Bioactive Trichothecenes Produced by the Myrothecium sp. QB‐1

Three new simple trichothecenes, 15‐acetyltrichoverrol B ( 3 ), 13′‐acetyltrichoverrin B ( 5 ), and 6′‐dehydroxytrichoverrin B ( 6 ), along with five known trichothecenes trichodermadienediol B ( 1 ), trichoverrol B ( 2 ), trichoverrin B ( 4 ), and roridins A ( 7 ) and D ( 8 ), have been isolated from the liquid culture of Myrothecium roridum (strain no. QB‐1). The structures of the new compounds were established by comprehensive analysis of 1D‐ and 2D‐NMR data. All the compounds were evaluated for antifungal activity, only compounds 7 and 8 showed significant antifungal activity against the tested fungi (MIC ranged from 10 to 5 μg/ml).     

Structural investigation and elucidation of new communesins from a marine‐derived Penicillium expansum Link by liquid chromatography/electrospray ionization mass spectrometry

Penicillium expansum is a ubiquitous species for which there are only few reports for chemical investigation in marine environments. Among the numerous secondary metabolites produced by this species, communesins represent a new class of cytotoxic and insecticidal indole alkaloids. In this study, we investigated a marine P. expansum strain exhibiting neuroactivity on a Diptera larvae bioassay. Bio‐guided purification led to the isolation and the identification of communesin B as the main active compound by HRMS and ¹H and ¹³C NMR. Liquid chromatography analyses with detection by electrospray ionization coupled with tandem mass spectrometry (LC/ESI‐MS/MS) and high‐resolution tandem mass spectrometry (LC/HRMS/MS) allowed the identification and characterization of four other known communesins (A, D, E and F) in the crude extract. A fragmentation model for dimethyl epoxide communesins was proposed after detailed interpretation of their MS/MS spectra. Further analyses of the extract using the modelled fragmentations led to the detection of seven new communesins found as minor compounds. Chemical structural elucidation of these new derivatives is discussed based on their fragmentation characteristics. Copyright © 2009 John Wiley & Sons, Ltd.     

A Stereoselective [3+1] Ring Expansion for the Synthesis of Highly Substituted Methylene Azetidines

The reaction of rhodium‐bound carbenes with strained bicyclic methylene aziridines results in a formal [3+1] ring expansion to yield highly substituted methylene azetidines with excellent regio‐ and stereoselectivity. The reaction appears to proceed through an ylide‐type mechanism, where the unique strain and structure of the methylene aziridine promotes a ring‐opening/ring‐closing cascade that efficiently transfers chirality from substrate to product. The resultant products can be elaborated into new azetidine scaffolds containing vicinal tertiary‐quaternary and even quaternary‐quaternary stereocenters.     

Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti‐Cancer Properties

Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti‐fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF‐1α) as the primary target for this compound class. Nannocystin A ( 1 ) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site of 1 with the anti‐cancer compound didemnin B on EF‐1α. This myxobacterial chemotype thus offers an interesting starting point for further investigations of the potential of therapeutics targeting elongation factor 1.     

Advances in Copper‐Catalyzed C?C Coupling Reactions and Related Domino Reactions Based on Active Methylene Compounds

Active methylene compounds are a major class of reaction partners for C? C bond formation with sp² C? X (X=halide) fragments. As one of the most‐classical versions of the Ullmann‐type coupling reaction, activated‐methylene‐based C? C coupling reactions have been efficiently employed in a large number of syntheses. Although this type of reaction has long relied on noble‐metal catalysis, the renaissance of copper catalysis at the end of last century has led to dramatic developments in Ullmann C? C coupling reactions. Owing to its low cost, abundance, as well as excellent catalytic activity, the exceptional atom economy of copper catalysis is gaining widespread attention in various organic synthesis. This review summarizes the advances in copper‐catalyzed intermolecular and intramolecular C? C coupling reactions that use activated methylene species as well as in tandem reactions that are initiated by this transformation.     

