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Methicillin-resistant S aureus (MRSA) contributes to patient mortality and extended hospital stays. 3-O-alpha-L-(2″,3″-di-p-coumaroyl)rhamnoside (KCR) is a natural product antibiotic that is effective against MRSA but has no known mechanism of action (MOA). We used proteomics to identify the MOA for KCR. Methicillin sensitive S aureus and a mixture of four KCR stereoisomers were tested. A time-kill assay was used to choose a 4 h treatment using KCR at 5× its MIC for proteomic analysis. S aureus was treated in triplicate with KCR, oxacillin or vehicle and quantitative proteomic analysis was carried out using isobaric tags and mass spectrometry. 1190 proteins were identified and 552 were affected by KCR (q 0.01). Ontology analysis identified 6 distinct translation-related categories that were affected by KCR (PIANO, 10% false-discovery rate) including structural constituent of ribosome, translation, rRNA binding, tRNA binding, tRNA processing and aminoacyl-tRNA ligase activity. Median fold changes (KCR vs Control) for small and large ribosomal components were 1.46 and 1.43 respectively. KCR inhibited the production of luciferase protein in an in vitro assay (IC50 39.6 μg/ml). Upregulation of translation-related proteins in response to KCR indicates that KCR acts to disrupt S aureus protein synthesis. This was confirmed with an in vitro transcription/translation assay. SIGNIFICANCE: Methicillin-resistant S aureus (MRSA) contributes to patient mortality and extended hospital stays. 3-O-alpha-L-(2″,3″-di-p-coumaroyl)rhamnoside (KCR) is a natural product antibiotic that is effective against MRSA but has no known mechanism of action (MOA). Using proteomic analysis we determined that KCR acts by inhibiting protein synthesis. KCR is an exciting novel antibiotic and this work represents an important step in its development towards clinical use.

Recent changes in our planetary climate have and will continue to challenge historical knowledge and risk assumptions for weather-related disasters. While the public health community is rapidly working to develop epidemiological approaches and tools to mitigate and adapt to these weather-related disasters, recent high-profile events have exposed gaps in knowledge and response efforts. Limited work has been done to assess the climate readiness of the local public health and healthcare community as it pertains to local response planning and adaptation measures in the event of a weather-related disaster. The purpose of this paper is to review the existing literature related to climate change, weather-related disasters, and population health approaches to adapt to climate-related changes in weather-related disasters at the local level. We highlight a brief case study to illustrate an example of a local approach to adaptation planning in a coastal community. Few studies have put forth quantitative disaster epidemiology tools to aid public health officials in preparing for and responding to these weather-related disaster events. There is a general lack of understanding within the public health community about the epidemiological tools which are available to assist local communities in their preparation for, response to, and recovery from weather-related disasters. Cities around the nation are already working to assess their vulnerability and resilience to weather-related disasters by including climate change in emergency preparedness plans and developing adaptation strategies, as well as equipping local hospitals, health departments and other critical public health systems with climate information. But more work is needed and public health funding is lagging to support local and state-level efforts in preparing for and adapting to weather-related disasters in the context of a changing climate. Our population health disaster preparedness programs need to be adapted to address the increasing risks to local public health resulting from our changing climate.

The Wnt/&beta, catenin signaling pathway is known to play critical roles in a wide range of cellular processes: cell proliferation, differentiation, migration and embryonic development. Importantly, dysregulation of this pathway is tightly associated with pathogenesis in most human cancers. Therefore, the Wnt/&beta, catenin pathway has emerged as a promising target in anticancer drug screening programs. In the present study, we have isolated three previously unreported metabolites from an undescribed sponge, a species of Monanchora (Order Poecilosclerida, Family Crambidae), closely related to the northeastern Pacific species Monanchora pulchra, collected from deep waters off the Aleutian Islands of Alaska. Through an assortment of NMR, MS, ECD, computational chemical shifts calculation, and DP4, chemical structures of these metabolites have been characterized as spirocyclic ring-containing sesterterpenoid (1) and cholestane-type steroidal analogues (2 and 3). These compounds exhibited the inhibition of &beta, catenin response transcription (CRT) through the promotion of &beta, catenin degradation, which was in part implicated in the antiproliferative activity against two CRT-positive colon cancer cell lines.

Three new diastereomers of polyketides (PKs), raistrickiones A−C (1–3), together with two new analogues, raistrickiones D and E (4 and 5), were isolated from a highly productive strain of Penicillium raistrickii, which was subjected to an experimental thermo-change strategy to tap its potential of producing new secondary metabolites. Metabolites 1 and 2 existed in a diastereomeric mixture in the crystal packing according to the X-ray data, and were laboriously separated by semi-preparative HPLC on a chiral column. The structures of 1–5 were determined on the basis of the detailed analyses of the spectroscopic data (UV, IR, HRESIMS, 1D, and 2D NMR), single-crystal X-ray diffractions, and comparison of the experimental and calculated electronic circular dichroism spectra. Compounds 1–5 represented the first case of 3,5-dihydroxy-4-methylbenzoyl derivatives of natural products. Compounds 1–5 exhibited moderate radical scavenging activities against 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH).

