Natural Products Chemistry Breaking News

Chikungunya virus (CHIKV) has been spreading rapidly, with over one million confirmed or suspected cases in the Americas since late 2013. Infection with CHIKV causes devastating arthritic and arthralgic symptoms. Currently, there is no therapy to treat this disease, and the only medications focus on relief of symptoms. Recently, protein kinase C (PKC) modulators have been reported to inhibit CHIKV-induced cell death in cell assays. The salicylate-derived bryostatin analogues described here are structurally simplified PKC modulators that are more synthetically accessible than the natural product bryostatin 1, a PKC modulator and clinical lead for the treatment of cancer, Alzheimer’s disease, and HIV eradication. Evaluation of the anti-CHIKV activity of these salicylate-derived bryostatin analogues in cell culture indicates that they are among the most potent cell-protective agents reported to date. Given that they are more accessible and significantly more active than the parent natural product, they represent new therapeutic leads for controlling CHIKV infection. Significantly, these analogues also provide evidence for the involvement of a PKC-independent pathway. This adds a fundamentally distinct aspect to the importance or involvement of PKC modulation in inhibition of chikungunya virus replication, a topic of recent and growing interest.

A classic withanolide is defined as a highly oxygenated C28 ergostane-type steroid that is characterized by a C22-hydroxy-C26-oic acid δ-lactone in the nine-carbon side chain. Analysis of the reported 13C NMR data of classic withanolides with hydroxy groups (C-14, C-17, and C-20) revealed that (1) a hydroxy (C-14 or C-17) substituent significantly alters the chemical shifts (C-7, C-9, C-12, and C-21) via the γ-gauche effect; (2) the chemical shift values (C-9, C-12, and C-21) reflect the orientation (α or β) of the hydroxy moiety (C-14 or C-17); (3) a double-bond positional change in ring A (Δ2 to Δ3), or hydroxylation (C-27), results in a minuscule effect on the chemical shifts of carbons in rings C and D (from C-12 to C-18); and (4) the 13C NMR γ-gauche effect method is more convenient and reliable than the traditional approach (1H NMR shift comparisons in C5D5N versus CDCl3) to probe the orientation of the hydroxy substituent (C-14 and C-17). Utilization of these rules demonstrated that the reported 13C NMR data of withanolides 1a–29a were inconsistent with their published structures, which were subsequently revised as 1–16 and 12 and 18–29, respectively. When combined, this strongly supports the application of these methods to determine the relative configuration of steroidal substituents.

« In natural product research, the isolation of biomarkers or bioactive compounds from complex natural extracts represents an essential step for de novo identification and bioactivity assessment. When pure natural products have to be obtained in milligram quantities, the chromatographic steps are generally labourious and time-consuming. In this respect, an efficient method has been developed for the reversed-phase gradient transfer from high-performance liquid chromatography to medium-performance liquid chromatography for the isolation of pure natural products at the level of tens of milligrams from complex crude natural extracts. The proposed method provides a rational way to predict retention behaviour and resolution at the analytical scale prior to medium-performance liquid chromatography, and guarantees similar performances at both analytical and preparative scales. The optimisation of the high-performance liquid chromatography separation and system characterisation allows for the prediction of the gradient at the medium-performance liquid chromatography scale by using identical stationary phase chemistries. The samples were introduced in medium-performance liquid chromatography using a pressure-resistant aluminium dry load cell especially designed for this study to allow high sample loading while maintaining a maximum achievable flow rate for the separation. The method has been validated with a mixture of eight natural product standards. Ultraviolet and evaporative light scattering detections were used in parallel for a comprehensive monitoring. In addition, post-chromatographic mass spectrometry detection was provided by high-throughput ultrahigh-performance liquid chromatography time-of-flight mass spectrometry analyses of all fractions. The processing of all liquid chromatography-mass spectrometry data in the form of an medium-performance liquid chromatography x ultra high-performance liquid chromatography time-of-flight mass spectrometry matrix enabled an efficient localisation of the compounds of interest in the generated fractions. The methodology was successfully applied for the separation of three different plant extracts that contain many diverse secondary metabolites. The advantages and limitations of this approach and the theoretical chromatographic background that rules such as liquid chromatography gradient transfer are presented from a practical viewpoint. »

The physiology and ecology of complex microbial communities are strongly dependent on the immediate surroundings of each microbe, including the identity of neighboring microbes; however, information on the micron-scale organization of microbiomes is largely lacking. Using sequencing data combined with spectral fluorescence imaging, we have discovered a multigenus, highly organized microbial consortium in human dental plaque. The spatial structure of the consortium reveals unanticipated interactions and provides a framework for understanding the organization, metabolism, and systems biology of the microbiome and ultimately, its effect on the health of the human host. Our synthesis of high-throughput sequencing data with spatial and structural information shows the informative value of microbial biogeography at the micron scale.

1. Jessica L. Mark Welcha,b,1,
2. Blair J. Rossettia,b,
3. Christopher W. Riekenb,
4. Floyd E. Dewhirsta,c, and
5. Gary G. Borisya,b,1

PNAS,  E791–E800, doi: 10.1073/pnas.1522149113

Two bioactive merocytochalasans, epicochalasines A (1) and B (2), a new class of cytochalasans bearing unexpected scaffolds consisting of fused aspochalasin and epicoccine dimer moieties, were isolated from the liquid culture broth of Aspergillus flavipes. Both 1 and 2 possess a hendecacyclic 5/6/11/5/6/5/6/5/6/6/5 ring system containing an adamantyl cage and as many as 19 stereogenic centers; however, the fusion patterns of 1 and 2 differ greatly, thus resulting in different carbon skeletons. The absolute configurations of 1 and 2 were determined by X-ray diffraction and calculated ECD, respectively. The biogenetic pathways of 1 and 2 are proposed to involve Diels–Alder and nucleophilic addition reactions. Both 1 and 2 induced significant G2/M-phase cell-cycle arrest. Furthermore, we found that merocytochalasans induce apoptosis in leukemia cells through the activation of caspase-3 and the degradation of PARP.

