Synthesis of the intermediate for fumimycin: a natural peptide deformylase inhibitor

Synthetic efforts toward the potential bacterial peptide deformylase inhibitor fumimycin are reported. The synthetic approach features a tandem Friedel–Crafts alkylation/lactonization access as key reaction to the α, α-disubstituted amino acid unit, and results in the synthesis of an advanced racemic intermediate with an Z configuration propenyl group starting from vanillin with 18 % total yield in five steps.     

Vibralactone: a lipase inhibitor with an unusual fused beta-lactone produced by cultures of the basidiomycete Boreostereum vibrans

The structure and absolute configuration of vibralactone (1) from the cultures of the Basidiomycete Boreostereum vibrans were established by spectroscopic methods and computational methods. Vibralactone, an unusual fused beta-lactone-type metabolite, was found to inhibit pancreatic lipase with an IC50 of 0.4 microg/mL. [structure: see text]     

Identification of a potent peptide deformylase inhibitor from a rationally designed combinatorial library

Peptide deformylase catalyzes the removal of the N-terminal formyl group from nascent polypeptides during prokaryotic protein synthesis and maturation and is essential for bacterial survival. Its apparent absence from mammalian organisms makes it an attractive target for designing novel antibacterial agents. Based on the substrate specificity of peptide deformylase from Escherichia coli, a focused library of peptide thiols was synthesized on TentaGel resin using a disulfide linkage. Screening of the library against the purified deformylase was carried out in solution phase after the inhibitors were released from the resin with a reducing agent. A potent deformylase inhibitor was obtained from a 750-member library and was further optimized through rational modification into a low nanomolar inhibitor (KI = 15 nM against E. coli deformylase).     

Belizeanic acid: a potent protein phosphatase 1 inhibitor belonging to the okadaic acid class, with an unusual skeleton

Belizeanic acid (BA), a novel metabolite belonging to the okadaic acid class of protein phosphatase inhibitors, was isolated from artificial cultures of the dinoflagellate Prorocentrum belizeanum. The structure and conformational behaviour of BA was elucidated by a combination of NMR spectroscopy and conformational analysis. The isolation of this metabolite, which possesses a simplified version of the okadaic acid skeleton, supports the biogenetic pathway previously reported for this class of compounds. BA showed potent inhibitory activity against protein phosphatase 1 (PP1) within the nM range. A plausible model for the interaction of BA with the PP1 binding pocket was derived from computational docking studies.     

Stereochemical definition and chirospecific synthesis of the peptide deformylase inhibitor Sch 382583

The recently reported natural product Sch 382583 (1), an inhibitor of peptide deformylase, has been synthesized in 16 steps from commercially available starting materials. The three chiral centers were set by a combination of chiral auxiliary and chiral pool approaches. The succinate 5 and piperazic acid 9 moieties were obtained by Evans oxazolidinone imide enolate alkylation and hydrazination/cyclization, respectively, and the aminohexanone side chain 13 was prepared via Grignard substitution of the Weinreb amide derived from l-valine. Spectroscopic data for the resulting synthetic material, compared with the data reported for the natural product, established that the previously unassigned valine ketone stereocenter (C-4) has the S-configuration.     

Synthetic studies toward swinhoeisterol A,a novel steroid with an unusual carbon skeleton

Swinhoeisterol A is a novel steroid with unusual 6/6/5/7 tetracyclic skeleton. The model compound with BCD rings is constructed by Friedel–Crafts acylation and an oxidative dearomatization as key steps.     

Euphoractone,a cytotoxic meroterpenoid with an unusual ent-abietane-phloroglucinol skeleton,from Euphorbia fischeriana Steud.

A novel meroterpenoid,euphoractone(1),was isolated from the extracts of the roots of Euphorbia fischeriana Steud.Its structure was determined by spectroscopic methods and X-ray crystallography.1 possesses an unusual ent-abietane-phloroglucinol skeleton.The plausible biosynthetic pathway for 1 was proposed.1 showed inhibitory activities against human lung cancer H23 and H460 cells with the IC₅₀values of 21.07±3.54 and 20.91±4.07 μmol/L.     