The leaves of Morus alba L. are an important herbal medicine in Asia. The systematic isolation of the metabolites of the leaves of Morus alba L. was achieved using a combination of liquid chromatography techniques. The structures were elucidated by spectroscopic data analysis and the absolute configuration was determined based on electronic circular dichroism (ECD) spectroscopic data and hydrolysis experiments. Their biological activity was evaluated using different biological assays, such as the assessment of their capacity to inhibit the aldose reductase enzyme; the determination of their cytotoxic activity and the evaluation of their neuroprotective effects against the deprivation of serum or against the presence of nicouline. Chemical investigation of the leaves of Morus alba L. resulted in four new structures 1–4 and a known molecule 5. Compounds 2 and 5 inhibited aldose reductase with IC50 values of 4.33 μM and 6.0 μM compared with the potent AR inhibitor epalrestat (IC50 1.88 × 10−3 μM). Pretreatment with compound 3 decreased PC12 cell apoptosis subsequent serum deprivation condition and pretreatment with compound 5 decreased nicouline-induced PC12 cell apoptosis as compared with control cells (p < 0.001).

After publication of karlotoxin 2 (KmTx2; 1), the harmful algal bloom dinoflagellate Karlodinium sp. was collected and scrutinized to identify additional biologically active complex polyketides. The structure of 1 was validated and revised at C49 using computational NMR tools including J-based configurational analysis and chemical-shift calculations. The characterization of two new compounds [KmTx8 (2) and KmTx9 (3)] was achieved through overlaid 2D HSQC NMR techniques, while the relative configurations were determined by comparison to 1 and computational chemical-shift calculations. The detailed evaluation of 2 using the NCI-60 cell lines, NMR binding studies, and an assessment of the literature supports a mode of action (MoA) for targeting cancer-cell membranes, especially of cytostatic tumors. This MoA is uniquely different from that of current agents employed in the control of cancers for which 2 shows sensitivity.

Mammals have complex biological systems and are constantly prone to infections by a wide array of bacteria, fungi, viruses, and parasites, a significant challenge to the constant development of disease-strains resistance to current drugs.1 As a result, there is always a need to identify new anti-infective agents against these organisms. An anti-infective agent is defined by Webster as “an agent capable of acting against an infection, by inhibiting the spread of an infectious agent or by killing the infectious agent outright”.2 Some of the emerging and drug-resistant infectious diseases having research priority are human immunodeficiency virus (HIV) or AIDS, hepatitis B and C viruses, respiratory infections such as influenza and respiratory syncytial virus (RSV), and dengue fever.1 Figures 1 and ​and22 provide us with the data in regards to the mortality and incidence rates, respectively, of people with viral diseases.3–5 Figure 1 Mortality versus viral diseases.3–5 Figure 2 Incidence rates versus viral diseases.3–5 Search engines utilized to identify the literature reviewed here include Google scholar, Scifinder, Pubmed, government documents from the CDC, NIH, and the World Health Organization (WHO), academic journals, and books.

Colorectal cancer has emerged as a major cause of death in Western countries. Down-regulation of β-catenin expression has been considered a promising approach for cytotoxic drug formulation. Eight 4,9-friedodrimane-type sesquiterpenoids (1-8) were acquired using the oxidative potential of Verongula rigida on bioactive metabolites from two Smenospongia sponges. Compounds 3 and 4 contain a 2,2-dimethylbenzo[d]oxazol-6(2H)-one moiety as their substituted heterocyclic residues, which is unprecedented in such types of meroterpenoids. Gauge-invariant atomic orbital NMR chemical shift calculations were employed to investigate stereochemical details with support of the application of advanced statistics such as CP3 and DP4. Compounds 2 and 8 and the mixture of 3 and 4 suppressed β-catenin response transcription (CRT) via degrading β-catenin and exhibited cytotoxic activity on colon cancer cells, implying that their anti-CRT potential is, at least in part, one of their underlying antineoplastic mechanisms.

Metabolomics is a well-established rapidly developing research field involving quantitative and qualitative metabolite assessment within biological systems. Recent improvements in metabolomics technologies reveal the unequivocal value of metabolomics tools in natural products discovery, gene-function analysis, systems biology and diagnostic platforms.We review here some of the prominent metabolomics methodologies employed in data acquisition and analysis of natural products and disease-related biomarkers.This review demonstrates that metabolomics represents a highly adaptable technology with diverse applications ranging from environmental toxicology to disease diagnosis. Metabolomic analysis is shown to provide a unique snapshot of the functional genetic status of an organism by examining its biochemical profile, with relevance toward resolving phylogenetic associations involving horizontal gene transfer and distinguishing subgroups of genera possessing high genetic homology, as well as an increasing role in both elucidating biosynthetic transformations of natural products and detecting preclinical biomarkers of numerous disease states.This review expands the interest in multiplatform combinatorial metabolomic analysis. The applications reviewed range from phylogenetic assignment, biosynthetic transformations of natural products, and the detection of preclinical biomarkers.

Five new norditerpene endoperoxides, named diacarperoxides H–L (1–5), and a new norditerpene diol, called diacardiol B (6), were isolated from the South China Sea sponge, Diacarnus megaspinorhabdosa. Their structures, including conformations and absolute configurations, were determined by using spectroscopic analyses, computational approaches and chemical degradation. Diacarperoxides H–J (1–3) showed some interesting stereochemical issues, as well as antimalarial activity.

Known linear knottins are unsuitable as scaffolds for oral peptide drug due to their gastrointestinal instability. Herein, a new subclass of knottin peptides from Porifera is structurally described and characterized regarding their potential for oral peptide drug development.Asteropsins B-D (ASPB, ASPC, and ASPD) were isolated from the marine sponge Asteropus sp. The tertiary structures of ASPB and ASPC were determined by solution NMR spectroscopy and that of ASPD by homology modeling.The isolated asteropsins B-D, together with the previously reported asteropsin A (ASPA), compose a new subclass of knottins that share a highly conserved structural framework and remarkable stability against the enzymes in gastrointestinal tract (chymotrypsin, elastase, pepsin, and trypsin) and human plasma.Asteropsins can be considered as promising peptide scaffolds for oral bioavailability.The structural details of asteropsins provide essential information for the engineering of orally bioavailable peptides.

