Modulating the Serotonin Receptor Spectrum of Pulicatin Natural Products.

Serotonin (5-HT) receptors are important in health and disease, but the existence of 14 subtypes necessitates selective ligands. Previously, the pulicatins were identified as ligands that specifically bound to the subtype 5-HT2B in the 500 nM to 10 µM range and that exhibited in vitro effects on cultured mouse neurons. Here, we examined the structure-activity relationship of 30 synthetic and natural pulicatin derivatives using binding, receptor functionality, and in vivo assays. The results reveal the 2-arylthiazoline scaffold as a tunable serotonin receptor-targeting pharmacophore. Tests in mice show potential antiseizure and antinociceptive activities at high doses without motor impairment.

Effective removal of nemacide fosthiazate from an aqueous solution using zero-valent iron.

In this study, the removal of fosthiazate in an aqueous solution using zero valent iron (ZVI) and the related removal reaction mechanism were investigated. The results indicate that the dissipation of fosthiazate adheres to a pseudo-first order reaction law. The apparent rate constant of fosthiazate removal could be improved by increasing the ZVI dosage, control temperature and initial pH. The observed pseudo-first-order degradation rate constants (Kobs) of fosthiazate removal using ZVI were varied in the different electrolyte solutions, and were determined as follows: Kobs (MgSO4) < Kobs (KCl) < Kobs (Control)

Glucosinolate hydrolysis products in the crucifer Barbarea vulgaris include a thiazolidine-2-one from a specific phenolic isomer as well as oxazolidine-2-thiones.

Two isomeric phenolic glucosinolates, m- and p-hydroxyl derivatives of epiglucobarbarin [(R)-2-hydroxy-2-phenylethylglucosinolate], co-occur in an eastern chemotype (P-type) of the crucifer Barbarea vulgaris along with epiglucobarbarin itself. Levels of the phenolic derivatives in B. vulgaris were low in summer but higher during fall and winter, allowing isolation of all three glucosinolates. Hydrolysis in vitro, catalyzed by Sinapis alba myrosinase at near neutral pH, resulted in expectable oxazolidine-2-thione type hydrolysis products of epiglucobarbarin and its m-hydroxyl derivative. In contrast, a thiazolidine-2-one type product was formed in vitro from p-hydroxy epiglucobarbarin and characterized by UV, IR, MS/MS and 2D NMR. Maceration of leaf material resulted in disappearance of the glucosinolates and formation of the same oxazolidine-2-thione and thiazolidine-2-one products as found in vitro. The detected amounts were comparable to initial amounts of precursor glucosinolates. The corresponding oxazolidine-2-thione type product was also detected quantitatively from glucobarbarin in foliage of a western genotype (G-type). We suggest that p-hydroxy epiglucobarbarin is initially converted into the conventional oxazolidine-2-thione, which would further rearrange to a thiazolidine-2-one due to the activating effect of the p-hydroxyl group. We conclude that a subtle difference between isomeric phenolic glucosinolates results in significantly different natural hydrolysis products.

Thiazoline peptides and a tris-phenethyl urea from Didemnum molle with anti-HIV activity.

As part of our screening for anti-HIV agents from marine invertebrates, the MeOH extract of Didemnum molle was tested and showed moderate in vitro anti-HIV activity. Bioassay-guided fractionation of a large-scale extract allowed the identification of two new cyclopeptides, mollamides E and F (1 and 2), and one new tris-phenethyl urea, molleurea A (3). The absolute configurations were established using the advanced Marfey's method. The three compounds were evaluated for anti-HIV activity in both an HIV integrase inhibition assay and a cytoprotective cell-based assay. Compound 2 was active in both assays with IC(50) values of 39 and 78 µM, respectively. Compound 3 was active only in the cytoprotective cell-based assay, with an IC(50) value of 60 µM.

Pulicatins A-E, neuroactive thiazoline metabolites from cone snail-associated bacteria.

