Copper(II)-mediated C-H sulphenylation or selenylation of tryptophan enabling macrocyclization of peptides.

Cu(II)-mediated C-H sulphenylation or selenylation of Trp indole by a derivative of cysteine or selenocysteine enables access to the tryptathionine unit or its selenium congener. The mechanism of these protocols, which allow macrocyclization of Trp-containing peptides, has been studied.

Phenols and γ-Lactams from the Aerial Part of Pseudolysimachion linariifolium subsp. dilatatum.

Linariifolioside II (1) and (2S)-2-hydroxy-5-oxoproline methyl ester (2), two new compounds along with 13 known compounds were obtained from the aerial part of Pseudolysimachion linariifolium Holub subsp. dilatatum (Nakai & Kitag.) D.Y. Hong. Their chemical structures were revealed mainly through NMR and MS data. The absolute configuration of 2 was deduced by comparing its experimental CD with the calculated ECD spectra. At a concentration of 1 mm, total antioxidant capacities of compounds 1-15 were measured using a rapid ABTS method in vitro. Compounds 1, 3-5, and 11-14 exhibited approximately equal antioxidant capacity to that of vitamin C (Vc).

Rapid and sensitive identification of ricin in environmental samples based on lactamyl agarose beads using LC-MS/MS (MRM).

Ricin, a plant-derived toxin extracted from the seeds of Ricinus communis (castor bean plant), is one of the most toxic proteins known. Ricin's high toxicity, widespread availability, and ease of its extraction make it a potential agent for bioterrorist attacks. Most ricin detection methods are based on immunoassays. These methods may suffer from low efficiency in matrices containing interfering substances, or from false positive results due to antibody cross reactivity, with highly homologous proteins. In this study, we have developed a simple, rapid, sensitive, and selective mass spectrometry assay, for the identification of ricin in complex environmental samples. This assay involves three main stages: (a) Ricin affinity capture by commercial lactamyl-agarose (LA) beads. (b) Tryptic digestion. (c) LC-MS/MS (MRM) analysis of tryptic fragments. The assay was validated using 60 diverse environmental samples such as soil, asphalt, and vegetation, taken from various geographic regions. The assay's selectivity was established in the presence of high concentrations of competing lectin interferences. Based on our findings, we have defined strict criteria for unambiguous identification of ricin. Our novel method, which combines affinity capture beads followed by MRM-based analysis, enabled the identification of 1 ppb ricin spiked into complex environmental matrices. This methodology has the potential to be extended for the identification of ricin in body fluids from individuals exposed (deliberately or accidentally) to the toxin, contaminated food or for the detection of the entire family of RIP-II toxins, by applying multiplex format.

Spirocyclic lactams and curvulinic acid derivatives from the endophytic fungus Curvularia lunata and their antibacterial and antifungal activities.

Curvularia lunata, isolated from the capitula of Paepalanthus chiquitensis (Eriocaulaceae), was cultured in potato dextrose broth (PDB) medium. The ethyl acetate extract yielded two new spirocyclic γ-lactams (3 and 4), and five known compounds, namely: triticones E (1) and F (2), 5-O-methylcurvulinic acid (5), curvulinic acid (6) and curvulin (7). Their structures were elucidated by spectroscopic analysis and by the comparison with literature data. Besides, a computational study was used to elucidate the absolute configuration of the C - 3' in the compounds (3) and (4). The extract and the compounds (1 and 2), (6) and (7) were assayed against gram-positive and gram-negative bacteria and fluconazole-resistant yeast. The triticones (1) and (2) showed good antibacterial activity for Escherichia coli, with a minimum inhibitory concentration of 62.5 µg/mL.

Glechomanamides A-C, Germacrane Sesquiterpenoids with an Unusual Δ8-7,12-Lactam Moiety from Salvia scapiformis and Their Antiangiogenic Activity.

