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Vicenistatin ( 1 ) is a potent polyketide antitumor antibiotic composed of a 20-membered macrolactam core appended to a unique aminosugar, vicenisamine. In this study, vicenistatin was isolated and its biosynthetic gene cluster identified from Monodonata labio -associated Streptomyces parvus SCSIO Mla-L010. A set of five genes, vicC , vicD , vicE , vicF , and vicG , was confirmed to be involved in the biosynthesis of the aminosugar by gene inactivations. VicG was characterized as an N -methyltransferase that catalyzes the methylation of the 4'-amino group in the last step of the aminosugar biosynthetic pathway; the N -demethyl intermediate 4'- N -demethylvicenistatin ( 2 ) was isolated from the Δ vicG mutant strain. In addition, vicR1 was characterized as a positive pathway-specific regulatory gene. Notably, N -demethyl compound 2 was found to exert impressive antibacterial activities, with MIC values spanning 0.06-4 μg/mL, against a panel of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus , Gram-negative Helicobacter pylori , and mycobacterium Mycobacterium smegmatis and the fungal pathogen Candida albicans . Compound 2 was also found to display reduced cytotoxicities relative to vicenistatin, especially against noncancerous human cell lines.

Three new germacrane sesquiterpenoid-type alkaloids with an unusual Δ 8 -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.

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 IC 50 values of 4.5 and 24.7 μM, respectively.

In our screening program for new biologically active secondary metabolites, a new strain, Nocardiopsis CG3 (DSM 106572), isolated from the saltpan of Kenadsa, was found to produce five new polyene macrolactams, the kenalactams A-E (1-5). Their structures were elucidated by spectral methods (NMR and HRESIMS), and the absolute configuration was derived by chemical derivatization (Mosher's method). Through a feeding experiment, alanine was proven to be the nitrogen-bearing starter unit involved in biosynthesis of the polyketide kenalactam A (1). Kenalactam E (5) was cytotoxic against human prostate cancer PC-3 cells with an IC 50 value of 2.1 μM.

Six new compounds, aristoloxazine A (1), aristoloxazine B (2), 7-methoxytaliscanine (3), humul-7-en-1,4,11-triol (4), 8-hydroxy-β-logipinene (5), and 1β-hydroxy-4(14)-eudesmene (6), corresponding to two sulfur-containing aristoloxazines (1 and 2), an aristolactam (3), and three sesquiterpenes (4-6) were isolated, along with 26 known compounds, from the roots of Aristolochia orbicularis. The structures of the new compounds were established based on their spectroscopic and spectrometric data and in the case of aristoloxazine A (1) by single-crystal X-ray crystallography. This is the first report of sulfur-containing aristoloxazines from a natural source. Furthermore, aristoloxazine A (1) was found to possess potent in vitro antimicrobial activity against all resistant Staphylococcus aureus and several fungal strains in which it was evaluated.

Monascustin (1), an unusual γ-lactam, was isolated from an ethanol extract of the Monascus purpureus fermented rice. Its structure including the absolute configuration was determined by spectroscopic data analysis and confirmed by X-ray crystallography. A plausible biosynthetic pathway is discussed on the basis of amino acid derivatization. Compound 1 showed inhibitory activity against histone deacetylase 1.

Heronamides are a class of potent antifungal metabolites produced by marine-derived actinomycetes. The number of hydroxy groups and the stereochemistry of the two hydroxylated methine carbons are important for the activity of heronamide C, whereas the effect of the hydrocarbon chains is not known. In this study, the stereochemistry and the biological activity of BE-14106, another member of the heronamide class of antibiotics, isolated from an actinomycete Actinoalloteichus cyanogriseus IFM 11549 was investigated. Spectroscopic analysis coupled with photo- and O2-induced conversion revealed that BE-14106 and the heronamides had the same stereochemistry. BE-14106 showed potent growth inhibition against fission yeast cells with an MIC value of 0.50 μM (0.21 μg/mL), being 4 times less potent than heronamide C, which revealed the importance of the structure of the hydrocarbon tail for the activity.