Structure determination of bioactive galloyl derivatives by NMR spectroscopy

The investigation of the chemical constituents of Symplocos racemosa Roxb led to the isolation of two new glycosides, symcomoside A (1) and symcomoside B (2), together with one known glycoside, tortoside C (3), which is reported for the first time from this plant. The structures of the new compounds were determined by 1D and 2D homonuclear and heteronuclear NMR spectroscopy, from chemical evidence and by comparison with published data for closely related compounds. Symcomoside B (2) showed potent inhibitory activity against alpha-glucosidase in a concentration-dependent fashion with an IC50 value of 0.733 +/- 0.033 mM whereas symcomoside A (1) showed very weak inhibitory activity against alpha-glucosidase (9.90% in 0.70 mM).     

Motuporamines, anti-invasion and anti-angiogenic alkaloids from the marine sponge Xestospongia exigua (Kirkpatrick): isolation, structure elucidation, analogue synthesis, and conformational analysis.

Extracts of the sponge Xestospongia exigua collected in Papua New Guinea were positive in a new assay for anti-invasion activity. Bioassay-guided fractionation led to the identification of the three known motuporamines A (1), B (2), and C (3) along with the new motuporamines D (4), E (5), and F (6) and a mixture of G, H, and I (15). Motuporamines A (1), B (2), and C (3) and the mixture of G, H, and I (15) were responsible for the anti-invasion activity of the crude extract. Motuporamine C (3) has also been found to be anti-angiogenic. A series of analogues of the motuporamines have been synthesized and evaluated for anti-invasive activity. These SAR results revealed that a saturated 15-membered cyclic amine fused to the natural motuporamine diamine side chain (13) represented the optimal structure for anti-invasive activity in this family. Single-crystal X-ray diffraction analysis of one of the analogues 20 showed that in the solid state its 16-membered macrocyclic amine fragment adopted the [4444] quadrangular conformation predicted by calculations to be the lowest energy conformation for the corresponding cycloalkane, cyclohexadecane. These data along with literature X-ray data and conformational analysis for derivatives of azacyclotridecane have been used as precedents for predicting the lowest energy ring conformations of other motuporamines. The SAR data from the natural and synthetic motuporamines have been combined with the conformational analyses to provide an outline of the functionality and shape required for activity in this family of alkaloids and to design a new analogue 49 that showed good anti-invasion activity.     

Poly(acrylonitrile‐co‐methyl methacrylate‐co‐methyl acrylate): Synthesis and stereosequence distribution analysis by 2D NMR

Terpolymers of acrylonitrile (A), methyl methacrylate (B), and methyl acrylate (M) were synthesized under optimized atom transfer radical polymerization conditions using 2‐bromopropionitrile as an initiator and CuBr/dinonyl bipyridine as a catalyst. Variation of the feed composition led to terpolymers with different compositions. Composition of synthesized terpolymers were calculated from quantitative ¹³C{¹H} NMR spectra. Number average molecular weight and polydispersity index were determined by gel permeation chromatography. The overlapping and broad signals of the terpolymers were assigned completely to various compositional and configurational sequences by correlation of one‐dimensional ¹H, ¹³C{¹H}, and distortionless enhancement by polarization transfer and two‐dimensional heteronuclear single quantum coherence (HSQC) and total correlation spectroscopy (TOCSY). 2D HSQC NMR study shows one to one correlation between carbon and proton signals, while 2D TOCSY spectra were used to confirm 1, 2 bond geminal couplings between nonequivalent protons of same methylene group. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 25–37, 2009     

Hydrindanone Synthesis: An Incisterol Model

Ethyl 1‐methyl‐2‐oxocyclohexanecarboxylate ( 1a ) and its homologue 1b were converted to hydroisobenzofuran acids 7 (via 6‐[(butylsulfanyl)methylene] and epoxide derivatives), one of which furnished hexalone derivative 11 (via an intermediate diazomethyl ketone derivative). The above‐mentioned starting esters were converted to ethylene ketals, the free‐radical oxidations of which led to hydrobenzofuran acids. One of the latter led to a hydrindanone (via a diazomethyl ketone), whose further chemical elaboration yielded an incisterol model. A second hydrobenzofuran acid gave a cyclobutenone (via the diazomethyl ketone), which was transformed into a more‐stable cyclopentenone isomer by treatment with Lewis acid.     