Highly oxygenated nortriterpenoids are the principle bioactive chemical constituents isolated from plants of the genera Schisandra and Kadsura. The stereochemistry of these molecules remains a highly challenging problem to solve. To establish the stereochemistry and develop a general nuclear magnetic resonance-electric circular dichroism-computational approach to solve these complex metabolites, we reviewed the published methods to solve the stereochemistry of these triterpenoids. A key goal of this review is to provide a protocol to solve the problems hampering the assignment of the relative absolute configurations of other members of this natural product class.

Significance In this report we describe a group of highly complex glycosides active against hepatitis C virus and a separate group of natural products active against established targets for the control of diabetes mellitus. These complex metabolites were found in the rare plant Diplostephium rhododendroides Hieron. from the mountains of Ecuador. This report illustrates the human health significance of protecting rare and endangered plants for the control of new and emerging diseases. The extinction of this particular plant would have taken with it promising opportunities to develop unique treatments for the control of two modern-day disease challenges. The genus Diplostephium is represented by several plant species with a history of use in traditional medicine in Central and South America.

Endangered plant species are an important resource for new chemistry. Lindera melissifolia is native to the Southeastern U.S. and scarcely populates the edges of lakes and ponds. Quantum mechanics (QM) used in combination with NMR/ECD is a powerful tool for the assignment of absolute configuration in lieu of X-ray crystallography.The EtOAc extract of L. melissifolia was subject to chromatographic analysis by VLC and HPLC. Spin-spin coupling constant (SSCC) were calculated using DFT at the MPW1PW91/6-31G(d,p) level for all staggered rotamers. ECD calculations employed Amber* force fields followed by PM6 semi-empirical optimizations. Hetero- and homo-nuclear coupling constants were extracted from 1D (1)H, E.COSY and HETLOC experiments.Two meroterpenoids, melissifolianes A (1) and B (2) were purified and their 2-D structures elucidated using NMR and HRESIMS. The relative configuration of 1 was established using the combination of NOE-based distance restraints and the comparisons of experimental and calculated SSCCs. The comparison of calculated and experimental ECD assigned the absolute configuration of 1. The relative configuration of a racemic mixture, melissifoliane B (2) was established utilizing J-based analysis combined with QM and NMR techniques.Conclusion Our study of the Lindera melissifolia metabolome exemplifies how new chemistry remains undiscovered among the numerous endangered plant species and demonstrates how analysis by ECD and NMR combined with various QM calculations is a sensible approach to support the stereochemical assignment of molecules with conformationally restricted conformations.QM-NMR/ECD combined approaches are of utility for unambiguous assignment of 3-D structures, especially with limited plant material and when a molecule is conformationally restricted. Conservation of an endangered plant species can be supported through identification of its new chemistry and utilization of that chemistry for commercial purposes.

Marine microbes are capable of producing secondary metabolites for defense and competition. Factors exerting an impact on secondary metabolite production of microbial communities included bioactive natural products and co-culturing. These external influences may have practical applications such as increased yields or the generation of new metabolites from otherwise silent genes in addition to reducing or limiting the production of undesirable metabolites. In this paper, we discuss the metabolic profiles of a marine Pseudomonas aeruginosa in the presence of a number of potential chemical epigenetic regulators, adjusting carbon sources and co-culturing with other microbes to induce a competitive response. As a result of these stressors certain groups of antibiotics or antimalarial agents were increased most notably when treating P. aeruginosa with sceptrin and co-culturing with another Pseudomonas sp. An interesting cross-talking event between these two Pseudomonas species when cultured together and exposed to sceptrin was observed.

A new pyrroloiminoquinone alkaloid, named atkamine, with an unusual scaffold was discovered from a cold, deep water Alaskan sponge Latrunculia sp. collected from the Aleutian Islands. Olefin metathesis was utilized to determine the location of the double bond in the hydrocarbon chain. The absolute configuration was determined by using computational approaches combing with the ECD (electronic circular dichroism) spectroscopy.

Herein we report the discovery of a cystine-crosslinked peptide from Porifera along with high-quality spatial details accompanied by the description of its unique effect on neuronal calcium influx.Asteropsin A (ASPA) was isolated from the marine sponge Asteropus sp., and its structure was independently determined using X-ray crystallography (0.87 angstroms) and solution NMR spectroscopy.An N-terminal pyroglutamate modification, uncommon cis proline conformations, and absence of basic residues helped distinguish ASPA from other cystine-crosslinked knot peptides. ASPA enhanced Ca2+ influx in murine cerebrocortical neuron cells following the addition of the Na+ channel activator veratridine but did not modify the oscillation frequency or amplitude of neuronal Ca2+ currents alone. Allosterism at neurotoxin site 2 was not observed, suggesting an alternative to the known Na+ channel interaction.Together with a distinct biological activity, the origin of ASPA suggests a new subclass of cystine-rich knot peptides associated with Porifera.The discovery of ASPA represents a distinctive addition to an emerging subclass of cystine-crosslinked knot peptides from Porifera.