Lajollamycins (1-4), each of which bears a spiro-β-lactone-γ-lactam ring and a nitro-tetraene moiety, were obtained from a marine-derived Streptomyces strain isolated from the southern area of Jeju Island, Republic of Korea. The planar structures of the lajollamycins were elucidated on the basis of spectroscopic analyses by NMR, UV, IR, and MS. The absolute configuration of lajollamycin (1), the planar structure of which has been previously reported, was determined using J-based configuration analysis based on (1)H-(1)H and (1)H-(13)C coupling constants, as well as ROESY correlations, followed by the modified Mosher's method. The absolute configurations of lajollamycins B-D (2-4) were established by comparing their CD spectra with that of 1. The lajollamycins exhibited moderate inhibitory activity toward Candida albicans isocitrate lyase.

Twelve new lactam-bearing limonoids, amooramides A-L (1-12), were isolated from the twigs and leaves of Amoora tsangii, and their structures fully elucidated by spectroscopic analysis. These compounds represent the first examples of rings A,B-seco-limonoids bearing unusual lactam side chains at C-17, including a 3-substituted 1,5-dihydro-2H-pyrrol-2-one moiety in 1-7 and a 4-substituted 1,5-dihydro-2H-pyrrol-2-one unit in 8-12. Compound 9 inhibited TNFα-induced NF-κB activity by 64% at a concentration of 10 μM.

The enantiomeric lactams (-)-8, (+)-8, (+)-9, and (-)-9 were formed by the reaction of the dimeric phthalide rac-tokinolide B (rac-3) with (R)-(+)-α-methylbenzylamine and (S)-(-)-α-methylbenzylamine. The absolute configurations of compounds 8 and 9 were assigned by experimental and theoretically calculated electronic circular dichroism methods for (+)-8 and (-)-9. Compounds 3, 5, (-)-8, (+)-8, (+)-9, and (-)-9 displayed cytotoxic activity toward several human tumor cell lines, with (-)-8 and (-)-9 being the most potent.

Large-scale fermentation of the marine actinomycete Salinispora tropica for production of salinosporamide A (NPI-0052; 1) clinical trials materials provided crude extracts containing minor secondary metabolites, including salinosporamide B (2) and a new congener, 3. Spectroscopic characterization revealed that 3 is identical to antiprotealide, a molecular hybrid of 20S proteasome inhibitors 1 and omuralide (4) not previously described as a natural product. Analysis of crude extracts from shake flask cultures of three wild-type S. tropica strains confirmed the production of antiprotealide at 1.1, 0.8, and 3.0 mg/L. Thus, antiprotealide is a natural product metabolite of S. tropica.

A new cycloartane, monocarpinine (1), incorporating a fused tetrahydrofuranyl ring, and a cytotoxic tetracyclic lactam, monomarginine (2), were isolated from a stem bark extract of the Malayan species Monocarpia marginalis. The structures of these compounds were determined using NMR and MS analysis. Monomarginine (2) showed appreciable cytotoxicity toward human KB (both drug-sensitive and drug-resistant) and Jurkat cells.

Eleven new indole alkaloids, in addition to the previously reported rhazinal (1), and 14 other known alkaloids, were obtained from the Malayan Kopsia singapurensis, viz., kopsiloscines A-F (2-7), 16-epikopsinine (8), kopsilongine- N-oxide (9), 16-epiakuammiline (10), aspidophylline A (11), and vincophylline (12). The structures of these alkaloids were determined using NMR and MS analyses. Rhazinal (1), rhazinilam (17), and rhazinicine (18) showed appreciable cytotoxicity toward drug-sensitive as well as vincristine-resistant KB cells, while kopsiloscines A (2), B (3), and D (5) and aspidophylline A (11) were found to reverse drug-resistance in drug-resistant KB cells.

Two new macrolactams, 6-desmethyl-N-methylfluvirucin A1 (1) and N-methylfluvirucin A1 (2), have been isolated from the acetone extract of Nonomuraea turkmeniaca MA7364. These compounds were isolated by bioassay-guided fractionation as part of our search for new anthelmintics. The structures of these compounds were elucidated by comparison of their NMR and MS data to those of previously reported fluvirucins and confirmed by 2D NMR. Compound 1 exhibited in vitro activity (EC(90) 15 +/- 5 microg/mL) against Haemonchus contortus larvae, whereas compound 2, while a bit less active in vitro (EC(90) 29 +/- 8 microg/mL), showed modest in vivo activity against a surrogate organism, Heligmosomoides polygyrus in mice, at 50 mg/kg.

