Search Results (46)

Epidithiodiketopiperazines (ETPs) are a class of fungal secondary metabolites (SMs) featuring a transannular disulfide bridge at the diketopiperazine (DKP) core. The complex structures and biological activities have attracted widespread attention from biologists and chemists. In this study, we identified five novel ETP derivatives 4–7 and 4′ from three gene deletion mutants of Trichoderma hypoxylon CGMCC 3.17906, including ΔtdaP, ΔtdaQ, and ΔtdaQΔtdaI. Their structures were characterized through NMR and HR-ESI-MS data analysis. Compounds 4 and 4′ have unique heteroatom substitutions at the α and α′ positions, compound 5 possesses a unique α, β′-disulfide bridge, and compounds 6 and 7 contain a C3′-(thio)carbonyl group. Based on structural elucidation and biosynthetic pathway of α, β′-disulfide bridged ETPs, we also proposed the formation of 4–7 and 4′. This study not only expands the chemical diversity of ETPs, but also offers new mechanistic insights into the biosynthetic pathways of fungal ETPs. Full article

A new generalized (3+1)-dimensional Kadomtsev–Petviashvil (3dKP) equation is derived from the inverse scattering transform method. This equation can be reduced to the standard KP equation and the well-know (3+1)-dimensional equation. In making use of the Lax pair transformation, a Bäcklund transformation of the generalized (3+1)-dimensional KP equation is constructed and some soliton solutions are produced. Finally, a superposition formula is singled out as well by making use of the Bäcklund transformation. As far as we know, the work presented in this paper has not been studied up to now. Full article

The simplest cyclo-peptides, also known as diketopiperazines (DKPs), are widespread in nature. The growing interest in these simplest cyclo-peptides is driven by their significant potential for therapeutic applications. In this study, we identified a biosynthetic gene cluster from Aspergillus aculeatus CRI323-04 through genome mining and heterologous expression in Aspergillus nidulans. The two core genes, aacA and aacB, within the gene cluster were characterized for their role in the biossoynthesis of aspkyncin, a novel DKP compound that incorporates a l-kynurenine (l-Kyn) unit. Furthermore, we successfully reconstituted the activities of the minimal bimodular non-ribosomal peptide synthetase (NRPS) AacA and the methyltransferase AacB both in vivo and in vitro. Our findings demonstrate that AacA catalyzes the condensation and cyclization of two non-proteinogenic amino acids, l-Kyn and N-methyl-l-alanine, to produce aspkyncin without the involvement of any release domain. Notably, the N-methyl-l-alanine is generated by a specialized l-alanine N-methyltransferase AacB prior to NRP assembly. This study reveals an unconventional pathway for the biosynthesis of fungal DKPs. Full article

Malaria, Chagas disease, and leishmaniasis are tropical diseases caused by protozoan parasites of the genera Plasmodium, Trypanosoma and Leishmania, respectively. These diseases constitute a major burden on public health in several regions worldwide, mainly affecting low-income populations in economically poor countries. Severe side effects of currently available drug treatments and the emergence of resistant parasites need to be addressed by the development of novel drug candidates. Natural 2,5-Diketopiperazines (2,5-DKPs) constitute N-heterocyclic secondary metabolites with a wide range of biological activities of medicinal interest. Its structural and physicochemical properties make the 2,5-DKP ring a versatile, peptide-like, and stable pharmacophore attractive for synthetic drug design. In the present work, twenty-three novel synthetic 2,5-DKPs, previously synthesized through the versatile Ugi multicomponent reaction, were assayed for their anti-protozoal activities against P. falciparum, T. cruzi, and L. infantum. Some of the 2,5-DKPs have shown promising activities against the target protozoans, with inhibitory concentrations (IC₅₀) ranging from 5.4 to 9.5 µg/mL. The most active compounds also show low cytotoxicity (CC₅₀), affording selectivity indices ≥ 15. Results allowed for observing a clear relationship between the substitution pattern at the aromatic rings of the 2,5-DKPs and their corresponding anti-Plasmodium activity. Finally, calculated drug-like properties of the compounds revealed points for further structure optimization of promising drug candidates. Full article

