IB-01212, a new cytotoxic cyclodepsipeptide isolated from the marine fungus Clonostachys sp. ESNA-A009

IB-01212, a new cytotoxic cyclodepsipeptide featuring C2 symmetry, was isolated from the mycelium extract of Clonostachys sp. ESNA-A009. The amino acid sequence of the compound was determined by spectroscopy techniques. The absolute configuration of the amino acids was determined by a combination of the Marfey and menthol methods. The structure, which was confirmed by comparison of the analytical data for the natural product with a sample obtained by solid-phase peptide synthesis, was revealed to be a cyclic dimer formed by two chains of L-N,N-Me2Leu-L-Ser-L-N-MeLeu-L-N-MePhe bound by the two esters formed between the carboxylic acid of the L-N-MePhe and the hydroxyl function of the L-Ser. IB-01212 is highly cytotoxic to different tumor cell lines.     

Aspercyclide A-C, three novel fungal metabolites from Aspergillus sp. as inhibitors of high-affinity IgE receptor

Immunoglobin E (IgE) binds to the high-affinity IgE receptor on mast cells and basofils and causes release of inflammatory compounds that leads to allergic diseases. Inhibition of the ligand binding could lead to blockade of the release of inflammation causing compounds and thus alleviate asthma and other allergic diseases. Natural product screening and bioassay-guided isolation of an extract of Aspergillus sp. led to the identification of three novel 11-membered macrocyclic biphenyl ether lactones, aspercyclides A-C. Aspercyclide A inhibited the IgE binding with an IC₅₀ of 200 μM. The isolation, structure elucidation, absolute stereochemistry, and the binding activities of these compounds are described.     

A new furanosteroid from Talaromyces sp. lgt-4, a fungal endophyte isolated from Tripterygium wilfordii

Wortmannolol (1), a new furanosteroid, along with five known compounds, wortmannolone (2), ergosterol (3), p-hydroxyphenyl ethanol (4), trans-6-dodecene (5), (2Z, 4E) -5-(8-hydroxy-1,5-dimethyl-3-oxo-6-oxabicyclo [3.2.1] octan-8-yl) -3-methylpenta-2,4-dienoic acid (6) were isolated from a fungal endophyte Talaromyces sp. lgt-4. Their structures were elucidated by IR, MS, 1D and 2D NMR spectra. Compound 1 show weak monoamine oxidase inhibitory activity.     

Characterization of copper chromate as a new inorganic exchanger for the isolation of Sr radioisotopes from fission products

A new inorganic exchanger consisting of the normal copper chromate (CUCR) was prepared and studied: its application to radiochemical separations was explored after batchwise measuring the distribution coefficients of several elements. Radiostrontium isolation from fission products was performed by combined use of CUCR and PRTD, a new form of tin dioxide previously investigated.     

Rapid preparative isolation of a new phenylpropanoid glycoside and four minor compounds from Sparganium stoloniferum using high-speed counter-current chromatography as a fractionation tool

A rapid high-speed counter-current chromatography (HSCCC) method was used to isolate five minor compounds from rhizome of Sparganium stoloniferum namely San Leng in Chinese, including two phenylpropanoid glycosides, sparganiaside A (1) and 1-O-feruloyl-3-p-coumaroylglycerol (2), and three aromatic acids, vanillic acid (3), p-hydroxylcinnamic acid (4), and p-hydroxybenzoic acid (5), of which, compound 1 was a new one. Five compounds were preparatively enriched at top efficiency by one-step HSCCC operation in the isolation procedure. A suitable solvent system composed of chloroform-methanol-water (4:3.5:1.8, v/v/v) was used. And the operation time was less than 4 h. The purities of compounds (1-5) in the enriched fractions were determined to be 75.8%, 66.3%, 90.6%, 79.9%, and 98.2%, respectively. The mean recoveries of the five compounds were 84.8%, 87.3%, 81.8%, 90.3%, and 92.7%, respectively. Compounds 1-4 were further purified by semi-preparative high-performance liquid chromatography (HPLC). This is the first report on the use of HSCCC as a fractionation tool for preparative isolation of minor compounds from S. stoloniferum. The method was proved to be rapid, convenient, high yield, and low cost. HSCCC was shown to be a quick and effective tool in isolation of natural products even though the compounds were not abundant.     

