Diketopiperazine Dimer Research Articles

Antimicrobial secondary metabolites from a marine-derived fungus \(\textit{Penicillium}\) sp. OM07

Eight compounds, diketopiperazine dimer WIN 64821 (1), ergosterol peroxide (2), ergosterol (3), 3β,5α,9α-trihydroxyergosta-7,22-dien-6-one (4), 3,4-dihydroxy-6,7-dimethyl-quinolin-2-carboxylic (5), norhaman (6), dihydrocitrinin (7), and phenol A acid (8) were isolated and characterized from the culture broth of the marine-derived Penicillium sp. OM07 strain was isolated from sediment collecting at Son Cha, Hue, Vietnam. Their structures were determined by analyses of MS and NMR data. All compounds were evaluated for their antimicrobial activity against a panel of clinically significant microorganisms. Most showed high antifungal activity against Candida albicans ATCC10231 strain with MIC values ranging from 8 µg/mL to 256 µg/mL. All compounds had inhibitory activity against from one to three Gram-positive tested strains with MIC values from 64–256 µg/mL.

( ±)-Dibrevianamides Q1 and Q2, the key precursors of asperginulin A from a marine-derived fungus.

Two pairs of new dimeric diketopiperazine alkaloids, ( ±)-dibrevianamides Q1 and Q2 (( ±)-1 and ( ±)-2), together with seven previously reported analogues (( ±)-3, 4-6, and ( ±)-7) were obtained from a marine-derived fungus Aspergillus sp. The structures of ( ±)-1 and ( ±)-2 were clarified using comprehensive spectroscopic analyses, the calculated ECD, and DP4 + probability methods. Speculated from the biogenesis, ( ±)-dibrevianamides Q1 and Q2 (( ±)-1 and ( ±)-2) might be the key precursor of [2 + 2] diketopiperazine dimers (( ±)-3). Compounds ( +)-1 and ( -)-2 displayed anti-H1N1 virus activity with IC50 values of 12.6 and 19.5μM. Compound ( +)-1 showed significant activity against Mycobacterium tuberculosis (MIC, 10.2μg/mL). KEY POINTS: • Two pairs of new dimeric diketopiperazine alkaloids were obtained from the marine-derived fungus Aspergillus sp. • The structures of the new compounds were clarified using comprehensive spectroscopic analyses, the calculated ECD, and DP4 + probability methods. • ( ±)-Dibrevianamides Q1 and Q2 were speculated to be the key precursor of [2 + 2] diketopiperazine dimers ( ±)-asperginulin A.

Dimerization approach to (+)-asperazine A

Tryptophan-linked dimeric diketopiperazine alkaloids possess great molecular diversity and bioactivity. In this issue of <i>Chem</i>, Jiang and co-workers report an oxidative approach to those alkaloids containing an unsymmetrical C3-N1′ linkage. In their concise synthesis of (+)-asperazine, they successfully dimerized a designer tryptophan-alternative building block through the sustained release of electrophilic iodine.

Novel indole diketopiperazine stereoisomers from a marine-derived fungus Aspergillus sp.

ABSTRACT Four dimeric diketopiperazine stereoisomers (1–4) including two new ones (1–2) had been isolated from the culture broth of one marine-derived fungus Aspergillus sp. Z3, which was found in the gut of a marine isopod Ligia exotica. The planner structures and absolute configurations of the new compounds were determined by combination of NMR, HRESIMS, electronic circular dichroism calculation, Marfey’s method as well as single-crystal X-ray diffraction. Their cytotoxicity against the prostate cancer PC3 cell line was assayed by the MTT method.

Structure and Function of NzeB, a Versatile C-C and C-N Bond-Forming Diketopiperazine Dimerase.