Three new germacrane sesquiterpenoid-type alkaloids with an unusual Δ8-7,12-lactam moiety, glechomanamides A-C (1-3), and two pairs of 7,12-hemiketal sesquiterpenoid epimers (4a/b, 5a/b) were isolated from Salvia scapiformis. Their structures were elucidated by spectroscopic methods including HRESIMS, IR, UV, and 1D and 2D NMR and also confirmed by single-crystal X-ray diffraction analysis. The chemical transformation of compounds 1-5 in a solution environment was analyzed by 2D NMR spectroscopy. The aza acetallactams (1-3) were stable in organic solvent, while single crystals of the hemiacetal esters (4a/b, 5a/b) underwent a tautomeric equilibrium after being dissolved. Single crystals of 4a, 4b, and 5a were obtained for the first time as their naturally occurring forms. Glechomanamide B (2) exhibited antiangiogenic activity by suppression of vascular endothelial growth factor (VEGF)-induced tube formation through modulation of VEGF receptor 2 (VEGFR2)-mediated signaling pathways in human umbilical vascular endothelial cells (HUVECs). In addition, compound 2 also showed the significant suppression of mRNA expression associated with glycolysis and angiogenesis biomarkers in high glucose (30 mM)-induced HUVECs. These findings suggest that compound 2 might be a potential lead compound candidate for the management of diabetic retinopathy.

Dasymaschalolactams A-E, Aristolactams from a Twig Extract of Dasymaschalon dasymaschalum.

Five new aristolactam alkaloids (1-5), dasymaschalolactams A-E, and the first isolation of dasymaschalolactone (17) as a natural product, together with 19 known compounds (6-16 and 18-25) were isolated from the twig extract of Dasymaschalon dasymaschalum. Their structures were elucidated by spectroscopic methods as well as comparisons made from the literature. Compounds 20 and 21 showed α-glucosidase inhibitory activities with IC50 values of 4.5 and 24.7 µM, respectively.

Aporphine alkaloids from Piper erecticaule and acetylcholinesterase inhibitory activity / Alcaloides de aporfina obtenida de Piper erecticaule y actividad inhibitoria de la acetilcolinesterasa

Chemical constituents and biological activities of the aerial parts of Piper erecticaule C.DC. have been studied for the first time. Fractionation and purification of the extracts afforded aristolactam AII (1), aristolactam BII (2), piperolactam A (3), piperolactam C (4), piperolactam D (5), together with terpenoids of ß-sitosterol, ß-sitostenone, taraxerol, and lupeol. The structures of these compounds were obtained by analysis of their spectroscopic data, as well as the comparison with that of reported data. Acetylcholinesterase inhibitory activity revealed that compounds 1 and 3 showed strong AChE inhibitory effects with the percentage inhibition of 75.8% and 74.8%, respectively.

Se estudiaron por primera vez los constituyentes químicos y actividad biológica de las partes aéreas de Piper erecticaule C.DC. El fraccionamiento y la purificación de los extractos proporcionaron aristolactama AII (1), aristolactama BII (2), piperolactama A (3), piperolactama C (4), piperolactama D (5), junto con terpenoides de ß-sitosterol, ß-sitostenona, taraxerol, y el lupeol. Las estructuras de estos compuestos se obtuvieron mediante el análisis de sus datos espectroscópicos, así como mediante la comparación con datos ya informados. La actividad inhibidora de la acetilcolinesterasa reveló que los compuestos 1 y 3 mostraron un potente efecto inhibidor de la AChE con un porcentaje de inhibición del 75.8% y 74.8%, respectivamente.

Identification of benzo[cd]indol-2(1H)-ones as novel Atg4B inhibitors via a structure-based virtual screening and a novel AlphaScreen assay.