Two new phloroglucinols, named eucalyptals D (1) and E (2), along with a related known compound (euglobal-In-3, 3) were isolated from the fruits of Eucalyptus globulus. Their structures were established on the basis of extensive spectroscopic studies, revealing that they share a common 3,5-diformyl-isopentyl phloroglucinol unit, but each is instead coupled to a different sesquiterpenoid skeleton (aromadendrene in 1, cadinene in 2, and a spirosesquiterpene in 3). Compound 1 possessed an unusual seven-membered D ring with an ether bridge between C-2 of the aromadendrene moiety and C-2′ of the aromatic unit. The absolute configuration of the isolates was defined by the comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1–3 exhibited significant in vitro cytotoxicities against a few human cancer cell lines (Huh-7, Jurkat, BGC-823, and KE-97) using the CellTiter-Glo™ luminescent cell viability assay method.

In order to expand the repertoire of antifungal compounds a novel, high-throughput phenotypic drug screen targeting fungal phosphatidylserine (PS) synthase (Cho1p) was developed based on antagonism of the toxin papuamide A (Pap-A). Pap-A is a cyclic depsipeptide that binds to PS in the membrane of wild-type Candida albicans, and permeabilizes its plasma membrane, ultimately causing cell death. Organisms with a homozygous deletion of the CHO1 gene (cho1ΔΔ) do not produce PS and are able to survive in the presence of Pap-A. Using this phenotype (i.e. resistance to Pap-A) as an indicator of Cho1p inhibition, we screened over 5,600 small molecules for Pap-A resistance and identified SB-224289 as a positive hit. SB-224289, previously reported as a selective human 5-HT1B receptor antagonist, also confers resistance to the similar toxin theopapuamide (TPap-A), but not to other cytotoxic depsipeptides tested. Structurally similar molecules and truncated variants of SB-224289 do not confer resistance to Pap-A, suggesting that the toxin-blocking ability of SB-224289 is very specific. Further biochemical characterization revealed that SB-224289 does not inhibit Cho1p, indicating that Pap-A resistance is conferred by another undetermined mechanism. Although the mode of resistance is unclear, interaction between SB-224289 and Pap-A or TPap-A suggests this screening assay could be adapted for discovering other compounds which could antagonize the effects of other environmentally- or medically-relevant depsipeptide toxins.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptors superfamily and are transcription factors activated by specific ligands. Liver X receptors (LXR) belong to the nuclear hormone receptors and have been shown to play an important role in cholesterol homeostasis. From the previous screening of several medicinal plants for potential partial PPARγ agonists, the extracts of Cornus alternifolia were found to exhibit promising bioactivity. In this paper, we report the isolation and structural elucidation of four new compounds and their potential as ligands for PPAR.The new compounds were extracted from the leaves of C. alternifolia and fractionated by high-performance liquid chromatography. Their structures were elucidated on the basis of spectroscopic evidence and analysis of their hydrolysis products.Three new iridoid glycosides including an iridolactone, alternosides A-C (1-3), a new megastigmane glycoside, cornalternoside (4) and 10 known compounds, were obtained from the leaves of C. alternifolia. Kaempferol-3-O-β-glucopyranoside (5) exhibited potent agonistic activities for PPARα, PPARγ and LXR with EC50 values of 0.62, 3.0 and 1.8 μM, respectively.We isolated four new and ten known compounds from C. alternifolia, and one known compound showed agonistic activities for PPARα, PPARγ and LXR.Compound 1 is the first example of a naturally occurring iridoid glycoside containing a β-glucopyranoside moiety at C-6.

Six new polyketides, simplexolides A-E (1-5) and a furan ester, plakorfuran A (6), together with four known furanylidenic methyl esters (7-10) were isolated from the marine sponge Plakortis simplex. Compounds 1-5 feature a tetrahydrofuran ring opened seco-plakortone skeleton. These new structures, including relative configurations, were determined on the basis of extensive analysis of spectroscopic data. The absolute configurations of 1-6 were established by the modified Mosher's method, and the CD exciton chirality method. However, configurations of the remote stereocenters at C-8 in compounds 1-5 were not determined. Antifungal, cytotoxicity, antileismanial, and antimalarial activities of these poly-ketides were evaluated.

Two new phloroglucinols, named eucalyptals D (1) and E (2), along with a related known compound (euglobal-In-3, 3) were isolated from the fruits of Eucalyptus globulus. Their structures were established on the basis of extensive spectroscopic studies, revealing that they share a common 3,5-diformyl-isopentyl phloroglucinol unit, but each is instead coupled to a different sesquiterpenoid skeleton (aromadendrene in 1, cadinene in 2, and a spirosesquiterpene in 3). Compound 1 possessed an unusual seven-membered D ring with an ether bridge between C-2 of the aromadendrene moiety and C-2′ of the aromatic unit. The absolute configuration of the isolates was defined by the comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1–3 exhibited significant in vitro cytotoxicities against a few human cancer cell lines (Huh-7, Jurkat, BGC-823, and KE-97) using the CellTiter-GloTM luminescent cell viability assay method.

A simple, mild, cost-effective, and green approach for the reductive mono-N-alkylation of nitroarenes has been developed. HOAc/Zn are utilized as the reducing system together with a carbonyl compound as an alkyl source in methanol. Excellent yields were obtained with stoichiometric control of mono- over dialkylated products. Application to five complex natural products demonstrated the practical utility of the method.

