Irregularly Bridged Epipolythiodioxopiperazines and Related Analogues: Sources, Structures, and Biological Activities.

Epipolythiodioxopiperazines (ETPs) are a class of biologically active fungal secondary metabolites characterized by a bridged polysulfide piperazine ring. Regularly, the sulfide functionality is attached in the α-positions of the dioxopiperazine scaffold. However, ETPs possessing irregular sulfur bridges have rarely been explored. This review summarizes that 83 compounds of this subtype have been isolated and characterized since the discovery of gliovirin in 1982. Herein, particular emphasis is given to the isolation, chemistry, and biological activity of this subtype. For a better understanding, a relevant summary focusing on the source microorganisms and their taxonomy is provided and will help elucidate the fascinating chemistry and biology of these unusual ETPs.

Novel Antimicrobial Indolepyrazines A and B from the Marine-Associated Acinetobacter sp. ZZ1275.

Two new alkaloids indolepyrazines A (1) and B (2) were isolated from the marine-derived Acinetobacter sp. ZZ1275. Their structures were elucidated through extensive nuclear magnetic resonance (NMR) spectroscopic analyses, high resolution electrospray ionization mass spectroscopy (HRESIMS) data, and electronic circular dichroism (ECD) calculation. Indolepyrazine A represents the first example of alkaloids with an indole-pyrazine-oxindole skeleton. Both 1 and 2 showed antimicrobial activities against methicillin-resistant Staphylococcus aureus, Escherichia coli, and Candida albicans with minimum inhibitory concentration (MIC) values of 12 µg/mL, 8⁻10 µg/mL, and 12⁻14 µg/mL, respectively.

Antimicrobial potential of aqueous extract of Camellia sinensis against representative microbes.

Camellia sinensis is being used for decades for its therapeutic efficacies against physiological problems and microbial infections. This study was undertaken to investigate the antibacterial and antifungal potential of aqueous extract of Camellia sinensis. Antibacterial activity was determined by disc and well diffusion assay. MIC and MBC were calculated by broth dilution method. Miles and Misra technique was used to find out colony forming unit per/ml. All the test organisms revealed a diverse range of vulnerability against aqueous extract. Among Gram positive, MRSA showed to be the most sensitive with least MIC and MBC while among Gram-negative Pseudomonas aeruginosa exhibited the highest sensitivity. In Miles and Misra, a progressive decline in log of CFU/ml was observed. In time-kill assay, a decline was noted in the viable count of S.aureus after exposure to 18% aqueous extract of Camellia sinensis. In the present study aqueous extract of Camellia sinensis found to be effective against Gram positive, Gram negative and fungi. The most important finding of this study is its aqueous extract inhibitory effect against drug-resistant microorganisms e.g. MRSA and P. aeruginosa and Candida albicans.

Bioactive Bafilomycins and a New N-Arylpyrazinone Derivative from Marine-derived Streptomyces sp. HZP-2216E.

A MeOH extract prepared from culture of an actinomycete Streptomyces sp. HZP-2216E isolated from marine green algae Ulva pertusa was found to significantly inhibit proliferation of human glioma cells. Two different media were applied to culture this marine actinomycete, which produced two new compounds of 23-O-butyrylbafilomycin D and streptoarylpyrazinone A, together with known bafilomycin D, 9-hydroxybafilomycin D, and bafilomycin A1. Structures of new compounds were determined by extensive NMR spectroscopic analyses and HRESIMS data. Bioactive assay indicated that all isolated bafilomycins significantly inhibited the proliferation of different glioma cell lines and the growth of methicillin-resistant Staphylococcus aureus with 23-O-butyrylbafilomycin D as the most active compound. Streptoarylpyrazinone A is a new N-arylpyrazinone derivative existing as a zwitterion, and this type of compounds was rarely found from natural resources.

Bioactive Polycyclic Quinones from Marine Streptomyces sp. 182SMLY.

Chemical investigation of the cultures of marine Streptomyces sp. 182SMLY led to the discovery of two new polycyclic anthraquinones, which were elucidated as N-acetyl-N-demethylmayamycin (1) and streptoanthraquinone A (2) based on the extensive spectroscopic analysis including 2D NMR, HRESIMS, and an electronic circular dichroism (ECD) calculation. Both anthraquinones remarkably suppressed the proliferation of four different glioma cell lines with IC50 values in a range from 0.5 to 7.3 µM and induced apoptosis in the glioma cells. The ratios of IC50 for normal human astrocytes to IC50 for glioma cells were 6.4-53 for 1 and >14-31 for 2. N-acetyl-N-demethylmayamycin (1) also inhibited the growth of methicillin-resistant Staphylococcus aureus with MIC 20.0 µM.

Synthesis and bioactivity of tripolinolate A from Tripolium vulgare and its analogs.