Targeting autophagy is a promising therapeutic strategy for cancer treatment. As a result, the identification of novel autophagy inhibitors is an emerging field of research. Herein, we report the development of a novel AlphaScreen HTS assay that combined with a MS-based assay and a structure-based high-throughput virtual screening have enabled the identification of benzo[cd]indol-2(1H)-one as a novel scaffold that targets Atg4B. Thus, an initial screening campaign led to the identification of NSC126353 and NSC611216 bearing a chlorohydrin moiety. Structural-activity relationship analysis of the initial hits provided an optimized lead, compound 33, bearing a 7-aminobenzo[cd]indol-2-[1H]-one scaffold and a propyl group replacing the chlorine. Inhibition of autophagy was also investigated in cells by measuring LC3-II and p62 protein levels. Moreover, the synergistic effect of 33 combined with oxaliplatin resulted in an enhanced cell death in the human colorectal adenocarcinoma cell line HT-29. We are convinced that the developed AlphaScreen and MS-based assays can be key tools enabling the high-throughput identification of novel Atg4B inhibitors. Moreover, the aminobenzo[cd]indol-2-[1H]-one scaffold represents a novel chemotype for the further development of small molecule inhibitors of Atg4B.

ß-Thujone and Its Derivatives Modify the Probing Behavior of the Peach Potato Aphid.

Thujone is a natural biologically active monoterpene ketone component of essential oils of numerous plants. The aim of the study was to evaluate the effect of ß-thujone and ß-thujone derivatives bisulfite adduct, lactone, oxime, and lactam application on behavior of Myzus persicae (Sulz.) (Hemiptera: Aphididae) during probing and settling. The choice and no-choice tests (aphid settling and Electrical Penetration Graph (EPG), respectively) revealed that stereochemistry of thujone was important for biological activity (ß-thujone caused changes in aphid behavior while α-thujone did not) and that cyclopentane ring modifications and functional groups addition gave derivatives that possessed stronger and more durable deterrent effects. The most effective modification was the incorporation of a lactam moiety into the ß-thujone molecule. Application of ß-thujone lactam limited aphid settling for at least 24 h, caused restlessness in aphids and a delay or failure in reaching phloem phase by M. persicae. ß-Thujone lactam can be considered a deterrent of medium potency with activity expressed at preingestive phase of aphid probing. Other compounds did not restrain aphid stylet penetration in non-phloem tissues but slightly limited sap ingestion (lactone, oxime), and restrained aphid settling for a period of less than 24 h (ß-Thujone, bisulphite adduct, lactone).

A new lactam 28-norlimonoid from the leaves of Azadirachta indica A. Juss. (Meliaceae).

From an EtOAc-soluble fraction of the leaves of Azadirachta indica, one new lactam 28-norlimonoid named nimbandiolactam-21 (1), together with 2 known limonoids (2 and 3) were isolated. Their relative structures were elucidated based on NMR spectroscopic analysis. Nimbandiolactone-23 (2) showed the most potent α-glucosidase inhibitory activity, with an IC50 value of 38.7 µM. Compound 1 represents the first naturally occurring example of a 28-norlimonoid having the lactam moiety. The plausible biosynthetic pathway for the formation of lactam moiety in 1 was proposed.

Scalalactams A⁻D, Scalarane Sesterterpenes with a γ-Lactam Moiety from a Korean Spongia Sp. Marine Sponge.

Intensive study on the chemical components of a Korean marine sponge, Spongia sp., has led to the isolation of four new scalarane sesterterpenes, scalalactams A⁻D (1⁻4). Their chemical structures were elucidated from the analysis of spectroscopic data including 1D-and 2D-NMR as well as MS data. Scalalactams A⁻D (1⁻4) possess a scalarane carbon skeleton with a rare structural feature of a γ-lactam moiety within the molecules. Scalalactams A and B (1 and 2) have an extended isopropanyl chain at the lactam ring, and scalalactams C and D (3 and 4) possess a phenethyl group at the lactam ring moiety. Scalalactams A⁻D (1⁻4) did not show FXR antagonistic activity nor cytotoxicity up to 100 µM.

Expanding lysine industry: industrial biomanufacturing of lysine and its derivatives.

L-Lysine is widely used as a nutrition supplement in feed, food, and beverage industries as well as a chemical intermediate. At present, great efforts are made to further decrease the cost of lysine to make it more competitive in the markets. Furthermore, lysine also shows potential as a feedstock to produce other high-value chemicals for active pharmaceutical ingredients, drugs, or materials. In this review, the current biomanufacturing of lysine is first presented. Second, the production of novel derivatives from lysine is discussed. Some chemicals like L-pipecolic acid, cadaverine, and 5-aminovalerate already have been obtained at a lab scale. Others like 6-aminocaproic acid, valerolactam, and caprolactam could be produced through a biological and chemical coupling pathway or be synthesized by a hypothetical pathway. This review demonstrates an active and expansive lysine industry, and these green biomanufacturing strategies could also be applied to enhance the competitiveness of other amino acid industry.

