a solid rice medium. Subsequently, their ethyl acetate crude extracts were pretested for biological activity. One endophytic fungal isolate demonstrated the highest activity and was chosen for further investigation. Based on its phenotypic, ITS ribosomal gene sequences, and phylogenetic characterization, this isolate was identified as Aspergillus tubingensis strain AN103 with the accession number (KR184138). Chemical investigations of its fermented cultures yielded four compounds: Pyranonigrin A (1), Fonsecin (2), TMC 256 A1 (3), and Asperazine (4). Furthermore, 1H-NMR, HPLC, and LC-MS were performed for the identification and structure elucidation of these metabolites. The isolated pure compounds showed moderate-to-potent antibacterial activities against Pseudomonas aeruginosa and Escherichia coli (MIC value ranged from 31 and 121 to 14.5 and 58.3 µg/mL), respectively; in addition, the time−kill kinetics for the highly sensitive bacteria against isolated compounds was also investigated. The antifungal activity results show that (3) and (4) had the maximum effect against Fusarium solani and A. niger with inhibition zones of 16.40 ± 0.55 and 16.20 ± 0.20 mm, respectively, and (2) had the best effect against Candida albicans, with an inhibition zone of 17.8 ± 1.35 mm. Moreover, in a cytotoxicity assay against mouse lymphoma cell line L5178Y, (4) exhibited moderate cytotoxicity (49% inhibition), whereas (1−3) reported weak cytotoxicity (15, 26, and 19% inhibition), respectively. Our results reveal that these compounds might be useful to develop potential cytotoxic and antimicrobial drugs and an alternative source for various medical and pharmaceutical fields.

Nanoemulsions of Jasminum humile L. and Jasminum grandiflorum L. Essential Oils: An Approach to Enhance Their Cytotoxic and Antiviral Effects.

Unprecedented nanoemulsion formulations (NE) of Jasminum humile and Jasminum grandiflorum essential oils (EO) were prepared, and examined for their cytotoxic and antiviral activities. NE characterization and stability examination tests were performed to ensure formula stability. The antiviral activity was determined against hepatitis A (HAV) and herpes simplex type-1 (HSV-1) viruses using MTT assay, while the cytotoxic potential was determined against liver (HepG-2), breast (MCF-7), leukemia (THP-1) cancer cell lines and normal Vero cells. Statistical significance was determined in comparison with doxorubicin as cytotoxic and acyclovir as antiviral standard drugs. GC-MS analysis indicated twenty four compounds in the EO of J. humile and seventeen compounds in the EO of J. grandiflorum. Biological investigations of pure EOs revealed weak cytotoxic and antiviral effects. Nevertheless, their NE formulations exhibited high biological value as cytotoxic and antiviral agents. NE formulations also showed feasible selectivity index for the viral-infected and cancer cells (especially HepG-2) than normal Vero cells. Both nanoemulsions showed lower IC50 than standard doxorubicin against HepG-2 (26.65 and 22.58 vs. 33.96 µg/mL) and MCF-7 (36.09 and 36.19 vs. 52.73 µg/mL), respectively. The study results showed the dramatic effect of nanoemulsion preparation on the biological activity of EOs and other liposoluble phytopharmaceuticals.

Pyrone derivatives from Helichrysum italicum.

Chemical investigation of aerial parts of Helichrysum italicum yielded two new pyrone derivatives (1 and 2) along with ten known compounds. The structures of the new compounds were established by 1D and 2D NMR spectra as well as by HRESIMS data. Compound 1 represented a rare dimer of substituted α- and γ-pyrone units. DFT-NMR and TDDFT-ECD calculations were carried out to determine the absolute configuration of 1 but failed, representing the limitation of TDDFT-ECD calculation for the configurational assignment. All compounds were measured for their antibacterial and cytotoxic activity but proved to be inactive.

A new depsidone derivative from mangrove sediment derived fungus Lasiodiplodia theobromae.

A new depsidone derivative botryorhodine I (1), along with eight known compounds (2-9) were obtained from solid rice cultures of the fungal strain, Lasiodiplodia theobromae M4.2-2 isolated from a mangrove sediment sample. The structures of the isolated compounds were elucidated on the basis of 1 D and 2 D NMR analysis as well as by HRESIMS. All compounds were evaluated for their cytotoxic potential against the mouse lymphoma cell line L5178Y as well as for their antibacterial activities against a panel of Gram-positive and Gram-negative bacterial strains. Compound 3 revealed potent cytotoxic activity with an IC50 of 7.3 µM whereas compound 7 showed selective anti-bacterial activity against different S. aureus and E. faecium bacterial strains with MIC value of 25 µg/ml.

Induction of new metabolites from sponge-associated fungus Aspergillus carneus by OSMAC approach.

A comparative study on the metabolic profile of the sponge-associated fungus Aspergillus carneus using the OSMAC approach was conducted. The fungal strain was fermented on three different media including solid rice medium with or without sea salt and modified Czapek medium. Three new natural products, isopropylchaetominine (1), isoterrelumamide A (2) and 5'-epi-averufanin (3), together with fourteen known compounds (4-17) were isolated. The structures of the new compounds were established by 1D and 2D NMR spectroscopic analysis as well as by HRESIMS. Compound 2 was only found when the fungus was cultivated on modified Czapek medium, whereas compounds 4, 7, 11, 12, and 14 were only detected in fungal extracts from solid rice media lacking sea salt. Compounds 8 and 13 on the other hand were only found when A. carneus was cultured on solid rice with sea salt. The cytotoxic and antimicrobial activities of all isolated compounds were evaluated. Compounds 1, 9 and 17 showed strong cytotoxicity against the mouse lymphoma cell line L5178Y with IC50 values of 0.4, 0.3 and 0.2 µM, respectively. In addition, compounds 3, 5 and 6 showed inhibitory activity against different Gram-positive bacterial strains with MIC values ranging from 2.3 to 18.4 µg/mL.

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.

Lactones from the Sponge-Derived Fungus Talaromyces rugulosus.

The marine-derived fungus Talaromyces rugulosus isolated from the Mediterranean sponge Axinella cannabina and cultured on solid rice medium yielded seventeen lactone derivatives including five butenolides (1-5), seven (3S)-resorcylide derivatives (6-12), two butenolide-resorcylide dimers (13 and 14), and three dihydroisocoumarins (15-17). Among them, fourteen compounds (1-3, 6-16) are new natural products. The structures of the isolated compounds were elucidated by 1D and 2D NMR (Nuclear Magnetic Resonance) spectroscopy as well as by ESI-HRMS (ElectroSpray Ionization-High Resolution Mass Spectrometry). TDDFT-ECD (Time-Dependent Density Functional Theory-Electronic Circular Dichroism) calculations were performed to determine the absolute configurations of chiral compounds. The butenolide-resorcylide dimers talarodilactones A and B (13 and 14) exhibited potent cytotoxicity against the L5178Y murine lymphoma cell line with IC50 values of 3.9 and 1.3 µM, respectively.

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).

Cytotoxic rocaglamide derivatives from Aglaia duppereana.

Phytochemical investigation of Aglaia duppereana flowers led to the isolation of a new rocaglamide derivative and twelve known congeners. The structure of the new compound was unambiguously elucidated by spectroscopic techniques (1D- and 2D-NMR, HRESIMS). The isolated compounds exhibited a potent cytotoxic activity against mouse lymphoma (L5178Y) cells with EC50 values ranging from 5.1 to 54.8 nM.

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.