In our ongoing quest to design effective antimicrobial peptides (AMPs), this study aimed to elucidate the mechanisms governing cyclic amphiphilic AMPs and their interactions with membranes. The objective was to discern the nature of these interactions and understand how peptide sequence and structure influence antimicrobial activity. We introduced modifications into the established cyclic AMP peptide, [W₄R₄], incorporating an extra aromatic hydrophobic residue (W), a positively charged residue (R), or the unique 2,5-diketopiperazine (DKP). This study systematically explored the structure–activity relationships (SARs) of a series of cyclic peptides derived from the [W₄R₄] scaffold, including the first synthesis and evaluation of [W₄R₄(DKP)]. Structural, dynamic, hydrophobic, and membrane-binding properties of four cyclic peptides ([W₄R₄], [W₅R₄], [W₄R₅], [W₄R₄(DKP)]) were explored using molecular dynamics simulations within a DOPC/DOPG lipid bilayer that mimics the bacterial membrane. The results revealed distinct SARs linking antimicrobial activity to parameters such as conformational plasticity, immersion depth in the bilayer, and population of the membrane binding mode. Notably, [W₄R₅] exhibited an optimal “activity/binding to the bacterial membrane” pattern. This multidisciplinary approach efficiently decoded finely regulated SAR profiles, laying a foundation for the rational design of novel antimicrobial peptides. Full article

2,5-diketopiperazines (2,5-DKPs) are the smallest cyclic peptides in nature and display a variety of antibacterial, antifungal, and anticancer properties. Very little has been reported on the one-pot synthesis of 2,5-DKPs. Herein, we report a novel one-pot synthesis of 2,5-DKPs via the Ugi-4CR/S_N2-cyclization strategy, under mild conditions, and ethanol was used as a solvent for both procedures. Full article

Semiconductor minerals are widely present on the surface of Earth, but their roles in the process of peptide formation from amino acids are less studied, especially the role of different crystal facets in the origin of life. In this research, High Performance Liquid Chromatography (HPLC), thermogravimetric analysis (TA/DTA), Nuclear Magnetic Resonance (NMR) and simulation calculations were used to study the condensation of glycine on the surface of anatase with (001) crystal facets and ordinary anatase as well as the reaction mechanism. Combined with TA/DTA and heating experiments (80–130 °C), it was found that anatase with (001) crystal facets and ordinary anatase could both catalyze the condensation of glycine to form corresponding oligopeptides (mainly DKP, Gly₂ and Gly₃). Anatase with (001) crystal facets shows better catalytic effect, which can reduce the condensation temperature of glycine to 90 °C. With the increase in temperature, the condensation efficiency of anatase with (001) crystal facets for Gly₂ is relatively higher, and the maximum yield is about 0.20 mg/m². The condensation efficiency of ordinary anatase for Gly₃ is relatively higher, and the maximum yield is about 0.28 mg/m². The results of FTIR and simulation calculation show that the electron density of the carboxyl group changes after glycine is adsorbed on the surface of anatase, which is easily subject to the nucleophilic attack of amino groups to promote the condensation reaction. These results can provide reference for the research of condensation of small biomolecules on semiconductor mineral surfaces in the origin of life. Full article

Streptomyces sp. N11-50 was isolated from deep-sea water and found to produce diketopiperazine (DKP) compounds such as albonoursin and cyclo(Phe-Leu). This study aimed to reveal the potential to synthesize diverse nonribosomal peptide and polyketide compounds as the other secondary metabolites different from DKP after clarifying the taxonomic position. Strain N11-50 was identified as Streptomyces albus, as it showed 100% 16S rRNA gene sequence similarities and 95.5% DNA–DNA relatedness to S. albus NBRC 13014^T. We annotated the nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) gene clusters in the genome. Consequently, five NRPS, one hybrid PKS/NRPS, five type-I PKS and one type-II PKS gene clusters were observed, of which we predicted the products through bioinformatic analysis. These gene clusters were well conserved in already whole-genome sequence (WGS)-published strains belonging to S. albus. On the other hand, our taxonogenomic analysis revealed that three WGS-published S. albus strains were not S. albus. Two of the three should be classified as Streptomyces albidoflavus, and the remaining one was likely a new genomospecies. After reclassifying these appropriately, we demonstrated species-specific profiles of the NRPS and PKS gene clusters with little strain-level diversities. Full article