Supercritical fluid extraction as a tool for isolation of monoterpenes from coniferous needles and walnut-tree leaves

Several monoterpenes, i.e., (+)-α-pinene, (−)-camphene, sabinene, (−)-β-pinene, myrcene, R-(+)-limonene, (−)-bornylacetate, (−)-trans-caryophyllene and a-humulene were identified and determined by gas chromatography-mass spectrometry (GC-MS) in needles of Pinaceae (Picea abies, P. omorika, P. pungens, P. Breweriana, Pinus nigra, P. mungo turra, P. black, P. sylvestris, Abies pinsapo, A. holophylla, A. Bronmuelleris, A. alba, Larix Kaempferi L. decidua) and tree-leaves of Juglandaceae (Juglans regia, J. nigra, J. sieboldiana var. Cordiformis) families. Supercritical fluid extraction (SFE) was found to be very useful for their isolation at optimised conditions (needles/leaves: pressure 20/30 MPa, temperature 80/130°C, time of extraction 60/60 min, modifier chloroform/chloroform). Their seasonal distribution, evaluation of differences in concentrations and relative amounts in different trees and their varieties grown in different localities were evaluated.      

Identification of nitriles in petroleum products : Complex formation as a method of isolation

Nitrogen compounds were completely removed from a hydrogenated furnace oil by shaking with a mixture of ferric chloride and zinc chloride. The resulting complexes were separated from the oil and thermally decomposed to liberate the nitrogen compounds. After removal of nitrogen bases with hydrochloric acid and indoles, carbazoles, and phenazines with perchloric acid, the nitrogen compounds remaining in the concentrate were separated by fractional clution from an aluminum oxide column and gas chromatography. The following compounds were identified or their presence was indicated in the resulting fractions by their ultraviolet and/or mass spectra: dicyanobenzene, dicyanocyclohexane, cyanoindene, cyano-2,3-dihydroindene, cyanonaphthalene, dicyanoindene, dicyano-2,3-dihydroindene, dicyanonaphthalene, cyanobiphenyl, dicyanooctahydronaphthalene, and/or several of their alkyl derivatives.     

(+)-Echinobetaine B: isolation, structure elucidation, synthesis and preliminary SAR studies on a new nematocidal betaine from a southern Australian marine sponge, Echinodictyum sp

The principle nematocidal agent present in a southern Australian marine sponge of the genus Echinodictyum has been isolated and identified as the novel betaine (+)-echinobetaine B (6), and the structure assigned by spectroscopic analysis has been confirmed by total synthesis. Preliminary SAR conclusions are drawn from analysis of synthetic intermediates and the known marine metabolites zooanemonin (12) and norzooanemonin (13), and the new sponge metabolite norzooanemonin methyl ester (14). The latter compound is reported for the first time from a selection of Australian sponges, including an Axinyssa sp., a Niphates sp., an Axinella sp. and a Ptilocaulis sp.     

The genomisotopic approach: a systematic method to isolate products of orphan biosynthetic gene clusters

With the increasing number of genomes sequenced and available in the public domain, a large number of orphan gene clusters, for which the encoded natural product is unknown, have been identified. These orphan gene clusters represent a tremendous source of novel and possibly bioactive compounds. Here, we describe a "genomisotopic approach," which employs a combination of genomic sequence analysis and isotope-guided fractionation to identify unknown compounds synthesized from orphan gene clusters containing nonribosomal peptide synthetases. Analysis of the Pseudomonas fluorescens Pf-5 genome led to the identification of an orphan gene cluster predicted to code for the biosynthesis of a lipopeptide natural product. Application of the genomisotopic approach to isolate the product of this gene cluster resulted in the discovery of orfamide A, founder of a group of bioactive cyclic lipopeptides.     

Characterization of TrdL as a 10-hydroxy dehydrogenase and generation of new analogues from a tirandamycin biosynthetic pathway

TrdL, encoding a flavin-dependent oxidoreductase in the tirandamycin gene cluster, was inactivated to afford a ΔtrdL mutant, the fermentation of which yielded a new intermediate, tirandamycin E (5), and an additional early intermediate, tirandamycin F (6), if XAD-16 resin was introduced. TrdL was overexpressed in E. coli, and the protein was shown to efficiently catalyze the transformations from 5 to tirandamycin A (1) and from 6 to tirandamycin D (4), demonstrating its function as a 10-hydroxy dehydrogenase.     

Marine natural products: dactylol,a new sesquiterpene alcohol from a sea hare

A new sesquiterpene alcohol, dactylol, having an uncommon bicyclo [6.3.0] undecane skeleton has been isolated from the sea hare Aplysia dactylomela. Chemical degradation and NMR studies using a shift reagent established the structure and relative stereochemistry. The absolute configuration was derived from ORD/CD data of a substituted cyclopentanone degradation product.     