Two new chondropsin-type macrolide lactams, poecillastrins B (1) and C (2), were isolated from aqueous extracts of the marine sponge Poecillastra sp. These trace metabolites were isolated in low yield (400-600 microg), and their structures were determined primarily by analysis of NMR data acquired using a cyrogenically cooled probe. High-quality 1D and 2D NMR data sets allowed complete assignment of the spectroscopic data and defined the new structures as 35-membered ring analogues of poecillastrin A (3). Compounds 1 and 2 showed potent cytotoxic activity against a human melanoma tumor cell line (LOX) with an IC50 value of less than 1 microg/mL.

The new fungal metabolite awajanomycin (1), which has gamma-lactone-delta-lactam rings, was isolated from the marine-derived fungus Acremonium sp. AWA16-1, which had been collected from sea mud off Awajishima Island in Japan. The structure of 1 was elucidated by spectroscopic analysis and chemical methods. Awajanomycin (1) and its derivative (2) inhibited the growth of A549 cells with IC(50) values of 27.5 and 46.4 microg/mL, respectively.

A strain of Streptomyces nodosus (NPS007994) isolated from a marine sediment collected in Scripps Canyon, La Jolla, California, was found to produce lajollamycin (1), a nitro-tetraene spiro-beta-lactone-gamma-lactam antibiotic. The structure was established by complete analysis of spectroscopic data and comparison with known antibiotics oxazolomycin (2), 16-methyloxazolomycin (3), and triedimycin B (4). Lajollamycin (1) showed antimicrobial activity against both drug-sensitive and -resistant Gram-positive bacteria and inhibited the growth of B16-F10 tumor cells in vitro.

During the course of our screening program designed to discover novel anticancer and anti-infective agents from marine microorganisms, a strain of Streptomyces aureoverticillatus (NPS001583) isolated from a marine sediment was found to produce a novel macrocyclic lactam with cytotoxicity against various tumor cell lines. Using extensive MS, UV, and NMR spectral analyses, the structure has been established as compound 1, aureoverticillactam, a 22-atom macrocyclic lactam incorporating both triene and tetraene conjugated olefins.

Investigation of extracts of Fissistigma balansae and Fissistigma oldhamii resulted in the isolation of 11 aristolactams-stigmalactam (1), piperolactam A (2), piperolactam C (3), aristolactam AII (4), aristolactam AIIIa (5), aristolactam BII (6), aristolactam BIII (7), aristolactam FII (8), goniothalactam (9), enterocarpam I (10), and velutinam (11)-as well as two dioxoaporphines, noraristolodione (12) and norcepharadione B (13). The new compound 1 was identified by spectral data interpretation. Compounds 1-13 were subjected to antiplatelet aggregation testing.

Cryptophycin 46 (2), -175 (3), and -176(4) have been identified as three new trace constituents of Nostoc sp. GSV 224. Cryptophycin-46 is an epimer of cryptophycin-3 (5) and to date is the only naturally occurring analogue having the S configuration at C-10 (C-2 in Unit B). Cryptophycins-175 and -176 also differ in unit B where 3 is the O-methyl analogue of cryptophycin-45 (6) and 4 is the O-desmethyl analogue of cryptophycin-21 (8). The relative and absolute stereochemistries of the three new analogues have been related to known cryptophycins by synthesis.

Two new teleocidin-related metabolites, (-)-7-geranylindolactam-V [2] and blastmycetin F [3], were isolated from fermentation broths of the actinomycete Streptoverticillium blastmyceticum NA34-17, and their structures were determined by spectroscopic methods. Compound 2 bound strongly to phorbol ester receptors in a mouse epidermal particulate fraction, suggesting that it is a potent in vivo tumor promoter comparable to teleocidins A-1 [4] and B-4 [5].