Porifera have long been a reservoir for the discovery of bioactive compounds and drug discovery. Most research in the area has focused on sponges from tropical and temperate waters, but more recently the focus has shifted to the less accessible colder waters of the Antarctic and, to a lesser extent, the Arctic. The Antarctic region in particular has been a more popular location for natural products discovery and has provided promising candidates for drug development. This article reviews groups of bioactive compounds that have been isolated and reported from the southern reaches of the Arctic Circle, surveys the known sponge diversity present in the Arctic waters, and details a recent sponge collection by our group in the Aleutian Islands, Alaska. The collection has yielded previously undescribed sponge species along with primary activity against opportunistic infectious diseases, malaria, and HCV. The discovery of new sponge species and bioactive crude extracts gives optimism for the isolation of new bioactive compounds from a relatively unexplored source.

With drug discovery from marine natural products hailing a renaissance over the past 5 years, the use of marine extracts in the search for biologically active natural products continues to be a powerful approach for the identification of lead compounds for chemistry programs involved in drug discovery.1 Natural products continue to serve as valuable starting points in developing druglike candidates, and the first step in the development of therapeutic agents is the identification of lead compounds that bind to a specific target or receptor of interest.2 Structure-activity relationships (SARs) of lead compounds are then studied by synthesis or semisynthesis of a number of analogues to define the key recognition elements for maximal activity.3 However, the role of natural products in drug discovery became a lower priority in terms of participation by the major pharmaceutical companies by the mid-1990s.4 Reasons for this decline include the perceived disadvantages of natural products, including difficulties in access and supply, structure elucidation and synthesis because of the complexity of natural products, and concerns about intellectual property rights associated with published structures and international collections. In addition, the availability of large collections of compounds prepared by combinatorial chemistry methods provides inexpensive access to large numbers of molecules for random screening and starting materials for rational design.5,6 Nevertheless, the natural products chemistry field has welcomed a renaissance over the past 5 years because of new developments in analytical chemistry, spectroscopy highthroughput screening, and a disappointing number of leads generated through combinatorial chemistry.1,7-9 Currently, basic scientific research in chemistry and biology of marine natural products that started in the 1970s has finally borne fruit for marine-derived drug discovery. Ziconotide (Prialt; Elan Pharmaceuticals), a peptide originally discovered from a tropical cone snail, was the first marine-derived compound approved in the United States in December 2004 for the treatment of pain. Then, in October 2007, trabectedin (Yondelis; PharmaMar) was approved and became the first marine anticancer drug in the European Union. Collaborations between industrial and academic scientists continue to meet the challenges involved in discovering, understanding, and developing new anticancer drugs.10 Several other candidate compounds from marine origins are in the pipeline and are being evaluated in phase I-III clinical trials for the treatment of various cancers in the United States and in Europe.11-13 Here, we review the kahalalides, a family of structurally unrelated depsipeptides isolated from the herbivorous marine mollusk Elysia rufescens, Elysia ornata, or Elysia grandifolia and their algal diet of Bryopsis pennata.14-27 Two of the most active compounds of this family, kahalalide F (KF) (6) and isoKF (22), have been evaluated in phase II clinical trials in hepatocellular carcinoma, non-small-cell lung cancer (NSCLC), and melanoma. Moreover, KF (6) is being evaluated in phase II clinical trials in patients with severe psoriasis.83-93 Of greatest significance is the fact that KF (6) can effectively inhibit receptor tyrosine kinase ErbB3 (HER3) and the phosphatidylinositol 3-kinase-Akt signaling pathways in sensitive cell lines, which suggests that KF (6) and isoKF (22) are involved in an unknown oncosis signaling pathway, though the mechanism of action has not yet been completely characterized.103-107 The kahalalides would represent the first anticancer drugs that can inhibit HER3 receptors.

Plakortide F acid (PFA), a marine-derived polyketide endoperoxide, exhibits strong inhibitory activity against the opportunistic fungal pathogens Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus . In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae to investigate the mechanism of action of this compound. PFA elicited a transcriptome response indicative of a Ca 2+ imbalance, affecting the expression of genes known to be responsive to altered cellular calcium levels. Several additional lines of evidence obtained supported a role for Ca 2+ in PFA's activity. First, mutants lacking calcineurin and various Ca 2+ transporters, including pumps (Pmr1 and Pmc1) and channels (Cch1 and Mid1), showed increased sensitivity to PFA. In addition, the calcineurin inhibitors FK506 and cyclosporine strongly enhanced PFA activity in wild-type cells. Furthermore, PFA activated the transcription of a lacZ reporter gene driven by the calcineurin-dependent response element. Finally, elemental analysis indicated a significant increase in intracellular calcium levels in PFA-treated cells. Collectively, our results demonstrate that PFA mediates its antifungal activity by perturbing Ca 2+ homeostasis, thus representing a potentially novel mechanism distinct from that of currently used antifungal agents.

Oil production from single cells has been in development since the 1980s primarily for the pharmaceutical and neutraceutical industries, but the technology for using microorganisms to convert plant cellular material directly into oil is still undeveloped. The unusual amount of oil extracted from the imported fire ant ( Solenopsis sp.) may be an indication of the presence of oleaginous microorganisms or enzymes supporting the digestion of raw sugars. Yield of the ant oil is 16% dry weight and contains most of the fatty acids also found in other biomass resources. Heat of combustion of the ant oil was 133,000 BTU/gal, an amount within the range of reported values for vegetable oil and biodiesel. This investigation also explores the potential source of the oil through stable isotope labeling and offers a unique perspective of a potentially new source of microorganisms or enzymes useful for reducing the cost of producing an alternative fuel.