The dimeric diketopiperazine (DKPs) alkaloids are a diverse family of natural products (NPs) whose unique structural architectures and biological activities have inspired the development of new synthetic methodologies to access these molecules. However, catalyst-controlled methods that enable the selective formation of constitutional and stereoisomeric dimers from a single monomer are lacking. To resolve this long-standing synthetic challenge, we sought to characterize the biosynthetic enzymes that assemble these NPs for application in biocatalytic syntheses. Genome mining enabled identification of the cytochrome P450, NzeB (Streptomyces sp. NRRL F-5053), which catalyzes both intermolecular carbon-carbon (C-C) and carbon-nitrogen (C-N) bond formation. To identify the molecular basis for the flexible site-selectivity, stereoselectivity, and chemoselectivity of NzeB, we obtained high-resolution crystal structures (1.5 Å) of the protein in complex with native and non-native substrates. This, to our knowledge, represents the first crystal structure of an oxidase catalyzing direct, intermolecular C-H amination. Site-directed mutagenesis was utilized to assess the role individual active-site residues play in guiding selective DKP dimerization. Finally, computational approaches were employed to evaluate plausible mechanisms regarding NzeB function and its ability to catalyze both C-C and C-N bond formation. These results provide a structural and computational rationale for the catalytic versatility of NzeB, as well as new insights into variables that control selectivity of CYP450 diketopiperazine dimerases.

New Anti-inflammatory Cyclopeptides From a Sponge-Derived Fungus Aspergillus violaceofuscus

Three new cyclic peptides including a cyclic tetrapeptide (1), an aspochracin-type cyclic tripeptide sclerotiotide L (2) and a diketopiperazine dimer (3), have been isolated from the ethyl acetate extract of a marine sponge-derived fungus Aspergillus violaceofuscus. The structures of all compounds were unambiguously elucidated on the basis of HRESIMS, 1D and 2D NMR spectroscopic data, MS/MS experiments and chemical methods. Compounds 1 and 3 showed anti-inflammatory activity against IL-10 expression of the LPS-induced THP-1 cells with inhibitory rates of 84.3 and 78.1% respectively at concentration of 10 μM.

Concise total synthesis of (+)-asperazine A and (+)-pestalazine B.

The highly convergent total synthesis of dimeric diketopiperazine alkaloids (+)-asperazine A and (+)-pestalazine B is described. A critical aspect of our expedient route was the development of a directed regio- and diastereoselective C3-N1' coupling of complex tetracyclic diketopiperazine components. This late-stage heterodimerization reaction was made possible by design of tetracyclic diketopiperazines that allow C3-carbocation coupling of the electrophilic component to the N1' locus of the nucleophilic fragment. The application of this new coupling reaction to the first total synthesis of (+)-asperazine A led to our revision of the sign and magnitude of the optical rotation for the reported structure.

Isolation and structure determination of a new diketopiperazine dimer from marine-derived fungus Aspergillus sp. SF-5280

A new diketopiperazine dimer designated as SF5280-415 (1) was isolated from an EtOAc extract of the marine-derived fungus Aspergillus sp. SF-5280 by various chromatographic methods. The structure of 1 was mainly determined by analysis of the NMR spectroscopic data and MS data, along with Marfey’s method. This compound is a new diastereoisomer of known bispyrrolidinoindoline diketopiperazine alkaloid WIN 64745, which possesses unique architecture biosynthetically derived from an indole oxidation reaction of tryptophan.

Naseseazine C, a new anti-plasmodial dimeric diketopiperazine from a marine sediment derived Streptomyces sp.

A new dimeric diketopiperazine, naseseazine C, and the known naseseazines A and B were isolated from solid culture extracts of an Australian marine sediment derived Streptomyces species. Naseseazine C displayed a new C-6′/C-3 linkage between the two diketopiperazine subunits and showed moderate activity against the chloroquine-sensitive malaria parasite, Plasmodium falciparum (3D7 strain).

