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Abstract Apicidins are a class of naturally occurring cyclic tetrapeptides produced by few strains within the Fusarium genus. These secondary metabolites have gained significant attention due to their antiprotozoal activity through HDAC inhibition, thereby highlighting their potential for the treatment of malaria. Predominantly, apicidins have been isolated from Fusarium semitectum, offering a deep insight into the biosynthetic pathway responsible for their formation. A similar biosynthetic gene cluster has also been identified in the rice pathogenic fungus F. fujikuroi, leading the discovery of three additional apicidins through genetic manipulation. Routine mass spectrometric screening of these compound-producing strains revealed another metabolite structurally related to previously studied apicidins. By optimizing culture conditions and developing an effective isolation method, we obtained a highly pure substance, whose chemical structure was fully elucidated using NMR and HRMS fragmentation. Further studies were conducted to determine cytotoxicity, antimalarial activity, and HDAC inhibitory activity of this new secondary metabolite alongside the previously known apicidins. This work not only expands the apicidin class with a new member but also provides extensive insights and comparative analysis of apicidin-like substances produced by F. fujikuroi. Graphical Abstract

Apicidins are a class of naturally occurring cyclic tetrapeptides produced by few strains within the Fusarium genus. These secondary metabolites have gained significant attention due to their antiprotozoal activity through HDAC inhibition, thereby highlighting their potential for the treatment of malaria. Predominantly, apicidins have been isolated from Fusarium semitectum, offering a deep insight into the biosynthetic pathway responsible for their formation. A similar biosynthetic gene cluster has also been identified in the rice pathogenic fungus F. fujikuroi, leading the discovery of three additional apicidins through genetic manipulation. Routine mass spectrometric screening of these compound-producing strains revealed another metabolite structurally related to previously studied apicidins. By optimizing culture conditions and developing an effective isolation method, we obtained a highly pure substance, whose chemical structure was fully elucidated using NMR and HRMS fragmentation. Further studies were conducted to determine cytotoxicity, antimalarial activity, and HDAC inhibitory activity of this new secondary metabolite alongside the previously known apicidins. This work not only expands the apicidin class with a new member but also provides extensive insights and comparative analysis of apicidin-like substances produced by F. fujikuroi. [ABSTRACT FROM AUTHOR]

Fungal natural products play a prominent role in the development of pharmaceuticalagents. Two new cyclic tetrapeptides (CTPs), westertide A (1) and B (2), with eight known compounds (3–10) were isolated from the fungus Aspergillus westerdijkiae guided by OSMAC (one strain-many compounds) and molecular networking strategies. The structures of new compounds were unambiguously determined by a combination of NMR and mass data analysis, and chemical methods. All of the isolates were evaluated for antimicrobial effects, synergistic antifungal activity, cytotoxic activity, and HDAC inhibitory activity. Compounds 1–2 showed synergistic antifungal activity against Candida albicans SC5314 with the presence of rapamycin and weak HDAC (histone deacetylase) inhibitory activity. These results indicate that molecular networking is an efficient approach for dereplication and identification of new CTPs. CTPs might be a good starting point for the development of synergistic antifungal agents.

• Accomplished the total synthesis of macrocyclic depsipeptide Met 10 -teixobactin, a potent antibiotic. • An unusual amino acid l - allo -enduracididine of teixobactin was replaced by l -methionine. • Serine ligation strategy in solution-phase synthesis was used in present total synthesis. The total synthesis of cyclic depsipeptide Met 10 -teixobactin in solution-phase is described. Teixobactin is a structurally and mechanistically novel antimicrobial peptidic natural product with very impressive activities against Gram-positive pathogens. It happens to possess an l - allo -enduracididine (End) residue as part of macrocyclic ring which is not readily accessible. In this report, we have used serine ligation strategy as the key step to prepare an analogue of teixobactin where End being replaced with a readily available amino acid methionine. [ABSTRACT FROM AUTHOR]

In an attempt towards the total synthesis of Pseudoxylallemycin B, a homo dimeric, N -methylated macrocyclic tetrapeptidic natural product, synthesis of its epimer at position 3 ( d -Tyr instead of l -Tyr) is described here. During the course of synthesis we came across a striking yet unusual observation of complete epimerization which led to the formation of 3- epi -Pseudoxylallemycin B. [ABSTRACT FROM AUTHOR]