Pursuing sesterterpene lactams in Australian Irciniidae sponges.

Chemical investigation of two Irciniidae sponges collected by hand (SCUBA) from Australian near shore waters, afforded six new examples of a rare class of sesterterpene lactam; ircinialactams B (1), G (2), H (5), and I (6), and 8-hydroxyircinialactams C (3) and G (4); together with the new biosynthetically related lactone, ircinialactone A (7). Also isolated were seven biosynthetically related known Irciniidae metabolites; ircinialactams A (8) and C (9), (7E,12E,20Z,18S)-variabilin (10), (7Z,12Z,20Z,18S)-variabilin (11), (7E,12Z,20Z,18S)-variabilin (12), (7Z,12E,20Z,18S)-variabilin (13) and irciniafuran A (14). The structure elucidation of 1-14 was achieved by detailed spectroscopic analysis, and consideration of a plausible biosynthetic relationship linking Irciniidae sesterterpene ß-furans, lactams and lactones.

Eight new γ-lactam alkaloids from the roots of the Hemerocallis minor Mill.

Eight new γ-lactam alkaloids, hemerominors A-H (1-8), including two pair of epimers (1-4), together with six known compounds (9-14) were isolated from the roots of Hemerocallis minor Mill. The structures of 1-8 were established on the basis of extensive NMR studies and HR-MS measurements as well as comparison with literature data. The absolute configurations of 1-8 were determined by CD spectral analysis and modified Mosher's method. All of compounds were evaluated for their inhibitory effects against LPS-induced NO production in RAW264.7 macrophages. Among them, compound 13 exhibited moderate inhibitory activity against NO production and with IC50 value of 18.0 µM.

Tamaractam, a New Bioactive Lactam from Tamarix ramosissima, Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Chemical investigation of Tamarix ramosissima Ledeb, a traditional herbal medicine used for rheumatoid arthritis (RA) treatment in northwest China, led to the discovery of a new phenolic aromatic rings substituted lactam, tamaractam (1), together with the previously reported compounds cis-N-feruloyl-3-O-methyldopamine (2) and trans-N-feruloyl-3-O-methyldopamine (3). The structures of the compounds were determined by high resolution electrospray ionization mass spectroscopy (HRESIMS) and 1D and 2D-NMR experiments, as well as comparison with the literature data. The effects of the three compounds on the viability of RA fibroblast-like synoviocytes (RA-FLS) were assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Pro-apoptosis effect of compound 1 in RA-FLS was further investigated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, activated caspase-3/7 level assessment using luminescence assay, and sub-G1 fraction measurement using flow cytometry. It was found that these three compounds displayed variable proliferation inhibitory activity in RA-FLS, and compound 1 exhibited the strongest effect. Compound 1 could remarkably induce cellular apoptosis of RA-FLS, increase activated caspase-3/7 levels, and significantly increase sub-G1 fraction in the cell cycle. The results suggested that compound 1 may inhibit the proliferation of RA-FLS through apoptosis-inducing effect, and these compounds may contribute to the anti-RA effect of T. ramosissima.

New Fluvirucinins C1 and C2 Produced by a Marine Derived Actinomycete.

Two new fluvirucin aglycones, named fluvirucinins C, and C2 (1-2), have been isolated from the ethyl acetate mycelial cake extract of the fermentation broth of.a marine sponge-associated actinomycete. Fluvirucinins C, (1) and C2 (2) represent a new type of 14-membered macrolactam aglycon, structurally related with the common aglycon of the known fluvirucins. Their structures were elucidated on the basis of ID and 2D NMR analyses, as well as HRESIMS experiments. The antimicrobial and cytotoxic activities of compounds 1 and 2 have been evaluated, but no significant activities found for fluvirucinins C, and C2.