Three new diastereomers of polyketides (PKs), raistrickiones A&minus, C (1&ndash, 3), together with two new analogues, raistrickiones D and E (4 and 5), were isolated from a highly productive strain of Penicillium raistrickii, which was subjected to an experimental thermo-change strategy to tap its potential of producing new secondary metabolites. Metabolites 1 and 2 existed in a diastereomeric mixture in the crystal packing according to the X-ray data, and were laboriously separated by semi-preparative HPLC on a chiral column. The structures of 1&ndash, 5 were determined on the basis of the detailed analyses of the spectroscopic data (UV, IR, HRESIMS, 1D, and 2D NMR), single-crystal X-ray diffractions, and comparison of the experimental and calculated electronic circular dichroism spectra. Compounds 1&ndash, 5 represented the first case of 3,5-dihydroxy-4-methylbenzoyl derivatives of natural products. Compounds 1&ndash, 5 exhibited moderate radical scavenging activities against 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH).

Marine sponges of the Genus Plakortis are typically unfouled; they can have a distinctive pleasant smell and an oily surface. A significant quantity of fragrant oil was obtained from a Jamaican Plakortis sp. by cryo-trap. The oil was determined to be exclusively 2-decanone. The antifouling character of the oil was evaluated by its effects on surface attachment of a gram negative bacterial model using confocal fluorescence microscopy as well as its effects on the attachment of Dreissena polymorpha (zebra mussel). The ketone dramatically inhibited attachment of the bacteria and zebra mussels. The results suggest that the oil impacts establishment of related epifauna on the Plakortis sponge in nature. Although the aliphatic ketone alone is not a potential commercial alternative for antifouling coatings, incorporating the functionality into coating design should be considered in future studies.

Fractionation of an extract from American sycamore leaves produced the small molecule, kaempferol-3- O-alpha-L-(2″,3″-di- p-coumaroyl)rhamnoside (KCR), which exists in four stereoisomeric forms ( EE, EZ, ZE, and ZZ) at the olefin in the p-coumaroyl; all four isomers exhibit potent anti-MRSA activity in vitro. As part of the preclinical development of KCR, we set out to investigate the metabolites of KCR in mouse plasma as a prelude of ADME studies and therapeutic assessment. When KCR was added to mouse plasma at 37 °C, two new HPLC peaks appeared with increasing intensity as the incubation time increased; their retention times were shorter than that of KCR indicating that KCR was metabolized to produce two compounds that were more polar. HPLC results indicated that the two metabolites mainly came from the ZE and EE isomers and that the ZZ isomer was the most stable. Based on their respective HPLC retention times and UV spectra, these two metabolites were tentatively identified as p-coumaric acid and afzelin; both of which are more polar than KCR. The molecular weights of both metabolites were then confirmed by a Waters Acquity UPLC system with a QDa mass detector. UPLC chromatograms and molecular ions of metabolites 1 and 2 match well with those of reference materials, p-coumaric acid and afzelin, thus confirming the identities of the two major metabolites of KCR. In summary, KCR was metabolized in mouse plasma and two major metabolites ( p-coumaric acid and afzelin) were identified; the metabolites were mainly converted from the ZE and EE isomers.

Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3beta (GSK-3beta), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases.

Twenty manzamine amides were synthesized and evaluated for in vitro antimalarial and antimicrobial activities. The amides of manzamine A (1) showed significantly reduced cytotoxicity against Vero cells, although were less active than 1. The structure–activity analysis showed that linear, short alkyl groups adjacent to the amide carbonyl at position 8 are favored for antimalarial activity, while bulky and cyclic groups at position 6 provided the most active amides. Most of the amides showed potent activity against Mycobacterium intracellulare. The antimicrobial activity profile for position 8 series was similar to that for antimalarial activity profile, in which linear, slightly short alkyl groups adjacent to the amide carbonyl showed improved activity. Two amides 14 and 21, which showed potent antimalarial activity in vitro against Plasmodium falciparum were further evaluated in vivo in Plasmodium berghei infected mice. Oral administration of 14 and 21 at the dose of 30 mg/kg (once daily for three days) caused parasitemia suppression of 24% and 62%, respectively, with no apparent toxicity.

Crude extracts and column fractions from the red algae Asparagopsis taxiformis and A. armata from the Strait of Messina (Italy) were screened for the production of antimicrobial compounds. Extracts from both species revealed remarkable antiprotozoal activity against Leishmania, revealing such algae as a great source of natural antiprotozoal products.

A simple and practical approach for the one-pot conversion of nitroarenes into amide derivatives has been developed. Zinc and acetic acid are utilized as a reducing agent, and acyl chloride and triethylamine are used as the acylating agent in DMF with good yield (∼60%) of the amide. This method was applicable to manzamine A (1), where the yield of 6-cyclohexamidemanzamine A (7) was significantly improved (56%) by this approach relative to (17%) by beginning with the amine.

Background The review presents the 2005–2006 peer-reviewed marine pharmacology literature, and follows a similar format to the authors' 1998–2004 reviews. The preclinical pharmacology of chemically characterized marine compounds isolated from marine animals, algae, fungi and bacteria is systematically presented. Results Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 78 marine chemicals. Additionally 47 marine compounds were reported to affect the cardiovascular, immune and nervous system as well as possess anti-inflammatory effects. Finally, 58 marine compounds were shown to bind to a variety of molecular targets, and thus could potentially contribute to several pharmacological classes. Conclusions Marine pharmacology research during 2005–2006 was truly global in nature, involving investigators from 32 countries, and the United States, and contributed 183 marine chemical leads to the research pipeline aimed at the discovery of novel therapeutic agents. General significance Continued preclinical and clinical research with marine natural products demonstrating a broad spectrum of pharmacological activity will probably result in novel therapeutic agents for the treatment of multiple disease categories.