A new coniferol derivative, named as tripolinolate A (1), and 11 known compounds (2-12) were isolated from whole plants of Tripolium vulgare Nees. The structure of this new compound was determined as 4-(2S-methylbutyryl)-9-acetyl-coniferol based on its NMR and HRESIMS spectral analyses. A simple and efficient method was designed to prepare tripolinolate A and its 19 analogs including nine new chemical entities for bioactive assay. Tripolinolate A and its analog 4,9-diacetyl-coniferol were found to be the two most active compounds that significantly inhibited the proliferation of different cancer cell lines with IC50 values ranging from 0.36 to 12.9µM and induced apoptosis in tumor cells. Structure-activity relationship analysis suggested that the molecular size of acyl moieties at C-4 and C-9 position might have an effect on the activity of this type of coniferol derivatives.

New cyclic dipeptide discovered from deep-sea derived Aspergillus sp. HDN20-1401.

A new alkaloid named aspergilalkaloid A (1) with pyridoindole hydroxymethyl piperazine dione structure along with six known compounds 2-7 were isolated from deep-sea derived fungus Aspergillus sp. HDN20-1401. The structure including absolute configuration was elucidated by extensive NMR analyses, HRESIMS, ECD calculation, and theoretical NMR calculation with DP4+ analysis. All isolated compounds were tested for antimicrobial and anticancer activity. Aspergilalkaloid A (1) showed inhibitive activity against Bacillus cereus with MIC value of 12.5 µM and weak activity against MRCNS.

Dual Role of Indoles Derived From Intestinal Microbiota on Human Health.

Endogenous indole and its derivatives (indoles), considered as promising N-substituted heterocyclic compounds, are tryptophan metabolites derived from intestinal microbiota and exhibit a range of biological activities. Recent studies indicate that indoles contribute to maintaining the biological barrier of the human intestine, which exert the anti-inflammatory activities mainly through activating AhR and PXR receptors to affect the immune system's function, significantly improving intestinal health (inflammatory bowel disease, hemorrhagic colitis, colorectal cancer) and further promote human health (diabetes mellitus, central system inflammation, and vascular regulation). However, the revealed toxic influences cannot be ignored. Indoxyl sulfate, an indole derivative, performs nephrotoxicity and cardiovascular toxicity. We addressed the interaction between indoles and intestinal microbiota and the indoles' effects on human health as double-edged swords. This review provides scientific bases for the correlation of indoles with diseases moreover highlights several directions for subsequent indoles-related studies.

Antiglioma pseurotin A from marine Bacillus sp. FS8D regulating tumour metabolic enzymes.

Pseurotin A was isolated from a culture of marine Bacillus sp. FS8D and showed to be active against the proliferation of four different glioma cells with IC50 values of 0.51-29.3 µM. It has been found that pseurotin A downregulated the expression of tumour glycolytic enzymes pyruvate kinase M2 (PKM2) and lactate dehydrogenase 5 (LDH5) and upregulated the expression of pyruvate dehydrogenase beta (PDHB), adenosine triphosphate synthase beta (ATPB) and cytochrome C (Cyto-C), the important regulators for tricarboxylic acid cycle and oxidative phosphorylation. The data suggested that targeting multiple metabolic enzymes might be one of the antiglioma mechanisms of pseurotin A.

Emerging biopharmaceuticals from bioactive peptides derived from marine organisms.

Biologically active natural products are spontaneous medicinal entrants, which encourage synthetic access for enhancing and supporting drug discovery and development. Marine bioactive peptides are considered as a rich source of natural products that may provide long-term health, in addition to many prophylactic and curative medicinal drug treatments. The large literature concerning marine peptides has been collected, which shows high potential of nutraceutical and therapeutic efficacy encompassing wide spectra of bioactivities against a number of infection-causing agents. Their antimicrobial, antimalarial, antitumor, antiviral, and cardioprotective actions have achieved the attention of the pharmaceutical industry toward new design of drug formulations, for treatment and prevention of several infections. However, the mechanism of action of many peptide molecules has been still untapped. So in this regard, this paper reviews several peptide compounds by which they interfere with human pathogenesis. This knowledge is one of the key tools to be understood especially for the biotransformation of biomolecules into targeted medicines. The fact that different diseases have the capability to fight at different sites inside the body can lead to a new wave of increasing the chances to produce targeted medicines.

New streptophenazines from marine Streptomyces sp. 182SMLY.

Six phenazines including three new ones were isolated from the culture of a marine actinomycete Streptomyces sp. 182SMLY. Based on the analyses of NMR, HRESIMS, optical rotation value, and CD data, the structures of these isolated compounds were determined as new phenazines of (-)-streptophenazines M-O and known phenazines of 1-carbomethoxyphenazine and (-)-streptophenazines A and B. (-)-Streptophenazine B showed activity in suppressing the growth of methicillin-resistant Staphylococcus aureus with MIC value of 4.2 µg/mL.