Colletotrilactam A-D, novel lactams from Colletotrichum gloeosporioides GT-7, a fungal endophyte of Uncaria rhynchophylla.

Four novel lactams, colletotrilactam A-D (1-4), along with six known compounds (5-10) were isolated from the culture broth of Colletotrichum gloeosporioides GT-7, a fungal endophyte of Uncaria rhynchophylla. The structures of these compounds were elucidated by comprehensive NMR spectroscopy. Isolates were tested for monoamine oxidase (MAO) inhibitory activity and compound 9 showed potent MAO inhibitory activity with IC50 value of 8.93±0.34µg/mL, when the IC50 value of iproniazid as a standard was 1.80±0.5µg/mL.

Bioactivity-guided isolation of laevicarpin, an antitrypanosomal and anticryptococcal lactam from Piper laevicarpu (Piperaceae).

Crude CH2Cl2 extract from leaves of Piper laevicarpu (Piperaceae) displayed antitrypanosomal activity against trypomastigote forms of Trypanosoma cruzi (Y strain) and antimicrobial potential against Cryptococcus gattii (strain-type WM 178). Bioactivity-guided fractionation of crude extract afforded one new natural bioactive lactam derivative, named laevicarpin. The structure of isolated compound, which displayed a very rare ring system, was elucidated based on NMR, IR and MS spectral analysis. Using MTT assay, the trypomastigotes of T. cruzi demonstrated susceptibility to laevicarpin displaying IC50 value of 14.7µg/mL (49.6µM), about 10-fold more potent than the standard drug benznidazole. The mammalian cytotoxicity of laevicarpin was verified against murine fibroblasts (NCTC cells) and demonstrated a CC50 value of 100.3µg/mL (337.7µM-SI=7). When tested against Cryptococcus gattii, laevicarpin showed an IC50 value of 2.3µg/mL (7.9µM) and a MIC value of 7.4µg/mL (25µM). Based in the obtained results, laevicarpin could be used as a scaffold for future drug design studies against the Chagas disease and anti-cryptococosis agents.

γ-Lactam alkaloids from the flower buds of daylily.

Four new alkaloids, hemerocallisamines IV-VII, were isolated from the methanol extract of flower buds of daylily. The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. The absolute stereochemistry of the hemerocallisamines IV-VI was elucidated by the application of the modified Mosher's method, HPLC analysis, and optical rotation. In the present study, the isolated alkaloids significantly inhibited the aggregation of Aß42 in vitro. This is the first report about bioactive alkaloids with a γ-lactam ring from daylily. In addition, isolated nucleosides showed accelerative effects on neurite outgrowth under the non-fasting condition.

The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect.

Multi-target drugs, such as the cocktail therapy used for treating AIDS, often show stronger efficacy than single-target drugs in treating complicated diseases. This review will focus on clausenamide (clau), a small molecule compound originally isolated from the traditional Chinese herbal medicine, Clausenalansium. The finding of four chiral centers in clau molecules predicted the presence of 16 clau enantiomers, including (-)-clau and (+)-clau. All of the predicted enantiomers have been successfully synthesized via innovative chemical approaches, and pharmacological studies have demonstrated (-)-clau as a eutomer and (+)-clau as a distomer in improving cognitive function in both normal physiological and pathological conditions. Mechanistically, the nootropic effect of (-)-clau is mediated by its multi-target actions, which include mild elevation of intracellular Ca(2+) concentrations, modulation of the cholinergic system, regulation of synaptic plasticity, and activation of cellular and molecular signaling pathways involved in learning and memory. Furthermore, (-)-clau suppresses the pathogenesis of Alzheimer's disease by inhibiting multiple etiological processes: (1) beta amyloid protein-induced intracellular Ca(2+) overload and apoptosis and (2) tau hyperphosphorylation and neurodegeneration. In conclusion, the nature of the multi-target actions of (-)-clau substantiates it as a promising chiral drug candidate for enhancing human cognition in normal conditions and treating memory impairment in neurodegenerative diseases.