Two new cyclic tetrapeptides, cyclo( l-Val- l-Leu- l-Val- l-Ile) ( 1) and cyclo( l-Leu- l-Leu- l-Ala- l-Ala) ( 2), and 15 known compounds, cyclo(Gly- l-Leu-Gly- l-Leu) ( 3), cyclo( l-Ser- l-Phe) ( 4), cyclo( l-Leu- l-Ile) ( 5), cyclo( l-Tyr- l-Phe) ( 6), cyclo(Gly- l-Trp) ( 7), cyclo( l-Leu- l-Tyr) ( 8), cyclo(Gly- l-Phe) ( 9), cyclo( l-Phe- trans-4-hydroxy- l-Pro) ( 10), cyclo( l-Leu- l-Leu) ( 11), cyclo( l-Val- l-Phe) ( 12), cyclo( l-Val- l-Leu) ( 13), cyclo( l-Ile- l-Ile) ( 14), cyclo( l-Tyr- l-Tyr) ( 15), turnagainolide A ( 16), and bacimethrin ( 17) were isolated from the fermentation broth of Streptomyces rutgersensis T009 obtained from Elaphodus davidianus excrement. Their structures were identified on the basis of spectroscopic analysis. Meanwhile, the absolute configurations of the amino acid residues of compounds 1 and 2 were determined by advanced Marfey method. Compound 3 was obtained from a natural source for the first time. The X-ray single crystal diffraction data of bacimethrin ( 17) were also reported for the first time. Compounds 1 - 17 exhibited no antimicrobial activities with the MICs > 100 μg/ml. [ABSTRACT FROM AUTHOR]

The article discusses research on the role of an imine-induced ring-closing/contraction strategy in the synthesis of constrained head-to-tail cyclic tetrapeptides. It mentions the representation by head-to-tail cyclic peptides of biological activities. It states that the efficiency of synthetic methods is required in studying the use of cyclic peptides in medicinal chemistry.

Abstract: Two novel membrane sensors sensitive and reasonably selective for Cu2+ ions are described. These are based on the use of newly synthesized cyclic tetrapeptide derivatives as neutral ionophores and sodium tetraphenylborate (NaTPB) as an anionic excluder in plasticized PVC membranes. The sensors exhibit fast and stable near-Nernstian response over the concentration range 1.0×10−6 moll−1 to 1.0×10−2 moll−1 Cu2+ with a cationic slope of 30.2–25.9mV per decade at pH 4.5–7 with a lower detection limit of 0.05–0.13μgml−1. Effects of plasticizers, lipophilic salts and various foreign common ions are tested. The sensors display long life-span, long term stability, high reproducibility, and short response time. Selectivity of both sensors is significantly high for Cu2+ over Fe3+, Al3+, Zn2+, Cd2+, Hg2+, Ni2+, Co2+, Mn2+, alkaline earth and alkali metal ions. The sensors are used for direct measurement of copper content in different rocks and industrial wastewater samples from electroplating factories. The results agree fairly well with data obtained using atomic absorption spectrometry. [Copyright &y& Elsevier]

The basic element of chromatin is the nucleosome. Histones H4, H3, H2A and H2B form the core histone octamer by protein-protein interactions of their folded domains. The free, flexible N-terminal extensions of the histones protrude from the nuclesome; they contain conserved lysines undergoing posttranslational acetylation. Histone acetyltransferases (HATs) transfer the acetyl moiety of acetyl-coenzyme A to the ε-amino group; this reaction is reverted by histone deacetylases (HDACs). The dynamic equilibrium of the acetylation/ deacetylation reaction varies throughout the genome; some regions in chromatin undergo rapid acetylation/deacetylation, whereas others are fixed in a certain acetylation state without significant changes. In general, chromatin regions engaged in transcription display dynamic acetylation, i.e. HATs and HDACs are recruited to these regions. Higher plants and fungi have considerably contributed to the unraveling of the multiplicity of HDACs; in particular, plants possess HDACs that have so far not been identified in animal cells. [ABSTRACT FROM AUTHOR]