Antiproliferative cyclodepsipeptides from the marine actinomycete Streptomyces sp. P11-23B downregulating the tumor metabolic enzymes of glycolysis, glutaminolysis, and lipogenesis.

Two cyclodepsipeptides and a known cyclodepsipeptide valinomycin were isolated from a culture of the marine actinomycete Streptomyces sp. P11-23B. Their structures were established based on NMR, HRESIMS, and MS-MS spectroscopic interpretation as well as by chemical degradation. Both streptodepsipeptides P11A and P11B inhibited proliferation of different glioma cell lines, with IC50 values ranging from 0.1 µM to 1.4 µM. Streptodepsipeptide P11A was found to block the cell cycle at the G0/G1 phase and induce apoptosis in glioma cells. Further investigation demonstrated that streptodepsipeptide P11A downregulated expression of HK2, PFKFB3, PKM2, GLS, and FASN, important tumor metabolic enzymes. Data from this study suggested that targeting multiple tumor metabolic regulators might be one anti-glioma mechanism of streptodepsipeptide P11A. A possible mechanism for this class of streptodepsipeptides is reported herein.

Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review.

Glioblastoma multiforme (GBM) is the deadliest form of heterogeneous brain cancer. It affects an enormous number of patients every year and the survival is approximately 8 to 15 months. GBM has driven by complex signaling pathways and considered as a most challenging to treat. Standard treatment of GBM includes surgery, radiation therapy, chemotherapy and also the combined treatment. This review article described inter and intra- tumor heterogeneity of GMB. In addition, recent chemotherapeutic agents, with their mechanism of action have been defined. FDA-approved drugs also been focused over here and most importantly highlighting some natural and synthetic and novel anti- glioma agents, that are the main focus of researchers nowadays.

Emerging biopharmaceuticals from marine actinobacteria.

Actinobacteria are quotidian microorganisms in the marine world, playing a crucial ecological role in the recycling of refractory biomaterials and producing novel secondary metabolites with pharmaceutical applications. Actinobacteria have been isolated from the huge area of marine organisms including sponges, tunicates, corals, mollusks, crabs, mangroves and seaweeds. Natural products investigation of the marine actinobacteria revealed that they can synthesize numerous natural products including alkaloids, polyketides, peptides, isoprenoids, phenazines, sterols, and others. These natural products have a potential to provide future drugs against crucial diseases like cancer, HIV, microbial and protozoal infections and severe inflammations. Therefore, marine actinobacteria portray as a pivotal resource for marine drugs. It is an upcoming field of research to probe a novel and pharmaceutically important secondary metabolites from marine actinobacteria. In this review, we attempt to summarize the present knowledge on the diversity, chemistry and mechanism of action of marine actinobacteria-derived secondary metabolites from 2007 to 2016.

A new curvularin glycoside and its cytotoxic and antibacterial analogues from marine actinomycete Pseudonocardia sp. HS7.

Five curvularin macrolides (1-5) were isolated from the cultured broth of marine actinomycete Pseudonocardia sp. HS7 that was obtained from the cloacal aperture of sea cucumber Holothuria moebii. The structures of these isolates were characterized as (11S,15R)-11-hydroxycurvularin (1), (11R,15R)-11-hydroxycurvularin (2), curvularin-7-O-α-D-glucopyranoside (3), trans-dehydrocurvularin (4) and curvularin (5) based on their NMR and HRESIMS data as well as chemical degradation. Compound 3 is a new macrolide with a rare α-D-glucopyranose substituent. Compounds 1-4, 5a and 5c (the acyl products of 5), suppressed the proliferation of all six tested cancer cell lines and 4 is the most active compound with IC50 values ranging from 0.59 to 3.39 µM. The 11-hydroxycurvularins 1 and 2 also showed antibacterial activity inhibiting the growth of Escherichia coli.

Marine Sponges as a Drug Treasure.

Marine sponges have been considered as a drug treasure house with respect to great potential regarding their secondary metabolites. Most of the studies have been conducted on sponge's derived compounds to examine its pharmacological properties. Such compounds proved to have antibacterial, antiviral, antifungal, antimalarial, antitumor, immunosuppressive, and cardiovascular activity. Although, the mode of action of many compounds by which they interfere with human pathogenesis have not been clear till now, in this review not only the capability of the medicinal substances have been examined in vitro and in vivo against serious pathogenic microbes but, the mode of actions of medicinal compounds were explained with diagrammatic illustrations. This knowledge is one of the basic components to be known especially for transforming medicinal molecules to medicines. Sponges produce a different kind of chemical substances with numerous carbon skeletons, which have been found to be the main component interfering with human pathogenesis at different sites. The fact that different diseases have the capability to fight at different sites inside the body can increase the chances to produce targeted medicines.

Erratum to "Marine Sponges as a Drug Treasure" [Biomol.Ther. 24 (2016) 347-362].

The authors request to correct the title of Table 3 from 'Example of antiviral Compounds' to 'Example of Antifungal compounds.'