Reconstitution and characterization of a new desosaminyl transferase, EryCIII, from the erythromycin biosynthetic pathway

EryCIII converts alpha-mycarosyl erythronolide B into erythromycin D using TDP-d-desosamine as the glycosyl donor. We report the heterologous expression, purification, in vitro reconstitution, and preliminary characterization of EryCIII. Coexpression of EryCIII with the GroEL/ES chaperone complex was found to enhance greatly the expression of soluble EryCIII protein. The enzyme was found to be highly active with a kcat greater than 100 min-1. EryCIII was quite selective for the natural nucleotide sugar donor and macrolide acceptor substrates, unlike several other antibiotic glycosyl transferases with broad specificity such as desVII, oleG2, and UrdGT2. Within detectable limits, neither 6-deoxyerythronolide B nor 10-deoxymethynolide were found to be glycosylated by EryCIII. Furthermore, TDP-d-mycaminose, which only differs from TDP-d-desosamine at the C4 position, could not be transferred to alphaMEB. These studies lay the groundwork for detailed structural and mechanistic analysis of an important member of the desosaminyl transferase family of enzymes.     

Deciphering potential inhibitors targeting THI4 of Fusarium solani sp. to combat fungal keratitis: An integrative computational approach

Mycotic keratitis is a fungal infection of corneal epithelium. It is more common in tropical and subtropical countries and is one of the leading causes of blindness. Many of the antifungal drugs have been less effective in treating this condition and certain drugs which are efficient and yet limited in use due to its extreme side effects. Hence, in this study an attempt is made to identify potential and least toxic antifungal inhibitors that targets thiamine thiazole synthase, a novel target for suppressing Fusarium solani subsp.pisi (Nectria haematococca MPVI) infections, to combat mycotic keratitis. Integrative computational approaches involving model refinement, molecular dynamics simulation and High throughput virtual screening (HTVS) were applied through integrative multi precision mode in order to identify potential inhibitors. Moreover, machine learning approach was also implemented to prioritize potential inhibitors that are ophthalmic adaptive, as well as antifungal molecule. From the NCI and Maybridge datasets, for HTVS only 209,872 compounds that surpassed ligand property filtration were considered, which resulted in 209 compounds after XP docking. Among the top 5 compounds from XP docking, on cumulative analysis only 2-(1-hydroxyethyl)-1,3-thiazole-4-carboxamide was prioritized as the most potential hit, as it showed higher order of significance in terms of binding affinity, structural stability and therapeutic relevance for the treatment of Mycotic keratitis. Thus, widening the scope for novel antifungal therapy in ophthalmic infections.     

Anticancer drugs from nature--natural products as a unique source of new microtubule-stabilizing agents

This review article provides an overview on the current state of research in the area of microtubule-stabilizing agents from natural sources, with a primary focus on the biochemistry, biology, and pharmacology associated with these compounds. A variety of natural products have been discovered over the last decade to inhibit human cancer cell proliferation through a taxol-like mechanism. These compounds represent a whole new range of structurally diverse lead structures for anticancer drug discovery.     

Total synthesis of azumamide A and azumamide E, evaluation as histone deacetylase inhibitors, and design of a more potent analogue

The unprecedented diastereoselective Mannich reaction of a Z-allylsulfoximine was a key step in the total synthesis of the marine natural products azumamide A and E, and an unnatural analogue. Their relative potency as histone deacetylase inhibitors was evaluated and found to correlate with predicted zinc-binding affinity. [reaction: see text]     

A search for BACE inhibitors reveals new biosynthetically related pyrrolidones, furanones and pyrroles from a southern Australian marine sponge, Ianthella sp

Fractionation of a southern Australian marine sponge, Ianthella sp., yielded sixteen metabolites including a new class of pyrrolidone, ianthellidones A-F (1-6), a new class of furanone, ianthellidones G-H (7-8), new and known lamellarins, lamellarins O1 (9), O2 (10), O (11) and Q (12), plus the known 4-hydroxybenzaldehyde (13), 4-hydroxybenzoic acid (14), 4-methoxybenzoic acid (15) and ethyl 4-hydroxybenzoate (16). Structures for all Ianthella metabolites were determined by detailed spectroscopic analysis, supported by a plausible biosynthetic relationship. The ianthellidones were non-cytotoxic towards two human colon cancer cell lines (SW620 and SW620 Ad300), as well as Gram +ve and Gram -ve bacteria, and a fungus. Ianthellidone F (6) and lamellarins O2 (10) and O (11) displayed modest BACE inhibitory properties (IC(50) > 10 μM), while lamellarin O1 (9) was more potent (IC(50) < 10 μM). Lamellarin O (11) exhibited modest cytotoxicity towards SW620 and SW620 Ad300 cell lines (IC(50) > 22 μM), was an inhibitor of the multi-drug resistance efflux pump P-glycoprotein, and displayed selective growth inhibitory activity against the Gram +ve bacterium Bacillus subtilis (ATCC 6633) (IC(50) 2.5 μM).