Sesterterpenes and 2H‐Pyran‐2‐ones (=α‐Pyrones) from the Mangrove‐Derived Endophytic Fungus Fusarium proliferatum MA‐84

Two new tricyclic sesterterpenes, fusaprolifins A and B ( 1 and 2 ), and three new 2H‐pyran‐2‐one derivatives, prolipyrones A – C ( 3 – 5 ), were isolated and characterized from Fusarium proliferatum MA‐84, an endophytic fungus obtained from the fresh tissue of the marine mangrove plant Bruguiera sexangula. In addition, two known sesterterpenes, terpestacin ( 6 ) and fusaproliferin ( 7 ), and one known 2H‐pyran‐2‐one derivative, gibepyrone D ( 8 ), were also identified. The structures of these compounds were elucidated by detailed spectroscopic analyses. Fusaprolifin A ( 1 ) showed moderate activity against brine shrimp (Artemia salina), with a lethality rate of 49.5% at 100 μg/ml, while fusaprolifin B ( 2 ) showed weak activity.     

Probing a General Rule towards Thermodynamic Stabilities of Mono BN‐doped Lower Polyenes

The BN‐doped organic analogues are interesting as aliphatic amineboranes for hydrogen storage, precursors for aromatic borazines and adsorbent cage azaboranes. However, BN‐doped aliphatic polyenes remained undeveloped. Herein, we perform theoretical calculations on two mono BN‐doped aliphatic lower polyenes, 1,3‐butadiene and 1,3,5‐hexatriene. A general rule is proposed, i.e., isomers with terminal nitrogen and directly BN‐connected, N−B(R), in particular, are of significant thermodynamic stability as compared with their inverse analogues (where boron is at the terminal position). The N−B(R) type isomers are found to be the most stable ones in both polyenes. Isomers with terminal B and N are of intermediate stability. Highly destabilized isomers are those with one terminal methylene group and one terminal heteroatom in the butadiene series, and two terminal methylene groups in the hexatriene series. Rules established here may lead researchers to synthesize isomers with particular thermodynamic stability.     

Aryne‐Induced Novel Tandem 1,2‐Addition/(3+2) Cycloaddition to Generate Imidazolidines and Pyrrolidines

A new “single‐flask” method was developed for the synthesis of imidazolidines and pyrrolidines with high stereoselectivity. First, a Schiff base was arylated with an aryne. Second, an intramolecular proton transfer took place from the methylene position to the anionic aryne ring. Third, the resultant ylide reacted with a second equivalent of the same Schiff base in situ or an electron‐deficient alkene through a (3+2) cycloaddition. These sequential tandem 1,2‐addition/(3+2) cycloaddition reactions led to the desired heterocycles in 63–88 % yields.     

Syntheses,Characterization, and Antibacterial Activities of Four New Schiff Base Compounds Derived from 1‐Phenyl‐3‐methyl‐4‐benzoyl‐2‐pyrazolin‐5‐one

Four new Schiff bases were designed and synthesized. 5‐Methyl‐4‐(4‐aminophenylamino‐phenyl‐methylene)‐2‐phenyl‐2,4‐dihydro‐pyrazol‐3‐one (compound 1 ) and 5‐methyl‐4‐(2‐aminophenylamino‐phenyl‐methylene)‐2‐phenyl‐2,4‐dihydro‐pyrazol‐3‐one (compound 2 ) were synthesized by interaction of 1‐phenyl‐3‐methyl‐4‐benzoyl‐2‐pyrazolin‐5‐one (PMBP) with o‐ and p‐phenylenediamine, respectively; 4,4′‐(1,2‐phenylenebis(azanediyl)bis(phenylmethanylylidene))bis(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one) (compound 3 ) and 5‐methyl‐4‐(phenyl(2‐((3‐phenylallylidene)amino)phenylamino)methylene)‐2‐phenyl‐2,4‐dihydro‐pyrazol‐3‐one (compound 4 ) were synthesized by interaction of compound 2 with PMBP and cinnamaldehyde in an ethanolic medium, respectively. The molecular structures of the title compounds were first characterized by single‐crystal X‐ray diffraction, mass spectrometry, and elemental analysis. The title compounds were tested for antibacterial activity (Escherichia coli, Staphylococcus aureus, and Bacillus subtilis) by disk diffusion method.     