Chemical investigation of a dichloromethane extract of the aerial parts of Waltheria indica led to the isolation and characterization of five polyhydroxymethoxyflavonoids, namely, oxyanin A (1), vitexicarpin (3), chrysosplenol E (4), flindulatin (5), 5-hydroxy-3,7,4′-trimethoxyflavone (6), and six quinolone alkaloids, waltheriones M–Q (2, 7, 8, 10, 11) and 5(R)-vanessine (9). Among these, compounds 2, 7, 8, 10, and 11 have not yet been described in the literature. Their chemical structures were established by means of spectroscopic data interpretation including 1H and 13C, HSQC, HMBC, COSY, and NOESY NMR experiments and UV, IR, and HRESIMS. The absolute configurations of the compounds were established by ECD. The isolated constituents and 10 additional quinoline alkaloids previously isolated from the roots of the plant were evaluated for their in vitro antifungal activity against the human fungal pathogen Candida albicans, and 10 compounds (7, 9, 11–16, 18, 21) showed growth inhibitory activity on both planktonic cells and biofilms (MIC ≤ 32 μg/mL). Their spectrum of activity against other pathogenic Candida species and their cytotoxicity against human HeLa cells were also determined. In addition, the cytological effect of the antifungal isolated compounds on the ultrastructure of C. albicans was evaluated by transmission electron microscopy.

Covering: 2014. Previous review: Nat. Prod. Rep., 2015, 32, 116–211

This review covers the literature published in 2014 for marine natural products (MNPs), with 1116 citations (753 for the period January to December 2014) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1378 in 456 papers for 2014), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

DOI: 10.1039/C5NP00156K

Four limonoids, cipacinoids A–D (1–4), with spirocyclic skeletons were isolated from Cipadessa cinerascens. It is particularly notable that compounds 1–3 had a 17S-configuration for the first time in the limonoid family. Their structures with absolute configurations were assigned by spectroscopic data, X-ray crystallography, and CD analysis. Compound 1 showed moderate protein tyrosine phosphatase 1B (PTP1B) inhibition.

Marine and terrestrial organisms yield a remarkable chemical diversity and are important sources for discovery of new chemical products. In order to maximize the bioprospecting efficiency of natural products (NP), taxonomy, geography and biodiversity are starting to be used to draw conclusions on which taxonomic groups and/or regions may be of interest for future research. However, accurate taxonomic information and sampling location of source organisms have often been overlooked. Although these issues were already reported a few decades ago and improvements have been made, such outstanding problems are still recurrent in recent peer-reviewed literature. Here, we focus on the importance of taxonomic and geographic identification of source material and illustrate how taxonomic and geographic data of source organisms continues to be poorly handled. It is our opinion that this issue needs to be discussed within the NP community with the ultimate goal of improving publication standards and guaranteeing the scientific principle of research reproducibility. Moreover, by doing so, it will be possible to take advantage of information available in the literature to develop cross-disciplinary meta-analyses that may help to advance the state of the art of NP research and future bioprospecting endeavours.

DOI: 10.1039/C5NP00130G

A chemical investigation of the tropical sponge Agelas sceptrum from Plana Cays (Bahamas) led to the isolation of two hybrid pyrrole–imidazole alkaloids (PIAs), 15′-oxoadenosceptrin (1) and decarboxyagelamadin C (2). Herein, we report their challenging structure elucidation established by NMR and ECD spectroscopy. 15′-Oxoadenosceptrin (1) shows sceptrin merged with an adenine moiety, not yet encountered in the PIA family, whereas decarboxyagelamadin C (2) is a close derivative of agelamadins C to E recently isolated from an Agelas sp. from Okinawa

J. Nat. Prod., Article ASAP

This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a “natural product mimic”, or “NM”, to join the original primary divisions and the designation “natural product botanical”, or “NB”, to cover those botanical “defined mixtures” now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from around the 1940s to the end of 2014, of the 175 small molecules approved, 131, or 75%, are other than “S” (synthetic), with 85, or 49%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the “host from whence it was isolated”, and therefore it is considered that this area of natural product research should be expanded significantly.

We have deployed an efficient secondary electrospray ionization source coupled to an Orbitrap mass analyzer (SESI-MS) to investigate the emissions of a Begonia semperflorens. We document how hundreds of species can be tracked with an unparalleled time resolution of 2 min during day–night cycles. To further illustrate the capabilities of this system for volatile organic compounds (VOCs) analysis, we subjected the plant to mechanical damage and monitored its response. As a result, ∼1200 VOCs were monitored displaying different kinetics. To validate the soundness of our in vivo measurements, we fully characterized some key compounds via tandem mass spectrometry (MS/MS) and confirmed their expected behavior based on prior gas chromatography/mass spectrometry (GC/MS) studies. For example, β-caryophyllene, which is directly related to photosynthesis, was found to show a periodic day–night pattern with highest concentrations during the day. We conclude that the capability of SESI-MS to capture highly dynamic VOC emissions and wide analyte coverage makes it an attractive tool to complement GC/MS in plant studies.