Exiguaquinol: A Novel Pentacyclic Hydroquinone from Neopetrosia exigua that Inhibits Helicobacter pylori MurI

Abstract

Bioassay-guided fractionation of the methanol extract of the Australian sponge Neopetrosia exigua led to the isolation of exiguaquinol (2), a new pentacyclic hydroquinone that inhibited Helicobacter pylori glutamate racemase (MurI) with an IC(50) of 4.4 microM. Its structure and relative configuration were assigned on the basis of spectroscopic data. Exiguaquinol (2), bearing a novel pentacyclic ring skeleton, is the first natural product to show inhibition of H. pylori MurI. Its protein-ligand modeling is also discussed.

Quorum Sensing Inhibitors from the Sea Discovered Using Bacterial N-acyl-homoserine Lactone-Based Biosensors

“…It was evident from previous reports that several alkaloids from sponges exhibit QSI properties and hence it is noteworthy to screen previously isolated alkaloids from sponges. For example, Neopetrosia carbonaria , a rich producer of quinolinic type alkaloids and other nitrogen-containing compounds with cytotoxic and antimicrobial activity [116,117], could also possess QSI properties. Similarly, various acridine-type polar alkaloids were isolated from Xestospongia cf.…”

Diastereoselective syntheses of substituted cis-hydrindanones featuring sequential inter- and intramolecular Michael reactions

“…1 Within this family, substituted cis -1-hydrinanone ( 2 ) and its structural derivatives are found in numerous polycyclic natural products, such as pinguisone ( 3 ), 2 pleuromutilin ( 4 ), 3 exiguaquinol ( 5 ), 4 aplykurodinone-1 ( 6 ), 5 bromotetrasphaerol ( 7 ) 6 and thiersindole B ( 8 ) (Figure 1). 7 Our laboratory has a long-standing interest in the rapid generation of molecular complexity, particularly in the context of biologically active secondary metabolites, 8a and we became interested in applying this concept to the general construction of cis -1-hydrindanones, en route to pleuromutilin ( 4 ) and pleuromutilin-like scaffolds.…”

Synthesis of the Tetracyclic Core of Exiguaquinol

“…from the Australian sponge Neopetrosia exigua and reported in 2008. 1 High-throughput screening of natural product extracts against the Helicobacter pylori MurI enzyme—a glutamate racemase enzyme that is essential for bacterial cell wall biosynthesis—led to the identification of 1 as the first natural product inhibitor of this enzyme. As a result, exiguaquinol might serve as an excellent lead compound for the development of more potent inhibitors of MurI and ultimately selective antibiotics against H. pylori 1 With its complex and congested structure, the important link of H. pylori -induced gastritis to stomach cancer, 2 and the more general implications of MurI as a potential target for the development of new antibiotics, a research program aimed at the synthesis of this complex natural product was warranted on both chemical and biological grounds.…”

“…Also, in NMR studies of exiguaquinol performed in DMSO by the Quinn group, the R -configured hemiaminal was the only one observed. 1 …”