Secondary Metabolites from the Leaves of Litsea lii var. nunkao‐tahangensis

Investigation of the leaves extract of Litsea lii var. nunkao‐tahangensis led to the isolation of five new butanolides, litsealiicolide A ( 1 ), isolitsealiicolide A ( 2 ), litsealiicolide B ( 3 ), isolitsealiicolide B ( 4 ), and isolitsealiicolide C ( 5 ), along with 17 known compounds. Their structures were determined through in‐depth spectroscopic and mass‐spectrometric analyses. Among the isolates, compounds 1 and 2 were cytotoxic against MCF‐7, NCI‐H460, and SF‐268 cell lines in vitro. Compound 5 and isolinderanolide B ( 6 ) showed marginal cytotoxic activity against these three cell lines in vitro.     

Synthesis of New 9‐Methylene Analogs of Retinoids

We report herein a series of syntheses that provides diverse structural modifications of the side‐chain of retinoids to obtain new compounds with potential use in anticancer therapy. Starting from a β‐methylenealdehyde synthon, we have synthesized a series of new 9‐methylene‐13‐desmethyl‐14‐methyl analogs and a series of 9‐methylene‐11‐desmethyl trienic homologs. For the first series, the condensation of the C‐15 β‐methylenealdehyde with the anion of ethyl 4‐(diethoxyphosphoryl)‐2E‐methylbut‐2‐enoate led to the 7E,11E,13E‐ester. This gave the desired aldehyde by a reduction into the corresponding alcohol (DIBAL‐H) and subsequent oxidation by MnO₂. For the second series, the reaction of the C‐15 β‐methylenealdehyde with the anions of ethyl diethoxyphosphorylacetate, diethyl cyanomethylphosphonate, or diethyl 2‐oxopropylphosphonate led to the C‐17 ester, the C‐17 nitrile, and the C‐18 ketone, respectively.     

Liquid‐crystalline thermosets from liquid‐crystalline epoxy resins containing bisazomethinebiphenylene mesogens in the central core: Copolymerization with a nonmesomorphic epoxy resin

A new series of liquid‐crystalline epoxy resins was synthesized, and their mesomorphic behavior was investigated with differential scanning calorimetry, polarized optical microscopy, and wide‐angle X‐ray scattering. These glycidylic compounds had central aromatic imine mesogens derived from benzidine and aliphatic spacers of up to 10 methylene units that linked the mesogens to the glycidylic groups. Crosslinking these monomers with primary aromatic diamines led to nematic networks, some of which contained crystal inclusions. However, through curing with tertiary amines as catalytic agents or through copolymerization with different proportions of the nonmesomorphic epoxy monomer and primary amines as crosslinking agents, smectic C organized thermosets were prepared when the spacers had at least four methylene carbons. When they had fewer than four, the networks were nematic. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 3631–3643, 2004     

Discovery and Characterization of a New Family of Diterpene Cyclases in Bacteria and Fungi

Diterpene cyclases from bacteria and basidiomycete fungi are seldom studied. Here, we presented the identification and verification of EriG, a member of the UbiA superfamily, as the enzyme responsible for the cyclization of the cyathane skeleton in the mushroom Hericium erinaceum . Genome mining using the EriG protein sequence as a probe led to the discovery of a new family of ubiquitous UbiA‐related diterpene cyclases in bacteria and fungi. We successfully characterized seven new diterpene cyclases from bacteria or basidiomycete fungi with the help of an engineered Escherichia coli strain and determined the structures of their corresponding products. A new diterpene with an unusual skeleton was generated during this process. The discovery of this new family of diterpene cyclases provides new insight into the UbiA superfamily.     

