Chemical constituents of Coccoloba peltata Schott leaves and their cytotoxic activities.

Chromatographic fractionation of CH2Cl2:MeOH (1:1) extract of Coccoloba peltata Schott cultivated in Egypt afforded four compounds, lupeol acetate (1), ent-13-epi-manoyl oxide (2), 5-methoxymethyl-7,8-dimethyltocol (3), and α-tocopherol quinone (4). The planar structures of the isolated compounds were concluded based on HRESIMS and NMR spectroscopy. X-ray crystallography of 2 is reported herein for the first time and its unambiguous absolute configuration was deduced from anomalous dispersion. To the best of our knowledge, this is the first known report on the isolation of compounds 1-4 from this species. Among the isolated compounds, only compound 4 showed a moderate level of cytotoxic activity against six cancer cell lines out of seven cell lines tested.

Diverse bioactive secondary metabolites from Aspergillus terreus: antimicrobial, anticancer, and anti-SARS-CoV-2 activity studies.

Owing to its high interest as prolific source of diverse bioactive compounds referred in our previous research work, we have scaled-up the fermentation of the marine Aspergillus terreus LGO13 on a liquid culture medium to isolate and identify the very minor/further promising bioactive secondary metabolites and to study their antibacterial, cytotoxic, and antiviral properties. Twenty-three known bioactive metabolites, including the recently discovered microbial natural product N-benzoyl-tryptophan (1), were obtained herein. Their structures were determined using HR-ESI-MS 1D/2D NMR spectroscopy and data from the literature. The biological properties of the microbial extract and the resulting compounds were examined using a set of microorganisms, cervix carcinoma KB-3-1, nonsmall cell lung cancer (NSCLC) A549, and coronavirus (SARS-CoV-2), respectively. Molecular docking (MD) simulations were used to investigate the potential targets of the separated metabolites as anti-SARS-CoV-2 drugs. According to the current study, a viral protein that may be the target of anticovid drugs is a papain-like protease (PLpro), and chaetominine (2) appears to be a viable choice against this protein. We evaluated the antiviral efficacy of chaetominine (2), fumitremorgin C (6), and azaspirofuran A (9) against SARS-CoV-2 based on MD data. Chaetominine (2) and azaspirofuran A (9) displayed intermediate selectivity indices (SI = 6.6 and 3.2, respectively), while fumitremorgin C (6) displayed a high selectivity index (SI = 19.77). These findings show that fumitremorgin C has promising antiviral action against SARS-CoV-2.

Cannabinoid-like meroterpenoids from Peperomia incana.

Ten previously undescribed metabolites were isolated from Peperomia incana (Haw.) A. Dietr. (Piperaceae), among which four contained a chromene moiety, two were identified as meroterpene lactones, and four were cannabinoid-like compounds. While the chemical structures of the compounds were assigned based on HRESIMS and 1D and 2D-NMR spectra analyses, the relative and absolute configurations were assigned from NOE correlations and a combination of ECD data and X-ray single crystal analyses, respectively. In a cytotoxic assay against a panel of seven human cancer cell lines (A549, MDA-MB-231, HeLa, DU 145, 5637, Hep G2, and MIA PaCa-2, which represent non-small cell lung cancer, as well as breast, cervical, prostate, bladder, liver, and pancreas carcinomas, respectively) most of the isolated compounds showed promising cytotoxic activities. The incanachromenes B, and incanabinoids A and C exhibited the highest cytotoxicity toward all tested cancer cell lines with IC50 values in the range of 5.0-10.0 µM, whereas incanolides A, B, and incanabinoid B showed the lowest cytotoxic activity. In addition, incanachromene C and incanabinoid C produced a significant antibacterial effect toward planktonic cells and biofilms of multidrug-resistant Staphylococcus aureus strains.

Synthesis of ß-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms.

A series of aryl-substituted 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a-4q) were designed and synthesized via reaction of 6-methoxy-2-naphthol with a mixture of appropriate aromatic aldehydes and malononitrile under microwave conditions. The structures of the novel compounds 4b, 4c, 4f, 4g, 4i, 4l, 4m, and 4o-4q were established according to IR, 1H-NMR, 13C-NMR/13C-NMR-DEPT, and MS. The benzochromene derivative 4c with a single chlorine at the meta position of the phenyl ring and, to a lesser extent, other benzochromenes with monohalogenated phenyl ring (4a, 4c-4f) exhibited the highest cytotoxicity against six human cancer cell lines MDA-MB-231, A549, HeLa, MIA PaCa-2, 5,637, and Hep G2. The mechanisms of the cytotoxic activities of benzochromenes with monohalogenated phenyl ring (4a, 4c-4f) were further analyzed using triple-negative breast cancer cell line MDA-MB-231. Cell cycle analysis showed accumulation of the treated cells in S phase for 4a, 4d-4f, and S-G2/M phases for 4c. In vivo, 4a and 4c-4f inhibited growth, proliferation, and triggered apoptosis in preestablished breast cancer xenografts grown on the chick chorioallantoic membranes while exhibiting low systemic toxicity. Compounds 4a and 4c-4f increased levels of mitochondrial superoxide and decreased mitochondrial membrane potential resulting in initiation of apoptosis as demonstrated by caspase 3/7 activation. In addition, 4c induced general oxidative stress in cancer cells. The SAR study confirmed that halogens of moderate size at meta or para positions of the pendant phenyl ring enhance the cytotoxic activity of 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles, and these compounds could serve as leads for the development of novel anticancer therapies.

