Identification of Neuroprotective Spoxazomicin and Oxachelin Glycosides via Chemoenzymatic Glycosyl-Scanning

Abstract

The assessment of glycosyl-scanning to expand the molecular and functional diversity of metabolites from the underground coal mine fire-associated Streptomyces sp. RM-14-6 is reported. Using the engineered glycosyltransferase OleD Loki and a 2-chloro-4-nitrophenylglycoside-based screen, six metabolites were identified as substrates of OleD Loki, from which 12 corresponding metabolite glycosides were produced and characterized. This study highlights the first application of the 2-chloro-4-nitrophenylglycoside-based screen toward an unbiased set of unique microbial natural products and the first reported application of the 2-chloro-4-nitrophenylglycoside-based transglycosylation reaction for the corresponding preparative synthesis of target glycosides. Bioactivity analysis (including antibacterial, antifungal, anticancer, and EtOH damage neuroprotection assays) revealed glycosylation to attenuate the neuroprotective potency of 4, while glycosylation of the structurally related inactive spoxazomicin C (3) remarkably invoked neuroprotective activity.

Structural Reassignment and Absolute Stereochemistry of Madurastatin C1 (MBJ-0034) and the Related Aziridine Siderophores: Madurastatins A1, B1, and MBJ-0035

“…Thorson and Shaaban recently proposed that the madurastatin siderophores contain a N -terminal 2-(2-hydroxyphenyl)-oxazoline ring,9 a bidentate coordination moiety present in a number of other mixed ligand siderophores (e.g. acinetobactin,14 the amamistatins,15 the amychelins,16 brasilibactin A,17 gobichelin A and B,18 nocardichelins A and B,19 transvalencin Z20 and the spoxazomicins A-C21), in which the corresponding 13 C shifts typically occur from 65 to 72 ppm (Table 1).…”

“…Confirmation of the structure of 6 was given by single crystal X-ray analysis,22 including comparison to the closely related X-ray structure of spoxazomicin C (Scheme 2). 21a…”

“…In particular the 13 C NMR shifts for the α- and β-carbons of the serine residue are observed at 67 and 69 ppm, highly atypical of an aryloyl-substituted aziridine ring (shift range 25–45 ppm) . Thorson and Shaaban recently proposed that the madurastatin siderophores contain an N-terminal 2-(2-hydroxyphenyl)­oxazoline ring, a bidentate coordination moiety present in a number of other mixed ligand siderophores (e.g., acinetobactin, the amamistatins, the amychelins, brasilibactin A, gobichelins A and B, nocardichelins A and B, transvalencin Z, and the spoxazomicins A–C), in which the corresponding 13 C shifts typically occur from 65 to 72 ppm (Table ).…”

Modulating the Serotonin Receptor Spectrum of Pulicatin Natural Products

“…Previously, we reported that pulicatins and aerugine bind to serotonin (5-HT) receptors, with micromolar to nanomolar affinity . In addition, aerugine relatives have other demonstrated activities on neurons . Interestingly, 5-HT is also a critical component of the gut–brain axis and is regulated in part by the human microbiome .…”

“…4 In addition, aerugine relatives have other demonstrated activities on neurons. 5 Interestingly, 5-HT is also a critical component of the gut−brain axis and is regulated in part by the human microbiome. 6 While research has largely focused on bacteria that directly or indirectly regulate the metabolism of serotonin itself, bacteria inhabiting the gut produce secondary metabolites with the potential to affect the serotonin system.…”