Fungal natural products play a prominent role in the development of pharmaceuticalagents. Two new cyclic tetrapeptides (CTPs), westertide A (1) and B (2), with eight known compounds (3–10) were isolated from the fungus Aspergillus westerdijkiae guided by OSMAC (one strain-many compounds) and molecular networking strategies. The structures of new compounds were unambiguously determined by a combination of NMR and mass data analysis, and chemical methods. All of the isolates were evaluated for antimicrobial effects, synergistic antifungal activity, cytotoxic activity, and HDAC inhibitory activity. Compounds 1–2 showed synergistic antifungal activity against Candida albicans SC5314 with the presence of rapamycin and weak HDAC (histone deacetylase) inhibitory activity. These results indicate that molecular networking is an efficient approach for dereplication and identification of new CTPs. CTPs might be a good starting point for the development of synergistic antifungal agents. [ABSTRACT FROM AUTHOR]

The present study describes the synthesis and biological studies of a small series of head‐to‐tail cyclic tetrapeptides of the general structure c(Lys‐β2,2‐Xaa‐Lys) containing one lipophilic β2,2‐amino acid and Lys, Gly, Ala, or Phe as the Xaa residue in the sequence. The peptides were investigated for antimicrobial activity against gram‐positive and gram‐negative reference strains and 30 multiresistant clinical isolates including strains with extended spectrum β‐lactamase—carbapenemase (ESBL‐CARBA) production. Toxicity was determined against human red blood cells. The most potent peptides showed high activity against the gram‐positive clinical isolates with minimum inhibitory concentrations of 4–8 μg/mL and low haemolytic activity. The combination of high antimicrobial activity and low toxicity shows that these cyclic tetrapeptides containing lipophilic β2,2‐amino acids form a valuable scaffold for designing novel antimicrobial agents. Key findings: A small series of head‐to‐tail cyclic tetrapeptides of the general structure c(Lys‐β2,2‐Xaa‐Lys) was prepared containing one lipophilic β2,2‐amino acid and Lys, Gly, Ala, or Phe as the Xaa residue.Antimicrobial activity was investigated against 30 multi‐resistant Gram‐positive and Gram‐negative clinical isolates including strains with extended spectrum β‐lactamase ‐ carbapenemase (ESBL‐CARBA) production.The most potent cyclic tetrapeptide displayed minimum inhibitory concentration (MIC) of 4 μg/mL against Gram‐positive clinical isolates and MIC 8 – 32 μg/mL against Gram‐negative clinical isolates and low haemolytic activity. [ABSTRACT FROM AUTHOR]

The present study describes the synthesis and biological studies of a small series of head-to-tail cyclic tetrapeptides of the general structure c(Lys-β 2,2 -Xaa-Lys) containing one lipophilic β 2,2 -amino acid and Lys, Gly, Ala, or Phe as the Xaa residue in the sequence. The peptides were investigated for antimicrobial activity against gram-positive and gram-negative reference strains and 30 multiresistant clinical isolates including strains with extended spectrum β-lactamase-carbapenemase (ESBL-CARBA) production. Toxicity was determined against human red blood cells. The most potent peptides showed high activity against the gram-positive clinical isolates with minimum inhibitory concentrations of 4-8 μg/mL and low haemolytic activity. The combination of high antimicrobial activity and low toxicity shows that these cyclic tetrapeptides containing lipophilic β 2,2 -amino acids form a valuable scaffold for designing novel antimicrobial agents., (© 2018 European Peptide Society and John Wiley & Sons, Ltd.)

The histone deacetylase (HDAC) family is a promising drug target class owing to the importance of these enzymes in a variety of cellular processes. Docking studies were conducted to identify novel HDAC inhibitors. Subtle modifications in the recognition domain were introduced into a series of chlamydocin analogues, and the resulting scaffolds were combined with various zinc binding domains. Remarkably, cyclo(L-Asu(NHOH)-L-A3mc6c-L-Phe-D-Pro, compound 1 b), with a methyl group at positions 3 or 5 on the aliphatic ring, exhibited better antiproliferative effects than trichostatin A (TSA) against MCF-7 and K562 cell lines. In addition to cell-cycle arrest and apoptosis, cell migration inhibition was observed in cells treated with compound 1 b. Subsequent western blot analysis revealed that the balance between matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 1 (TIMP1) determines the degree of metalloproteinase activity in MCF-7 cells, thereby regulating cell migration. The improved inhibitory activity imparted by altering the hydrophobic substitution pattern at the bulky cap group is a valuable approach in the development of novel HDAC inhibitors., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)