As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents.Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases.Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections. Despite the long history of use of this class of drugs, very limited medicinal chemistry and drug optimization studies have been reported, thus leaving the door open to these opportunities in the future. Scifinder and PubMed were the main search engines used to locate articles relevant to the topic presented in the present review. Keywords used in our search were specific names of each of the 88 compounds presented in the review as well as more general terms such as polyethers, ionophores, carboxylic polyethers and polyether antibiotics.

In addition to twenty-nine known compounds, two new guaiane sesquiterpenes and two new furanocoumarins were isolated from the chloroform extract of the rhizomes of Notopterygium incisum. The new structures were elucidated by means of spectroscopic methods including 2 D NMR techniques and mass spectrometry to be 8 beta-acetoxy-4 alpha,6 alpha-dihydroxy-1 alpha,5 alpha( H)-guai-9-ene (incisumdiol A, 1), 4 alpha,6 alpha-dihydroxy-1 alpha,5 alpha( H)-guai-9-ene (incisumdiol B, 2), 5-[(2 E,5 Z)-7-hydroxy-3,7-dimethyl-2,5-octadienoxy]psoralene ( 3) and 5-[(2,5)-epoxy-3-hydroxy-3,7-dimethyl-6-octenoxy]psoralene ( 4).

Marine sponges in the genus Ircinia are known to be good sources of secondary metabolites with biological activities. A major obstacle in the development of sponge-derived metabolites is the difficulty in ensuring an economic, sustainable supply of the metabolites. A promising strategy is the ex situ culture of sponges in closed or semiclosed aquaculture systems. In this study, the marine sponge Ircinia strobilina (order Dictyoceratida: family Irciniidae) was collected from the wild and maintained for a year in a recirculating aquaculture system. Microbiological and molecular community analyses were performed on freshly collected sponges and sponges maintained in aquaculture for 3 months and 9 months. Chemical analyses were performed on wild collected sponges and individuals maintained in aquaculture for 3 months and 1 year. Denaturing gradient gel electrophoresis was used to assess the complexity of and to monitor changes in the microbial communities associated with I. strobilina . Culture-based and molecular techniques showed an increase in the Bacteroidetes and Alpha - and Gammaproteobacteria components of the bacterial community in aquaculture. Populations affiliated with Beta - and Deltaproteobacteria , Clostridia , and Planctomycetes emerged in sponges maintained in aquaculture. The diversity of bacterial communities increased upon transfer into aquaculture.

Two new cyclic hexapeptides, mollamides B (1) and C (2), were isolated from the Indonesian tunicate Didemnum molle along with the known peptide keenamide A (3). The structures were established using 1D and 2D NMR experiments. The relative configuration of mollamide B at the thiazoline moiety was determined using molecular modeling coupled with NMR-derived restraints. Their absolute configuration was determined using Marfeyʼs method. The new peptides have been evaluated for their antimicrobial, antimalarial, anticancer, anti-HIV-1, anti-Mtb, and anti-inflammatory activities. Keenamide A and mollamide B show cytotoxicity against several cancer cell lines.

Four new kahalalides, V (1), W (2), X (3), and Y (4), as well as six previously characterized kahalalides have been isolated from a two-year collection of the sacoglossan mollusk Elysia rufescens. Curiously, kahalalide B, previously isolated in high yield from E. rufescens, was found to be essentially absent from these collections despite identical collection sites and times with previous collections. In addition, kahalalide K, which to date has only been reported from Bryopsis sp., was found in this collection of E. rufescens, suggesting that the production of these metabolites could potentially be from a microbial association with the mollusk and algae, and this relationship is continuously evolving in response to changes in the environment and predation. The structures of new peptides have been established on the basis of extensive 1D and 2D NMR spectroscopic data analysis. Kahalalide V (1) was ascertained to be an acyclic derivative of kahalalide D (5), while kahalalide W (2) was determined to have a 4-hydroxy-L-proline residue instead of the proline in 5. The arginine residue of kahalalide X (3), an acyclic derivative of kahalalide C, was determined to have an L configuration. Kahalalide Y (4) was found to have an L-proline residue instead of the hydroxyproline in kahalalide K. It is clear from this collection of E. rufescens that the discovery of new kahalalide-related metabolites is still highly feasible.

The marine environment is a valuable resource for drug discovery due to its diversity of life and associated secondary metabolites. However, there is very little published data on the potential application of marine natural products to treat neuropsychiatric disorders. Many natural products derived from chemically defended organisms in the marine environment have pharmacophores related to serotonin or clinically utilized antidepressant drugs. Therefore, in the present study, compounds selected for their structural similarity to serotonin or established antidepressants were evaluated for antidepressant-like activity using the forced swim and tail suspension tests in mice. The antidepressant positive controls, citalopram (selective serotonin reuptake inhibitor) and despiramine (tricyclic antidepressant) both dose-dependently reduced immobility time in the forced swim and tail suspension tests. Two marine natural product compounds tested, aaptamine and 5,6-dibromo-N,N-dimethyltryptamine, also produced significant antidepressant-like activity in the forced swim test. In the tail suspension test, the antidepressant-like effects of 5,6-dibromo-N,N-dimethyltryptamine were confirmed, whereas aaptamine failed to produce significant results. None of the tested compounds induced hyperlocomotion, indicating that nonspecific stimulant effects could not account for the observed antidepressant-like actions of the compounds. These studies highlight the potential to rationally select marine derived compounds for treating depression and other neuropsychiatric disorders.