Based on the marine natural products piperafizine B, XR334, and our previously reported compound 4m, fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DKP) derivatives (1, 2, 4–6, 8–16), together with two known ones (3 and 7), were designed and synthesized as anticancer agents against the A549 and Hela cell lines. The MTT assay results showed that the derivatives 6, 8–12, and 14 had moderate to good anticancer capacities, with IC₅₀ values ranging from 0.7 to 8.9 μM. Among them, compound 11, with naphthalen-1-ylmethylene and 2-methoxybenzylidene functions at the 3 and 6 positions of 2,5-DKP ring, respectively, displayed good inhibitory activities toward both A549 (IC₅₀ = 1.2 μM) and Hela (IC₅₀ = 0.7 μM) cancer cells. It could also induce apoptosis and obviously block cell cycle progression in the G2/M phases in both cells at 1.0 μM. The electron-withdrawing functions might not be favorable for the derivatives with high anticancer activities. Additionally, compared to piperafizine B and XR334, these semi-N-alkylated derivatives have high liposolubilities (>1.0 mg mL⁻¹). Compound 11 can be further developed, aiming at the discovery of a novel anticancer candidate. Full article

(1) Background: The aim of this study was to identify the degradation product of ramipril (RAM) formed under dry air and to verify its potential modes of carcinogenicity. We intended to check whether its formation and presence in final dosage forms could pose a cancer risk to humans who are treated with RAM due to cardiological indications. The carcinogenicity of this compound was evaluated with respect to two mechanisms: a potential direct DNA-damage and indirect toxicity, secondary to forming mutagenic N-nitroso metabolites. (2) Methods: Firstly, a forced ageing test under dry air was conducted for pure RAM in order to induce its degradation. The validated HPLC system was used to describe the kinetic order of this reaction. The emerging degradation impurity was identified by HPLC-MS. In the second stage, the cancer risk of the identified RAM degradant was predicted using a structure-based assessment by in silico QSAR model, employing three endpoints: carcinogenicity, genotoxicity and mutagenicity. In the third stage, the obtained QSAR results were experimentally verified. To verify genotoxicity prediction, in vitro micronucleus assay was employed. It enabled us to assess the potential direct DNA-damaging properties of RAM degradant at high concentrations (as screening series) and at concentrations usually observed in human blood (to mimic the clinical scenario). To verify the QSAR mutagenicity prediction, an in vitro Ames test was carried out. It was designed so as to detect two mechanisms of mutagenicity: a direct one (for pure degradant) and an indirect one (via N-nitroso-metabolites formation). N-nitroso-metabolites for mutagenicity assessment were obtained using NAP test. (3) Results: The kinetic mechanism of RAM degradation was first-order, the degradation rate constant was k = 1.396 ± 0.133 × 10⁻⁵ s⁻¹ (T = 373 K), thus the formation of impurity was rapid. Energy of activation was 174.12 ± 46.2 kJ/mol, entropy was positive, thus reaction was bimolecular and favored; enthalpy was 171.65 ± 48.7 kJ/mol, thus reaction was endothermic. Only one degradation impurity was formed, and it was identified as RAM diketopiperazine derivative (DKP). QSAR simulation predicted that DKP could be carcinogenic and genotoxic, but this result had only moderate reliability. DKP was also predicted to be non-mutagenic and this prediction was strong (endpoint score 0.2). The confirmatory micronucleus experiment for genotoxicity prediction suggested that DKP was cytotoxic and it could be also aneugenic at a high concentration (0.22 mg/mL), evidenced by a three-fold increase in micronuclei relative to the control (11.86:33.33%, p = 0.0184). At physiologic concentrations, its cytotoxicity and genotoxicity did not occur. This means that the genotoxicity of DKP was limited by a threshold mechanism. In the mutagenicity in vitro assessment, pure DKP was not mutagenic, but its nitrosation product induced base substitutions mutations in test bacteria TA100 following metabolic activation at a concentration of 4.5 mg/mL, confirming its mutagenicity. (4) Conclusions: RAM rapidly cyclizes to diketopiperazine derivative under dry air. This impurity resides in drugs administered to patients. DKP is potentially aneugenic and cytotoxic at high concentrations, yet at concentrations typically occurring in human blood, this effect is unlikely. The exposure of patients to high concentrations of DKP, exceeding the typical blood level and standard RAM dosing, could lead to cancer development, thus the safe threshold for human exposure to DKP must be verified in follow-up in vivo experiments. Based on our results, it is impossible to establish the maximum safe dose of pure DKP to humans. Furthermore, DKP itself is not mutagenic, but it is liable to the formation of mutagenic nitroso-metabolites in vivo. Nitroso-derivatives of DKP are in vitro mutagens and their real-life impact on humans must be further evaluated in in vivo studies. Until this is carried out, RAM should not be formulated by manufacturers using dry procedures to minimize DKP formation and reduce risk of human carcinogenesis, since DKP could cause cancer via two independent mechanisms: direct genotoxicity when the exposure over standard RAM dosing occurs, and indirect mutagenicity via in vivo N-nitrosamine formation. Full article