Cyclo-(TRP-PHE) diketopiperazines from the endophytic fungus Aspergillus versicolor isolated from Piper aduncum

Six known compounds, three peptide derivatives: cyclo-(tryptophyl-phenylalanyl) (2), diketopiperazine dimer WIN 64821 (3) and 3-hydroxy-15H-tryptophenaline (4), one adenine derivative: 2-hydroxy-6-N-isopentenyl-adenine (5), one phtalide derivative: 4-methoxyphtalide (1) and one benzoic acid derivative: 3-hydroxy-4-(1-hydroxy-1,5-dimethyl-hexyl) benzoic acid (6), were isolated from the ethyl acetate extract of the endophytic fungus Aspergillus versicolor associated with the Piper aduncum plant. Their structures were determined on the basis of detailed interpretation of 1 D and 2D NMR spectra and in comparison with works reported in the literature. This paper, in effect, deals with the first report of these compounds in A. versicolor.

Evaluation of Biosynthetic Pathway and Engineered Biosynthesis of Alkaloids.

Varieties of alkaloids are known to be produced by various organisms, including bacteria, fungi and plants, as secondary metabolites that exhibit useful bioactivities. However, understanding of how those metabolites are biosynthesized still remains limited, because most of these compounds are isolated from plants and at a trace level of production. In this review, we focus on recent efforts in identifying the genes responsible for the biosynthesis of those nitrogen-containing natural products and elucidating the mechanisms involved in the biosynthetic processes. The alkaloids discussed in this review are ditryptophenaline (dimeric diketopiperazine alkaloid), saframycin (tetrahydroisoquinoline alkaloid), strictosidine (monoterpene indole alkaloid), ergotamine (ergot alkaloid) and opiates (benzylisoquinoline and morphinan alkaloid). This review also discusses the engineered biosynthesis of these compounds, primarily through heterologous reconstitution of target biosynthetic pathways in suitable hosts, such as Escherichia coli, Saccharomyces cerevisiae and Aspergillus nidulans. Those heterologous biosynthetic systems can be used to confirm the functions of the isolated genes, economically scale up the production of the alkaloids for commercial distributions and engineer the biosynthetic pathways to produce valuable analogs of the alkaloids. In particular, extensive involvement of oxidation reactions catalyzed by oxidoreductases, such as cytochrome P450s, during the secondary metabolite biosynthesis is discussed in details.

ChemInform Abstract: Collective Synthesis and Biological Evaluation of Tryptophan‐Based Dimeric Diketopiperazine Alkaloids.

AbstractNovel concise syntheses of a series of tryptophan‐based dimeric diketopiperazine alkaloids, such as eurocristatine (IV), WIN 64745, asperdimin, and naseseazine A and B are disclosed.

トリプトファン由来二量体型ジケトピペラジンアルカロイド類の網羅的全合成

トリプトファン由来二量体型ジケトピペラジンアルカロイド類の網羅的全合成

Collective Synthesis and Biological Evaluation of Tryptophan-Based Dimeric Diketopiperazine Alkaloids.

A concise two one-pot synthesis of WIN 64821, eurocristatine, 15,15'-bis-epi-eurocristatine, ditryptophenaline, ditryptoleucine A, WIN 64745, cristatumin C, asperdimin, naseseazine A, and naseseazine B is detailed, based on a unique bioinspired dimerization reaction of tryptophan derivatives in aqueous acidic solution and a one-pot procedure for the construction of diketopiperazine rings. Total yields of these alkaloid syntheses were from 10 up to 27 %. In addition, 1'-(2-phenylethylene)-ditryptophenaline was synthesized by using three one-pot operations. The studies detailed herein provided synthesized natural products for inhibitory activities of ubiquitin-specific protease 7 (USP7) and foam cell formation in macrophages. The newly listed biological evaluation for tryptophan-based dimeric diketopiperazine alkaloids discovered 15,15'-bis-epi-eurocristatine, 1'-(2-phenylethylene)-ditryptophenaline, and WIN 64745 as new drug candidates.

