Exploring gabosine and chlorogentisyl alcohol derivatives from a marine-derived fungus as EcGUS inhibitors with informatic assisted approaches

Abstract

β-Glucuronidase catalyzes the cleavage of glucuronosyl-O-bonds, whose inhibitors reduce the level of toxic substances present in the intestine caused by anti-cancer and anti-inflammatory therapies. Herein, we presented a new tool, Bioactive Fractions Filtering Platform (BFFP), which is able to reliably discern active candidate node from crude extracts. The source code for the BFFP is available on GitHub (https://github.com/BioGavin/msbff). With the assistant of BFFP, 25 gabosine and chlorogentisyl alcohol derivatives including 19 new compounds were isolated from a marine-derived fungus Epicoccum sp. GST-5. Compounds 7, 9–15 possessed an unusual hybrid skeleton of gabosine and chlorogentisyl alcohol units. Compounds 9–12, 16 and 17 possessed a novel three-membered spiral ring skeleton with one/two gabosine and one/two chlorogentisyl alcohol units. Compound 25 represented new gabosine-derived skeleton possessing an unusual 6/6/6/5/6 condensed ring system. All isolates were evaluated for in vitro E. coli β-glucuronidase (EcGUS) inhibitory activity. 14 Compounds demonstrated superior inhibitory activity (IC50 = 0.24–4.61 μM) to that of standard d-saccharic acid 1,4-lactone (DSL, IC50 = 56.74 ± 4.01 μM). Compounds with chlorogentisyl alcohol moiety, such as 17 (IC50 = 0.24 ± 0.02 μM) and 1 (IC50 = 0.74 ± 0.03 μM), exhibited the most potent inhibitory activity. Furthermore, literature based QSAR profiling by applying PCA and OPLS analysis was carried out to analyze the features of compounds against EcGUS, revealing that the introduction of substituents able to form polar interactions with binding sites of receptor would lead to more active structures.