oxepins and acetylaranotin

Acetylaranotin is an epipolythiodiketopiperazine (ETP) secondary metabolite with a broad range of bioactivities. We demonstrated that ATEG_01465.1 located outside of acetylaranotin gene cluster is responsible for catalyzing the S-methylation of its biosynthetic pathway. Combining the previous characterization of acetylaranotin biosynthetic gene cluster together with the identification of its S-methyltransferase provides a means to obtain second-generation acetylaranotin derivatives previously inaccessible. By permutations of targeted deletions of ATEG_01465.1, acetyltransferase (AtaH), and benzoate hydroxylase (AtaY), three novel acetylaranotin derivatives were produced by Aspergillus terreus.

Topics: Acetyltransferases; Aspergillus; Biosynthetic Pathways; Genome, Fungal; Methyltransferases; Multigene Family; Oxepins; Oxygenases; Piperazines; Sequence Deletion

Herein we suggest an approach to oxygenated bicyclic amino acids based on an aza-Cope-Mannich rearrangement. Seven distinct amino acid scaffolds analogous to the natural products were prepared on a gram scale with precise control of stereochemistry. Successful implementation of our strategy resulted in the formal synthesis of acetylaranotin.

Topics: Amino Acids; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Catalysis; Molecular Structure; Oxepins; Proline

Epipolythiodioxopiperazines (ETPs) are a class of fungal secondary metabolites derived from diketopiperazines. Acetylaranotin belongs to one structural subgroup of ETPs characterized by the presence of a seven-membered 4,5-dihydrooxepine ring. Defining the genes involved in acetylaranotin biosynthesis should provide a means to increase the production of these compounds and facilitate the engineering of second-generation molecules. The filamentous fungus Aspergillus terreus produces acetylaranotin and related natural products. Using targeted gene deletions, we have identified a cluster of nine genes (including one nonribosomal peptide synthetase gene, ataP) that is required for acetylaranotin biosynthesis. Chemical analysis of the wild-type and mutant strains enabled us to isolate 17 natural products from the acetylaranotin biosynthesis pathway. Nine of the compounds identified in this study are natural products that have not been reported previously. Our data have allowed us to propose a biosynthetic pathway for acetylaranotin and related natural products.

Topics: Aspergillus; Biosynthetic Pathways; Gene Deletion; Genome, Fungal; Multigene Family; Oxepins; Piperazines

The first total synthesis of the dihydrooxepine-containing epidithiodiketopiperazine (ETP) (-)-acetylaranotin (1) is reported. The key steps of the synthesis include an enantioselective azomethine ylide (1,3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide. This synthesis provides access to (-)-1 in 18 steps from inexpensive, commercially available starting materials. We anticipate that the approach described herein will serve as a general strategy for the synthesis of additional members of the dihydrooxepine ETP family.

Topics: Cyclization; Molecular Conformation; Oxepins; Stereoisomerism

The key step in this total synthesis of (-)-acetylaranotin is the efficient formation of the characteristic dihydrooxepine ring from cyclohexenone through an unusual vinylogous Rubottom oxidation and a regioselective Baeyer-Villiger oxidation. (-)-Acetylaranotin is obtained in 22 steps from commercially available L-Cbz-tyrosine (Cbz=benzyloxycarbonyl).

Topics: Cyclohexenes; Oxepins; Oxidation-Reduction; Piperazine; Piperazines; Stereoisomerism

Research is to identify the bioactive secondary metabolites produced by Aspergillus sp. KMD 901 isolated from marine sediment and to assess their apoptosis-inducing effects.. Aspergillus sp. KMD 901 was isolated from marine sediment obtained from the East Sea of Korea. An ethyl acetate extract of KMD 901 exhibited potent cytotoxic activity towards five cancer cell lines (HCT116, AGS, A549, MCF-7 and HepG2). Sequencing of the internal transcribed spacer (ITS) region in this strain allowed us to identify KMD 901 as a strain of Aspergillus versicolor. The cytotoxic compounds from Aspergillus sp. KMD 901 were purified by reversed-phase high-performance liquid chromatography and identified as diketopiperazine disulfides through spectroscopic analyses including extensive 2D NMR and mass spectrometry. The diketopiperazine disulfides were found to induce apoptosis in HCT116 cells based on cell morphology, DNA fragmentation observed by agarose gel electrophoresis, Annexin-V/PI staining using a flow cytometer and cleavage of poly (ADP-ribose) polymerase (PARP), caspase-3, caspase-8, caspase-9 and Bcl-2 family proteins (Bcl-2, Bcl-xL and Bax) using Western blotting analysis. Further study using an in vivo xenograft model showed inhibitory effects of acetylapoaranotin (2) on tumour proliferation.. A new diketopiperazine disulfide, deoxyapoaranotin (3), along with previously described acetylaranotin (1) and acetylapoaranotin (2) was separated from Aspergillus sp. KMD 901 and found to have direct cytotoxic and apoptosis-inducing effects towards HCT116 colon cancer cell lines.. These results suggest that the diketopiperazine disulfides produced from Aspergillus sp., KMD 901, could be candidates for the development of apoptosis-inducing antitumour agents. Also, this study indicates that marine natural products as potential source of pharmaceuticals.

Topics: Animals; Antineoplastic Agents; Apoptosis; Aspergillus; Caspases; Cell Line, Tumor; Diketopiperazines; Disulfides; Geologic Sediments; HCT116 Cells; Humans; Mice; Mice, Nude; Oceans and Seas; Oxepins; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2

A new antifungal diketopiperazine named haematocin was isolated from the culture broth of Nectria haematococca Berk. et Br. (880701a-1) causing blight disease on ornamental plants, Phalaenopsis spp. and Doritanopsis spp. Its structure was established by spectroscopic methods. Haematocin inhibited the germ-tube elongation and spore-germination of Pyricularia oryzae at the ED50 values of 30 microg/ml and 160 microg/ml, respectively.

Topics: Anti-Bacterial Agents; Antifungal Agents; Indoles; Oxepins; Piperazines; Stereoisomerism; Structure-Activity Relationship; Vegetables