Chemical transformation studies of the marine sesquiterpene phenol (S)-(+)-curcuphenol (1) isolated from the Jamaican sponges, Didiscus oxeata and Myrmekioderma styx, were accomplished. In order to optimize the activity and better understand the SAR of (S)-(+)-curcuphenol, nineteen semisynthetic analogs were prepared and evaluated for activity against infectious diseases. A number of analogs showed significant activity against Mtb and Leishmania donovani, while showing good to moderate activities in antibacterial and antifungal assays as well as against P. falciparium (D6 clone) and (W2 clone). The analogs a, c, h, and r exhibited Mtb activity with MICs of 24.6, 41.2, 6.90, and 50.5 μM, respectively. Analog f shows enhanced activity against L. donovani with an IC50 of 0.6 μM and IC90 of 40 μM respectively.

Five new polycyclic guanidine alkaloids, 16β-hydroxycrambescidin 359 (1), batzelladines K, L, M, and N (2–5), along with the previously reported ptilomycalin A (6), crambescidine 800 (7), batzelladine C (8), and dehydrobatzelladine C (9), were isolated from the Jamaican sponge Monanchora unguifera. Their structures were assigned on the basis of detailed analysis of 1D and 2D NMR, and mass spectral data. Their activities against cancer cell lines, protozoa, HIV-1 and AIDS opportunistic infectious pathogens (AIDS-OIs) including Mtb were evaluated.

Kahalalide F (1) shows remarkable antitumor activity against different carcinomas and has recently completed phase I clinical trials and is being evaluated in phase II clinical studies. The antifungal activity of this molecule has not been thoroughly investigated. In this report, we focused on acetylation and oxidation of the secondary alcohol of threonine, as well as reductive alkylation of the primary amine of ornithine, and each product was evaluated for improvements in antifungal activity. 1 and analogues do not exhibit antimalarial, antileishmania, or antibacterial activity; however, the antifungal activity against different strains of fungi was particularly significant. This series of compounds was highly active against Fusarium spp., which represents an opportunistic infection in humans and plants. The in vitro cytotoxicity for the new analogues of 1 was evaluated in the NCI 60 cell panel. Analogue 5 exhibited enhanced potency in several human cancer cell lines relative to 1.

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious pathogen that is resistant to current antibiotic therapy. Thus, there is an urgent need for novel antimicrobial agents that can effectively combat these new strains of drug-resistant "superbugs". Recently, fractionation of an extract from Platanus occidentalis (American sycamore) leaves produced an active kaempferol molecule, 3-O-alpha-L-(2",3"-di-p-coumaroyl)rhamnoside (KCR), in four isomeric forms; all four isomers exhibit potent anti-MRSA activity. In order to further the preclinical development of KCR as a new antibiotic class, we developed and validated a simple analytical method for assaying KCR plasma concentration. Because KCR will be developed as a new drug, although comprising four stereoisomers, the analytical method was devised to assay the total amount of all four isomers. In the present work, both a plasma processing procedure and an HPLC method have been developed and validated. Mouse plasma containing KCR was first treated with ethanol and then centrifuged. The supernatant was dried, suspended in ethanol, centrifuged, and the supernatant was injected into an HPLC system comprising a Waters C18, a mobile phase composing methanol, acetonitrile, and trifluoroacetic acid and monitored at 313 nm. The method was validated by parameters including a good linear correlation, a limit of quantification of 0.27 microg/mL, and high accuracy. In summary, this method allows a rapid analysis of KCR in the plasma samples for pharmacokinetics studies.

One approach to the management of common fish diseases in aquaculture is the use of antibiotic-laden feed. However, there are public concerns about the use of antibiotics in agriculture and the potential development of antibiotic resistant bacteria. Therefore, the discovery of other environmentally safe natural compounds as alternatives to antibiotics would benefit the aquaculture industries. Four natural compounds, commonly called platanosides, [kaempferol 3-O-α-L-(2",3"-di-E-p-coumaroyl)rhamnoside (1), kaempferol 3-O-α-L-(2"-E-p-coumaroyl- 3"-Z-p-coumaroyl)rhamnoside (2), kaempferol 3-O-α-L-(2"-Z-p-coumaroyl-3"-E-p-coumaroyl)rhamnoside (3), and kaempferol 3-O-α-L-(2",3"-di-Z-p-coumaroyl)rhamnoside (4)] isolated from the leaves of the American sycamore (Platanus occidentalis) tree were evaluated using a rapid bioassay for their antibacterial activities against common fish pathogenic bacteria including Flavobacterium columnare, Edwardsiella ictaluri, Aeromonas hydrophila, and Streptococcus iniae. The four isomers and a mixture of all four isomers were strongly antibacterial against isolates of F. columnare and S. iniae. Against F. columnare ALM-00-173, 3 and 4 showed the strongest antibacterial activities, with 24-h 50% inhibition concentration (IC50) values of 2.13 ± 0.11 and 2.62 ± 0.23 mg/L, respectively. Against S. iniae LA94-426, 4 had the strongest antibacterial activity, with 24-h IC50 of 1.87 ± 0.23 mg/L. Neither a mixture of the isomers nor any of the individual isomers were antibacterial against isolates of E. ictaluri and A. hydrophila at the test concentrations used in the study. Several of the isomers appear promising for the potential management of columnaris disease and streptococcosis in fish.