Synthesis and evaluation of antitumor activity of 9-methoxy-1H-benzo[f]chromene derivatives.

Herein, a series of aryl-substituted derivatives of 3-amino-1-aryl-9-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a-4q) were designed and synthesized via reaction of 7-methoxy-2-naphthol with a mixture of appropriate aromatic aldehydes and malononitrile under microwave conditions. Among the tested benzochromene, the known compound 4e and four novel compounds 4f, 4j, 4k, 4m exhibited the highest cytotoxicity towards a panel of six human cancer cell lines MDA-MB-231, A549, HeLa, MIA PaCa-2, RPMI 7951, and PC-3. Compound 4j with 2,4-dichloro substitution on the pendant phenyl ring exhibited the highest broad-spectrum cytotoxicity towards all tested cancer cell lines. Compounds 4e, 4f, 4j, 4k, 4m were further selected to study the mechanism of cellular toxicity using the triple-negative breast cancer cells MDA-MB-231. Compounds 4e, 4f, 4j, 4k, 4m induced accumulation of the treated MDA-MB-231 cells in the S phase and 4k additionally in the G2/M phase of the cell cycle. Compounds 4e, 4f, 4j, 4k, 4m induced dissipation of mitochondrial transmembrane potential and activation of caspase 3/7 in MDA-MB-231 cells with 4j being one of the most active. In an in vivo model, compound 4j and less efficiently 4e and 4f inhibited growth and proliferation and triggered DNA fragmentation in MDA-MB-231 xenografts grown on chick chorioallantoic membranes. SAR study confirmed that the 2,4-dichloro substitution pattern on the pendant phenyl ring enhanced the cytotoxic activity of benzochromene.

Meleagrin from marine fungus Emericella dentata Nq45: crystal structure and diverse biological activity studies.

The crystal structure and unambiguous absolute configuration of meleagrin (1) isolated from fungus Emericella dentata Nq45 is reported herein to first time on the bases of single crystal X-ray diffraction. Together with 1, haenamindole (2), isorugulosuvine (3), secalonic acid D (4), ergosterol (5) and cerebroside A (6) were obtained and their structures were determined by ESI MS and NMR data analysis. Diverse biological activity of meleagrin (1) was investigated. Compound 1 pronounced potent cytotoxicity against the human cervix carcinoma cell line KB-3-1 and its multidrug resistant sub-clone KB-V1 of IC50 3.07 and 6.07 µM, respectively, in comparison with the reference (+) - griseofulvin (IC50 19, 19.5 µM). Based on the antibiofilm activity, compound 1 displayed as well potent activity against Staphylococcus aureus with an MIC of 0.25 mg/mL. Isolation of the producing fungus and taxonomical characterization is stated as well.

RF-3192C and other polyketides from the marine endophytic Aspergillus niger ASSB4: structure assignment and bioactivity investigation.

Chemical investigation of the methanolic extract of endophytic Aspergillus niger SB4, isolated from the marine alga Laurencia obtuse, afforded the pentacyclic polyketide, RF-3192C (1), the dimeric coumarin orlandin (2), fonsecin B (3), TMC-256A1 (4), cyclo-(Leu-Ala) (5), and cerebroside A (6).The chemical structure of RF-3192C (1) is assigned herein for the first time using 1D/2D NMR and HRESI-MS. Additionally, the revision of the NMR assignments of orlandin (2) was reported herein as well. Investigation of the antimicrobial activities of isolated compounds revealed the high activity of RF-3192C (1) against Pseudomonas aeruginosa and Bacillus subtilis, and moderate activity against yeast. Moreover, an in vitro cytotoxic activity against liver (HEPG2), cervical (HELA), lung (A549), prostate (PC3), and breast (MCF7) cancer cell lines of the isolated compounds was evaluated. The isolation and taxonomical characterization of the producing fungus was reported as well.

Synthesis of novel feruloyl dipeptides with proapoptotic potential against different cancer cell lines.