The cone snail Conus pulicarius from the Philippines provides a specific habitat for actinomycetes and other bacteria. A phenotypic screen using primary cultures of mouse dorsal root ganglion neurons revealed that one C. pulicarius associate, Streptomyces sp. CP32, produces a series of natural products that enhance or diminish whole-cell Ca(2+) flux. These compounds include known thiazoline compounds and a series of new derivatives, pulicatins A-E (6-10). Individual compounds were shown to bind to a series of human receptors, with selective binding to the human serotonin 5-HT(2B) receptor. Here, we report the structure elucidation of the new compounds and results of the neurological assays.

Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.

Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on cervix cancer cells. Chemical library screening was used to identify hit compounds, which were further prioritized in profiling and kinetic experiments. SAR analysis was applied in the search for analogs with improved potency and selectivity, resulting in the discovery of novel inhibitors that are able to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR's active site. This multidentate binding mode was confirmed by X-ray crystallography. The inhibitors decreased the proliferation of cervix cancer cells, while growth of primary normal keratinocytes was not affected. These compounds may be a starting point to develop drugs for the treatment of cervical cancer.

Interrogating the bioactive pharmacophore of the latrunculin chemotype by investigating the metabolites of two taxonomically unrelated sponges.

This study involved a campaign to isolate and study additional latrunculin analogues from two taxonomically unrelated sponges, Cacospongia mycofijiensis and Negombata magnifica. A total of 13 latrunculin analogues were obtained by four different ways, reisolation (1-4), our repository (5, 6), new derivatives (7-12), and a synthetic analogue (7a). The structures of the new metabolites were elucidated on the basis of a combination of comprehensive 1D and 2D NMR analysis, application of DFT calculations, and the preparation of acetonide derivative 7a. The cytotoxicities against both murine and human cancer cell lines observed for 1, 2, 7, 7a, 8, 9, and 12 were significant, and the IC(50) range was 0.5-10 microM. Among the cytotoxic derivatives, compound 9 did not exhibit microfilament-disrupting activity at 5 microM. The implications of this observation and the value of further therapeutic study on key latrunculin derivatives are discussed.

An inhibitor of gram-negative bacterial virulence protein secretion.

Bacterial virulence mechanisms are attractive targets for antibiotic development because they are required for the pathogenesis of numerous global infectious disease agents. The bacterial secretion systems used to assemble the surface structures that promote adherence and deliver protein virulence effectors to host cells could comprise one such therapeutic target. In this study, we developed and performed a high-throughput screen of small molecule libraries and identified one compound, a 2-imino-5-arylidene thiazolidinone that blocked secretion and virulence functions of a wide array of animal and plant Gram-negative bacterial pathogens. This compound inhibited type III secretion-dependent functions, with the exception of flagellar motility, and type II secretion-dependent functions, suggesting that its target could be an outer membrane component conserved between these two secretion systems. This work provides a proof of concept that compounds with a broad spectrum of activity against Gram-negative bacterial secretion systems could be developed to prevent and treat bacterial diseases.

Axially chiral 2-arylimino-3-aryl-thiazolidine-4-one derivatives: enantiomeric separation and determination of racemization barriers by chiral HPLC.

Axially chiral 2-arylimino-3-aryl-thiazolidine-4-ones have been synthesized as racemic mixtures, and each mixture with the exception of 2-(o-chlorophenyl)imino-3-(o-chlorophenyl)-thiazolidine-4-one has been converted to the corresponding 5-benzylidene-2-arylimino-3-aryl-thiazolidine-4-one racemates by reaction with benzaldehyde. The thermally interconvertible enantiomers of each compound have been obtained by enantioselective HPLC separation on columns Chiralpak AD-H and Chiralcel OD-H, and the barriers to racemization have been found to be 98.1-114.1 kJ/mol. The barriers determined were compared to those of structurally related compounds to provide evidence for the stereochemistry of the aryl imino bond.

Phenolic marine natural products as aldose reductase inhibitors.

Four different types of marine natural compounds isolated from tunicates were found to inhibit human aldose reductase. They all are characterized by a heterocyclic system, and at least two phenolic groups are present in the structure. Two of the compounds tested showed an inhibitory potency 5/6-fold higher than that of the known AR inhibitor sorbinil. One notable structural feature of these active compounds is the lack of either the carboxylic acid or the spiro-hydantoin commonly present in the principal classes of currently used inhibitors.