α‑Glucosidase Inhibitors from a <i>Xylaria feejeensis</i> Associated with <i>Hintonia latiflora</i>

Two new compounds, pestalotin 4′-<i>O</i>-methyl-β-mannopyranoside (<b>1</b>) and 3<i>S</i>,4<i>R</i>-(+)-4-hydroxymellein (<b>2</b>), were isolated from an organic extract of a <i>Xylaria feejeensis</i>, which was isolated as an endophytic fungus from <i>Hintonia latiflora.</i> In addition, the known compounds 3<i>S</i>,4<i>S</i>-(+)-4-hydroxymellein (<b>3</b>), 3<i>S</i>-(+)-8-methoxymellein (<b>4</b>), and the quinone derivatives 2-hydroxy-5-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione (<b>5</b>), 4<i>S</i>,5<i>S</i>,6<i>S</i>-4-hydroxy-3-methoxy-5-methyl-5,6-epoxycyclohex-2-en-1-one (<b>6</b>), and 4<i>R</i>,5<i>R</i>-dihydroxy-3-methoxy-5-methylcyclohexen-2-en-1-one (<b>7</b>) were obtained. The structures of <b>1</b> and <b>2</b> were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configuration of the stereogenic centers of <b>1</b> and <b>2</b> was determined using ECD spectroscopy combined with time-dependent density functional theory calculations. In the case of <b>1</b>, comparison of the experimental and theoretical ³<i>J</i>_6–7 coupling constants provided further evidence for the stereochemical assignments. Compounds <b>2</b> and <b>3</b> inhibited <i>Saccharomyces cerevisiae </i>α-glucosidase (αGHY), with IC₅₀ values of 441 ± 23 and 549 ± 2.5 μM, respectively. Their activity was comparable to that of acarbose (IC₅₀ = 545 ± 19 μM), used as positive control. Molecular docking predicted that both compounds bind to αGHY in a site different from the catalytic domain, which could imply an allosteric type of inhibition

Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach

Synthetic biological approaches, such as site-directed biosynthesis, have contributed to the expansion of the chemical space of natural products, making possible the biosynthesis of unnatural metabolites that otherwise would be difficult to access. Such methods may allow the incorporation of fluorine, an atom rarely found in nature, into complex secondary metabolites. Organofluorine compounds and secondary metabolites have both played pivotal roles in the development of drugs; however, their discovery and development are often via nonintersecting tracks. In this context, we used the biosynthetic machinery of Trichoderma arundinaceum (strain MSX70741) to incorporate a fluorine atom into peptaibol-type molecules in a site-selective manner. Thus, fermentation of strain MSX70741 in media containing <i>ortho</i>- and <i>meta</i>-F-phenylalanine resulted in the biosynthesis of two new fluorine-containing alamethicin F50 derivatives. The fluorinated products were characterized using spectroscopic (1D and 2D NMR, including ¹⁹F) and spectrometric (HRESIMS/MSⁿ) methods, and their absolute configurations were established by Marfey’s analysis. Fluorine-containing alamethicin F50 derivatives exhibited potency analogous to the nonfluorinated parent when evaluated against a panel of human cancer cell lines. Importantly, the biosynthesis of fluorinated alamethicin F50 derivatives by strain MSX70741 was monitored <i>in situ</i> using a droplet–liquid microjunction–surface sampling probe coupled to a hyphenated system