In this study, a series of novel N-feruloyl dipeptides (10-17) have been synthesized through the coupling of N-feruloyl amino acids (6-9) with glycine/alanine methyl ester hydrochloride. Structures of the peptides were assigned using 1D and 2D NMR and HRESIMS. According to initial in vitro cytotoxic screening against the cervix carcinoma cell line KB-3-1, aromatic dipeptides (12, 13, 16, 17) were the most potent ones among all tested feruloyl dipeptides. Accordingly, these peptides were further intensively investigated as potential anticancer agents against a panel of ten cancer cell lines from different tissue origin. Based on that, compound 17 showed the strongest cytotoxic efficiency towards the whole panel of tested cell lines with IC50 values from 2.1 to 7.9 µM. By contrast, the dipeptides 12, 13 and 16 showed moderate to weak cytotoxicity (IC50 16.1-28.3 or >30, 5.7-21.9 and 3.9-21.2 or ≥30 µM, respectively). Mechanistically, compound 17 induced a strong dissipation of the mitochondrial transmembrane potential and an early activation of caspase 3/7 in the triple-negative MDA-MB-231 breast cancer cell line. In an in vivo model, compound 17 inhibited growth, proliferation and induced apoptosis in MDA-MB-231 xenografted onto the chick chorioallantoic membrane. All the synthesized compounds were also tested against a set of pathogenic bacterial strains, displaying no potential activity.

Isoshamixanthone: a new pyrano xanthone from endophytic Aspergillus sp. ASCLA and absolute configuration of epiisoshamixanthone.

Isoshamixanthone (1), a new stereoisomeric pyrano xanthone together with the previously known fungal metabolites, epiisoshamixanthone (2), sterigmatocystin (3), arugosin C (4), norlichexanthone (5), diorcinol (6), ergosterol and methyllinoleate, were obtained from the endophytic fungal strain Aspergillus sp. ASCLA isolated from leaf tissues of the medicinal plant Callistemon subulatus. The chemical structure of the new xanthone (1) was elucidated by extensive 1D, 2D NMR, and ESI HR mass measurements, and by comparison with literature data. The constitutions and absolute configurations of 1 and epiisoshamixanthone (2) were additionally confirmed by X-ray crystallography. Compounds 1,2 were evaluated for their potential anticancer activity using the human cervix carcinoma cell line (KB-3-1). The antimicrobial activities of the fungal extract and compounds 1,2 were studied using a panel of pathogenic microorganisms as well.

Terretonin O: a new meroterpenoid from Aspergillus terreus.

Terretonin O (1), a new meroterpenoid, was isolated individually from both methanolic extracts of thermophilic Aspergillus terreus TM8 and marine Aspergillus terreus LGO13. The recently reported terretonins M (2) and N (3) were further isolated from the fungus LGO13 along with nine known compounds, terrelumamide A (4), terrein (5), methyl-3,4,5-trimethoxyl-2-[2-(nicotinamide)benzamido] benzoate (6), butyrolactones I-III (7-9), aspulvinone O (10), ergosterol, ergost-4-ene-3-one and methyl linoleate. Structure of terretonin O (1) was established on the bases of HRESIMS, 1D and 2D NMR spectra and comparison with its analogues in literatures. The relative stereochemistry of 1 was assigned on the basis of NOESY spectra and comparison with reported configuration of its congener compounds 2 and 3. The antimicrobial and cytotoxic activities of the fungal extracts and obtained compounds were assayed using a set of microorganisms, and cervix carcinoma cell line (KB-3-1), respectively. Isolation and taxonomical characterization of the producing strains are reported.

Coumamarin: a first coumarinyl calcium complex isolated from nature.

The first calcium complex from nature, Coumamarin (1), 7-hydroxy-3-methoxy-2-oxo-2H-chromene-6-carboxylate Ca(II) complex, was isolated from Aspergillus sydowii ASTI, together with diorcinol (2), violaceol I (3), hydroxysydonic acid (4), cyclo (Trp-Phe), kojic acid, ergosterol, and uracil. The producing strain was isolated from marine water sample collected from Tiran Island, Red Sea, Egypt. Structure 1 was assigned by intensive 1D, 2D NMR, HR-ESIMS, and X-ray crystallography as well. Coumamarin is potentially active against certain tested bacteria and yeasts, while showing no cytotoxic activity against human cervix carcinoma cell line (KB-3-1). Taxonomically, the fungus was identified by phylogenetic analysis of its 18S rRNA gene sequence.

Diverse polyketides and alkaloids from Penicillium sp. KHMM: structural elucidation, biological and molecular docking studies.