2,5-DKPs are heterocyclic peptidomimetics, present in nature with high structural diversity, popular in the design of new bioactive molecules with potential application in medicinal chemistry, exhibiting anticancer and antimicrobial properties, among others. Therefore, in the present work, we report the one-pot synthesis of 2,5-DKPs and their links to another heterocycle 1,4-disubstituted 1,2,3-triazole under mild reaction conditions by one-pot process via the sequence IMCR/postransformation/CuAAC with several advantages over previously reported conventional methods. Full article

There is an increasing interest towards the development of new antimicrobial coatings, especially in light of the emergence of antimicrobial resistance (AMR) towards common antibiotics. Cyclodipeptides (CDPs) or diketopiperazines (DKPs) are attractive candidates for their ability to self-assemble into supramolecular polymers and yield gel coatings that do not persist in the environment. In this work, we compare the antimicrobial cyclo(Leu-Phe) with its heterochiral analogs cyclo(D-Leu-L-Phe) and cyclo(L-Leu-D-Phe), as well as cyclo(L-Phe-D-Phe), for their ability to gel. The compounds were synthesized, purified by HPLC, and characterized by ¹H-NMR, ¹³C-NMR, and ESI-MS. Single-crystal X-ray diffraction (XRD) revealed details of the intermolecular interactions within the supramolecular polymers. The DKPs were then tested for their cytocompatibility on fibroblast cells and for their antimicrobial activity on S. aureus. Overall, DKPs displayed good cytocompatibility and very mild antimicrobial activity, which requires improvement towards applications. Full article

Due to the prospective local and international markets, the neon tetra fish breeding industry has its own charm for fish lovers and as a side business. The purpose of this study is to analyze the opportunities and difficulties associated with the cultivation of neon tetra fish in order to build a policy of “Blue Economy”. The research method uses qualitative techniques, focusing on an evaluation of literature reviews and data collection techniques sourced from descriptive materials. The key elements selected were: (1) the Department of Food and Fisheries Security (DKP3), as the Board of Trustees (2) Researchers from BRIN (National Innovation Research Agency), (3) Government (Sub-districts and Kelurahan), (4) POKDAKAN (Fish Cultivation Group) and (5) LPM (Community Empowerment Institution) and Chairman of RW/RT. The conclusion of the study states that the relevant Dinas should support local policies based on nature identification that are strengthened at the national level, namely that routine human resource training needs to be improved, technology needs to be taken into account in collaboration with the private sector, and that post-harvest and market access are very important for POKDAKAN. The findings of the SWOT analysis, which is in quadrant 1, indicate that POKDAKAN is in a position for a somewhat aggressive expansion. Full article

Cyclodipeptides (CDPs) or diketopiperazines (DKPs) are often found in nature and in foodstuff and beverages and have attracted great interest for their bioactivities, biocompatibility, and biodegradability. In the laboratory, they can be prepared by green procedures, such as microwave-assisted cyclization of linear dipeptides in water, as performed in this study. In particular, five CDPs were prepared and characterized by a variety of methods, including NMR and ESI-MS spectroscopies and single-crystal X-ray diffraction (XRD), and their cytocompatibility and anti-aging activity was tested in vitro, as well as their ability to penetrate the different layers of the skin. Although their mechanism of action remains to be elucidated, this proof-of-concept study lays the basis for their future use in anti-age cosmetic applications. Full article

Based on the scaffolds widely used in drug design, a series of novel tryptophan derivatives containing 2,5-diketopiperazine and acyl hydrazine moieties have been designed, synthesized, characterized, and evaluated for their biological activities. The bioassay results showed that the target compounds possessed moderate to good antiviral activities against tobacco mosaic virus (TMV), among which compounds 4, 9, 14, 19, and 24 showed higher inactivation, curative, and protection activities in vivo than that of ribavirin (39 ± 1, 37 ± 1, 39 ± 1 at 500 mg/L) and comparable to that of ningnanmycin (58 ± 1, 55 ± 1, 57 ± 1% at 500 mg/L). Thus, these compounds are a promising candidate for anti-TMV development. Most of these compounds showed broad-spectrum fungicidal activities against 13 kinds of phytopathogenic fungi and selective fungicidal activities against Alternaria solani, Phytophthora capsica, and Sclerotinia sclerotiorum. Additionally, some of these compounds exhibited larvicidal activities against Tetranychus cinnabarinus, Plutella xylostella, Culex pipiens pallens, Mythimna separata, Helicoverpa armigera, and Pyrausta nubilalis. Full article