Total synthesis of biologically active alkaloids using bio-inspired indole oxidation

Many tryptophan-based dimeric diketopiperazine (DKP) alkaloids including WIN 64821 and ditryptophenaline, which exhibit fascinating biological activities, have been isolated from fungi. These alkaloids possess a unique architecture; therefore several total syntheses of these compounds have been accomplished via bio-inspired reactions. Despite these elegant strategies, we were convinced that a more direct bio-inspired solution for the preparation of tryptophan-based DKP alkaloids was possible because in a true biosynthesis, direct dimerization of tryptophan occurs in aqueous media without incorporation of a protecting group on the substrates. Thus we developed direct bio-inspired dimerization reactions in aqueous, acidic media, along with a novel biomimetic pathway, to provide C2-symmetric and non-symmetric dimeric compounds from commercially available amine-free tryptophan derivatives using Mn(OAc)3, VOF3, and V2O5 as one-electron oxidants. In addition, concise two-pot or three-step syntheses of the naturally occurring dimeric DKP alkaloids (+)-WIN 64821, (-)-ditryptophenaline, and (+)-naseseazine B were accomplished with total yields of 20%, 13%, and 20%, respectively. The present synthesis has several noteworthy features: 1) the tryptophan-based C2-symmetric and non-symmetric dimeric key intermediates can be prepared on a multigram scale in one step; 2) the developed oxidation reaction was carried out in aqueous, acidic solution without deactivation of the metal oxidants; 3) protection of the primary amine can be avoided by salt formation in aqueous acid; 4) for the total two-pot operation, the reaction media are environmentally friendly water and ethanol; 5) satisfactory total yields are obtained compared with previously reported syntheses.

Natural products from a filamentous fungal isolate of an unidentified species

Our ongoing studies of filamentous fungi resulted in the investigation of an isolate of an unidentified species (MSX-19583) that was obtained from spruce litter collected from La Mesa Pass and Cumbres Pass, Colorado. The solid-substrate fermentation cultures of this isolate exhibited cytotoxic activity against MDA-MB-435 human melanoma cells. Chemical separation of this extract afforded a new diketopiperazine dimer, cyclo-(Trp- Phe), S-syndonic acid, and S-sydonol. The groß structures of the secondary metabolites were established using various 1D and 2D NMR techniques. Relative configuration of the new compound was assigned by interpretation of NOESY data in conjuction with the results of Marfey's analysis. Overall absolute configuration of was determined using Marfey's method and comparison of electronic circular dichroism (ECD) data.

ChemInform Abstract: Synthesis of Tryptophan‐Based Dimeric Diketopiperazine Alkaloids Using Bioinspired Reactions

AbstractReview: 41 refs.+subrefs.

Synthesis of Tryptophan-Based Dimeric Diketopiperazine Alkaloids Using Bioinspired Reactions

Tryptophan-based dimeric diketopiperazine alkaloids such as ditryptophenaline, WIN 64821, naseseazine A, and naseseazine B, exhibit a unique architecture and interesting biological activity. These alkaloids have been the subject of intense study by the synthetic organic chemistry community, and several elegant total syntheses have been discovered, especially using bioinspired strategies. Described herein is a brief overview of these alkaloid syntheses via bioinspired transformations as key steps.

A cytotoxic pyrrolidinoindoline diketopiperazine dimer from the algal fungus Eurotium herbariorum HT-2

A new cytotoxic pyrrolidinoindoline diketopiperazine dimer, cristatumin E (1), was isolated from the fermentation broth of the algal fungus Eurotium herbariorum HT-2 associated with the marine algae, Enteromorpha prolifera. The structure was determined by spectroscopic analyses and Marfey's amino acid analysis. Cristatumin E (1) showed cytotoxicity against K562 tumor cell line and antibacterial activity against Enterobacter aerogenes and Escherichia coli with IC50 and MIC values of 8.3, 44.0 and 44.0 μmol/L, respectively.

Brevianamides with Antitubercular Potential from a Marine-Derived Isolate of Aspergillus versicolor

An Aspergillus versicolor isolated from sediment collected from the Bohai Sea, China, yielded the new dimeric diketopiperazine brevianamide S (1), together with three new monomeric cometabolites, brevianamides T (2), U (3), and V (4). Structures were determined by detailed spectroscopic analysis. Brevianamide S exhibited selective antibacterial activity against Bacille Calmette-Guérin (BCG), suggestive of a new mechanism of action that could inform the development of next-generation antitubercular drugs.