As a continuation of our earlier research concerning the investigation of microbial bioactive secondary metabolites from the terrestrial Penicillium sp.KH Link 1809 isolate KHMM, the fungus was re-cultivated on a large scale to explore its bioactive compounds intensively. Fifteen compounds, including seven alkaloids (1-7), one sesquiterpene (8), an acetylenic system (9), two sterols, and sphengolipid, were identified. Their structures were established on the bases of extensive one- and two-dimensional nuclear magnetic resonance and mass measurements, and by comparison with literature data. The antimicrobial activity of the fungal extract and the corresponding compounds were studied using a panel of pathogenic microorganisms, and their in vitro cytotoxicity against the human cervix carcinoma cell line (KB-3-1) was reported as well. The molecular docking of the isolated compounds showed promising affinities for the alkaloidal compounds 4-6 towards α, ß tubulins.

Penicisteroid C: New polyoxygenated steroid produced by co-culturing of Streptomyces piomogenus with Aspergillus niger.

Penicisteroid C, a new polyoxygenated steroid was isolated from co-cultivation of Streptomyces piomogenus AS63D and Aspergillus niger using solid-state fermentation on rice medium. Additional diverse eleven known metabolites were identified: Fumigaclavine C, fumiquinazoline C, physcion, methylsulochrin, methyllinoleate, glycerol linoleate, cerebroside A, thymine, adenine, thymidine and adenosine. The structure of penicisteroid C was determined by HRESIMS, 1D and 2D NMR data. The antimicrobial and in vitro cytotoxic activities of the microbial extract and penicisteroid C were reported as well.

Terretonin N: A New Meroterpenoid from Nocardiopsis sp.

Terretonin N (1), a new highly oxygenated and unique tetracyclic 6-hydroxymeroterpenoid, was isolated together with seven known compounds from the ethyl acetate extract of a solid-state fermented culture of Nocardiopsis sp. Their structures were elucidated by spectroscopic analysis. The structure and absolute configuration of 1 were unambiguously determined by X-ray crystallography. The isolation and taxonomic characterization of Nocardiopsis sp. is reported. The antimicrobial activity and cytotoxicity of the strain extract and compound 1 were studied using different microorganisms and a cervix carcinoma cell line, respectively.

Ecological and Phytochemical Studies on Euphorbia retusa (Forssk.) from Egyptian Habitat.

This study deals with the ecology, phytochemistry, and biological activity investigation of Euphorbia retusa, belonging to Euphorbiaceae family, obtained from Egypt. Ecologically, Euphorbia retusa secretes white sap inhibiting the growth of the other species, so Euphorbia retusa is forming complete patches. Phytochemical study of the plant was visualized intensively based on its extraction with a protic organic solvent, working up and purifying its entire bioactive compounds using a series of different chromatographic techniques. A broad range of diverse compounds were isolated, namely, 1-hexacosanol (1), 3ß-hydroxy-24-methylene-9,19-cyclolanostane; 24-methylenecycloartanol (2), 3ß-hydroxy-9,19-cyclolanostane; cyclolaudanol (3), 3ß,24S-Ergost-5-en-ol (4), and methyllinoleate. Additionally, GC-MS analysis of the unpolar fractions detected the existence of n-dodecane, methyllaurate, 6,10,14-trimethyl-pentadecan-2-one (5), 6,10-dimethyl-undecan-2-one (6), 2-methyl-hexadecanal (7), methylpalmitate, methyl-9,12,15-octadecatrienoate (8), and n-heneicosane (9). A full assignment for compounds 2 and 3 using 1 and 2 DNMR was carried out herein for the first time. The antimicrobial activity of the strain extract and obtained compounds was studied using a panel of pathogenic bacterial strains. The in vitro cytotoxicity of the compounds as well as the crude extract was studied against the human cervix carcinoma cell line (KB-3-1).

N-Acetylborrelidin B: a new bioactive metabolite from Streptomyces mutabilis sp. MII.

In the course of our screening program for new bioactive compounds, a naturally new 18-membered macrolide antibiotic, N-acetylborrelidin B (1) along with borrelidin (2) were obtained from the marine Streptomyces mutabilis sp. MII. The strain was isolated from a sediment sample collected in the Red Sea at the Hurghada Coast and characterized taxonomically. Additional nine diverse bioactive compounds were reported: 6-prenyl-indole-3-acetonitrile (3), sitosteryl-3ß-d-glucoside, campesterol, ferulic acid, linoleic acid methyl ester, linoleic acid, N-acetylanthranilic acid, indole 3-acetic acid methyl ester, indole 3-carboxylic acid, and adenosine. Structure 1 was confirmed by in-depth NMR studies and by mass spectra, and comparison with related literature data. The antimicrobial activity of the strain extract and compounds 1 and 2 were studied using a panel of pathogenic microorganisms. The in vitro cytotoxicity of compounds 1 and 2 as well as the crude extract were tested against the human cervix carcinoma cell line (KB-3-1).