Ainsliadimer A, a new sesquiterpene lactone dimer with an unusual carbon skeleton from Ainsliaea macrocephala

A phytochemical investigation of Ainsliaea macrocephala led to the isolation of a new dimeric sesquiterpene lactone, ainsliadimer A (1). The structure of 1 was elucidated by spectroscopic analysis, and confirmed by single crystal X-ray diffraction. Ainsliadimer A represents an unusual carbon skeleton with a cyclopentane system connecting the two monomeric sesquiterpene lactone units. This unique molecule exerted potent inhibitory activity against the production of nitric oxide in RAW264.7 stimulated by LPS.     

Justiciosides E-G, triterpenoidal glycosides with an unusual skeleton from Justicia betonica

Three new triterpenoidal glucosides, justiciosides E, F and G, were isolated from the aerial portion of Justicia betonica. Their structures were established through chemical and spectroscopic analyses, and showed an unusual A-nor-B-homo oleanan-12-ene skeleton type for the aglycone moiety as A-nor-B-homo-oleanan-10,12-diene-3β,11α,28-triol 28-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranoside, A-nor-B-homo-oleanan-10,12-diene-3β,11α,28-triol 28-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)-β-d-glucopyranoside, and 11α-methoxy-A-nor-B-homo-oleanan-10,12-diene-3β,11α,28-triol 28-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)-β-d-glucopyranoside, respectively.     

Macropodumines A-C: novel pentacyclic alkaloids with an unusual skeleton or zwitterion moiety from Daphniphyllum macropodum Miq

Three novel alkaloids, macropodumines A-C (1-3), were isolated from the stem of Daphniphyllum macropodum Miq. Interestingly, the structure of macropodumine A (1) was characterized as having a fused pentacyclic system including an unusual eleven-membered macrolactone ring, whereas macropodumine B (2) contains a rare cyclopentadienyl carbanion, which is stabilized as a zwitterion by an internal iminium cation. The structures of these new metabolites were established on the basis of their detailed spectroscopic analysis. In particular, the unique structure of zwitterion 2 was further confirmed by using single-crystal X-ray diffraction analysis.     

Modeling the inhibition of peptide deformylase by hydroxamic acids: influence of the sulfur donor

The first complexes containing both a sulfur atom and a hydroxamate moiety coordinated to a biologically relevant transition metal were synthesized as models for the structure of inhibited peptide deformylases. Two of these [(N(2)S)Zn(hydroxamate)] complexes were characterized by X-ray crystallography. The first contains a thioether and a simple hydroxamate, the second a thiolate and a N-substituted hydroxamate. Isolation of a complex with a thiolate and a simple hydroxamate group was not possible.     

Bolivianine, a new sesterpene with an unusual skeleton from Hedyosmum angustifolium, and its isomer, isobolivianine

Bolivianine, a novel sesterpene with an unprecedented skeleton, has been isolated from the trunk bark of Hedyosmum angustifolium (Chloranthaceae), with isobolivianine, an isomer formed under acidic conditions. The structure and relative stereochemistry were elucidated on the basis of spectroscopic data. A hypothesis for biogenesis was made.     

Importance of iron as the metal ion in peptide deformylase: a biomimetic computational study