Synthesis,Characterization, and Screening for Antiamoebic Activity of Palladium(II), Platinum(II), and Ruthenium(II) Complexes with NS‐Donor Ligands

Reaction of [PdCl₂(DMSO)₂], [PtCl₂(DMSO)₂], and [RuCl₂(η⁴‐C₈H₁₂)(MeCN)₂] with S‐acetyl N^β‐acetyldithiocarbazate (=2‐acetylhydrazinecarbodithioic acid anhydrosulfide with ethanethioic acid; aadt; 1 ), S‐methyl N^β‐[(5‐nitrothiophene‐2‐yl)methylene]dithiocarbazate (=S‐methyl 2‐[(5‐nitrothiophene‐2‐yl)methylene]hydrazinecarbodithioate; mntdt; 2 ), and S‐benzyl N^β‐[(5‐nitrothiophene‐2‐yl)methylene]dithiocarbazate (=S‐benzyl 2‐[(5‐nitrothiophene‐2‐yl)methylene]hydrazinecarbodithioate; bntdt; 3 ) led to new complexes [PdCl₂(L)], [PtCl₂(L)], and [RuCl₂(η⁴‐C₈H₁₂)(L)] (L=ligands 1 – 3 ). All these compounds were characterized by elemental analysis, IR, ¹H‐ and ¹³C‐NMR and UV/VIS spectra and thermogravimetric analysis. Ligand 1 coordinates through the thioxo S‐atom and the carbazate N(β) atom, whereas in ligands 2 and 3 the thioxo S‐atom and the azomethine N‐atom are coordinated to the metal ion. Screening of antiamoebic activity of these compounds was performed in vitro against the HK‐9 strain of E. histolytica. All the complexes were more active than their respective ligands; compound 3a showed the most promising activity.     

A high-throughput screening assay for assessing the viability of Cryptococcus neoformans under nutrient starvation conditions

Cryptococcus neoformans causes an estimated 600,000 AIDS-related deaths annually that occur primarily in resource-limited countries. Fluconazole and amphotericin B are currently available for the treatment of cryptococcal-related infections. However, fluconazole has limited clinical efficacy and amphotericin B requires intravenous infusion and is associated with high renal toxicity. Therefore, there is an unmet need for a new orally administrable anti-cryptococcal drug. We have developed a high-throughput screening assay for the measurement of C. neoformans viability in 1,536-well plate format. The signal-to-basal ratio of the ATP content assay was 21.9 fold with a coefficient of variation and Z' factor of 7.1 % and 0.76, respectively. A pilot screen of 1,280 known compounds against the wild-type C. neoformans (strain H99) led to the identification of four active compounds including niclosamide, malonoben, 6-bromoindirubin-3′-oxime, and 5-[(4-ethylphenyl)methylene]-2-thioxo-4-thiazolidinone. These compounds were further tested against nine clinical isolates of C. neoformans, and their fungicidal activities were confirmed. The results demonstrate that this miniaturized C. neoformans assay is advantageous for the high-throughput screening of large compound collections to identify lead compounds for new anti-cryptococcal drug development.     

Trifluoromethyl‐Radical‐Mediated Carbonylation of Alkanes Leading to Ethynyl Ketones

The carbonylation of alkanes 1 under radical‐reaction conditions was examined by using ethynyl triflone A as the unimolecular chain‐transfer (UMCT) reagent. Good to moderate yields of ethynyl ketones 2 were prepared by means of this three‐component coupling reaction. Higher CO pressures as well as lower concentrations of triflone A improved the efficiency of the reaction over the direct addition, the latter leading to alkylated ethynes 3 . In contrast to the reaction with A , the reaction of cyclohexane ( 1a ) with allyl triflone B (= ethyl 2‐methylene‐3‐[(trifluoromethyl)sulfonyl]propanoate) in the presence of CO gave a mixture of carbonylation products, including 8a formed from two molecules each of cyclohexane, CO, and allyl triflone B .