Sachiko Tsukamoto

Concise synthesis of halicyclamine-inspired bis-macrocycles enabled demonstration of functional engagement with DedA membrane proteins.

Ultra performance liquid chromatography (UPLC)-high resolution (HR)MS/MS and feature-based molecular networking analysis were performed for the extract of a fungus, Arachnomyces bostrychodes, obtained from a cold seep chemosynthetic ecosystem, revealing the presence of new peptides. LC-MS-guided purification afforded three new cyclic tetrapeptides (3–5) containing two N-methyl-l-leucine residues. During the isolation procedure, a new benzophenone (1) and MDN-0093 (2) were isolated. Compounds 4 and 5 exhibited cytotoxicity against HeLa cells with IC50 values of 3.1 and 5.8 μM, respectively.

Iron is an essential element for all living organisms, and various microorganisms, such as fungi and bacteria, produce siderophores that chelate iron and facilitate its uptake from the environment. Certain fungi produce ferrichrome-type cyclic hexapeptides containing three N^δ-acetyl-N^δ-hydroxyornithine residues as siderophores. In this study, we found that adding sodium nitrate to solid rice culture medium induced the production of several new ferrichrome-type siderophores in Fusarium lateritium (18F04506), isolated from tidal flat soil in Kumamoto, Japan. LC–MS-guided fractionation of the culture extract afforded two new metabolites, named fusariferins A and B. Their planar structures were determined by detailed analysis of 1D and 2D NMR spectra, and the absolute configurations of the amino acids were determined using Marfey’s method. Furthermore, we demonstrated that these compounds were produced by the fungus only when cultured on rice medium supplemented with sodium nitrate, but not on medium supplemented with ammonium chloride, ammonium sulfate, or ammonium nitrate. These findings not only expand the structural diversity of fungal siderophores through the discovery of new ferrichrome-type compounds but also provide new insights into the nitrogen-dependent regulatory mechanism of siderophore biosynthesis in fungi. Graphical Abstract (Figa)

Wild-type p53 acts as a tumor suppressor, but p53 is frequently mutated and inactivated in tumor cells, promoting cancer progression, invasion, and metastasis. Thus, compounds that reactivate p53 may be leveraged for cancer treatment, and the development of drugs targeting p53 reactivation is actively progressing. Notably, natural products exhibit diverse structures and biological activities and are used as therapeutic agents for various diseases worldwide. This review discusses the natural products that inhibit p53 degradation through p53–Mdm2 interaction, promote p53 reactivation by inducing conformational changes, and exhibit p53-dependent growth inhibition. Graphical abstract

This review describes natural products that modulate the ubiquitin–proteasome system and their potential for therapeutic agents and the study of life science.

Oncogenic mutant p53 is one of the targets for cancer therapy, and the development of anticancer drugs that reactivate mutant p53 is a promising strategy. The extract of fungus Pestalotiopsis sp. changed mutant p53 to wild-type-like p53 in Saos-2 (p53^R175H) cells, as shown by fluorescent immunostaining, and bioassay-guided purification of the extract afforded new dimeric epoxyquinoids, pestones A and B (1 and 2), and a known compound, rosnecatrone (3). The relative and absolute configurations of 1 and 2 were determined based on the spectroscopic data and semisynthesis from 3. Compounds 1 and 2 altered the conformation of mutant p53 in Saos-2 (p53^R175H) cells, as shown by immunofluorescence staining. The cellular thermal shift assay analysis showed that 1 increased the thermostability of mutant p53 in Saos-2 (p53^R175H) cells, suggesting the direct binding of 1 to mutant p53. Compounds 1 and 2 exhibited cytotoxic activities against Saos-2 (p53^R175H) cells with IC₅₀ values of 1.0 and 1.1 μM, respectively. Compound 1 was found to induce apoptosis in Saos-2 (p53^R175H) cells by flow cytometry analysis and decreased tumor growth in vivo using a mouse model with HuCCT1 (p53^R175H) cells.

Natural products that inhibit osteoclast differentiation are promising therapeutic and preventive agents for osteoporosis. Conventionally, identifying osteoclast differentiation involves visual inspection of the microscope images of stained osteoclasts. In this study, a supervised machine learning model was developed to classify bright-field microscope images of osteoclasts without staining. The model was used to screen a compound library, and osteoclast differentiation inhibitors were identified, demonstrating the validity of our method. Next, an in-house library of fungal extracts was screened, and pinolidoxin was revealed as an inhibitor of osteoclast differentiation. Our machine learning method enabled accurate, objective, and high-throughput evaluation of osteoclast differentiation and efficient screening of the inhibitors from natural product extracts. This study represents the first machine learning classification developed to evaluate the inhibitory activity of natural products in osteoclast differentiation.

HPLC-MS analysis revealed the presence of an unreported peptide in the extract of the marine sponge Neopetrosia sp. Its structure was determined as a tripeptide, named neopetromin (1), composed of two tyrosine and one tryptophan residues with a heteroaromatic C-N cross-link between side chains. The absolute configuration of amino acids was determined using Marfey's method after ozonolysis and hydrolysis of 1. Compound 1 promoted vacuole fragmentation in an actin-independent manner in tobacco BY-2 cells.