Peptide deformylase (PDF), a metalloamidase which catalyzes a deformylation step during eubacterial protein biosynthesis, shows a peculiar preference for Fe^II as its active site metal ion (in particular, as opposed to Zn^II, which is far more common among this class of enzymes). In order to explore the origin of this preference, density functional theory (DFT) calculations have been carried out using a biomimetic heteroscorpionate N₂S_thiolate ligand system (L) and the metal centers Fe^II, Zn^II, and Co^II. Comparison of computed ML(formate) complexes to crystal structures of PDF?Cformate complexes illustrates the viability of the biomimetic ligand for investigating the PDF chemistry. pK_a calculations on [ML(H₂O)]⁺ complexes show that the metal centers are effective Lewis acids in activating the water molecule to allow formation of a nucleophilic hydroxide ligand. Computed oxidation potentials predict the ML(OH) and ML(formate) complexes not to be unstable with respect to oxidation. However, while each of the metal centers was therefore seen to be suitable for PDF chemistry, examination of the entire deformylation reaction showed Fe^II to be uniquely suited to PDF. The deformylation reaction was thermodynamically and kinetically optimal with Fe^II as the metal center. This is attributed to the charge transfer that occurs from the thiolate ligand to the Fe^II center during the reaction and to the relative coordinative flexibility of Fe^II that allows for facile interconversion between tetra- and pentacoordination, leading to greater activation of the substrate carbonyl at the nucleophilic attack transition state.     

Azaspirene: a novel angiogenesis inhibitor containing a 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton produced by the fungus Neosartorya sp

[structure: see text] Azaspirene isolated from the fungus Neosartorya sp. is a novel angiogenesis inhibitor with a 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton. Azaspirene inhibits the endothelial migration induced by vascular endothelial growth factor (ED100 = 27.1 microM).     

Javaniside, a novel DNA cleavage agent from Alangium javanicum having an unusual oxindole skeleton

Bioassay-guided fractionation of an extract prepared from Alangium javanicum using an assay to monitor Cu(2+)-dependent DNA strand scission led to the isolation of javaniside, a new type of oxindole glycoside.     

Role of the metal ion in formyl-peptide bond hydrolysis by a peptide deformylase active site model

The catalytic mechanism of peptide deformylase enzymes containing zinc, iron, cobalt, and nickel dications was explored in the gas phase and in the protein environment. The study was performed at the density functional level using three model systems to simulate the active site. The work had the aim to evaluate the effect of metal substitution on the hydrolytic properties and the possible different performances of the various catalysts. Results indicated that all of the metallic forms are active to hydrolyze the formyl-peptide bond and that the reaction pathways do not show significant peculiarities on going from a particular metal ion to another. No significant modification of the reaction paths occurs in solvent.     

Cytotoxic polyprenylated benzoylphloroglucinol derivatives with an unusual adamantyl skeleton from Hypericum sampsonii (Guttiferae)

[formula: see text] The structures of sampsoniones I and J, isolated from the aerial parts of the Chinese medicinal plant Hypericum sampsonii, have been elucidated by detailed spectral analysis. They are complex adamantyl derivatives, and sampsonione I is the first polyprenylated benzoylphloroglucinol derivative with the unique caged tetracyclo[7.3.1.1.0]tetradecane-2,12,14-trione skeleton. Cytotoxic sampsonione I has also been obtained by the biomimetic transformation of sampsonione J.     

Artalbic acid, a sesquiterpene with an unusual skeleton from Artemisia alba (Asteraceae) from Sicily

From the aerial parts of Artemisia alba (Asteraceae) artalbic acid (1), a sesquiterpene with an unusual skeleton, was isolated. Its structure was elucidated on the basis of extensive proton, ¹³C and two-dimensional NMR experiments, as well as by transformation in its methyl ester derivative.     

Oxyphyllones A and B,novel sesquiterpenes with an unusual 4,5-secoeudesmane skeleton from Alpinia oxyphylla

Two novel 4,5-secoeudesmane sesquiterpenoids,oxyphyllones A(1) and B(2) were isolated from the fruits of Alpinia oxyphylla.Their structures were established by spectroscopic methods including 1D and 2D NMR spectra.These two compounds are the first example of naturally occurring sesquiterpenoids with a 4,5-secoeudesmane skeleton in the family of Zingiberaceae and oxyphyllone A(1) is the first 4,5-secoeudesmane type of 13-norsesquiterpenoid.Compounds 1 and 2 exhibited no cytotoxicities against three cancer...