Brasilianoids A-F, New Meroterpenoids From the Sponge-Associated Fungus Penicillium brasilianum.

Jianping Zhang,Shuang Gao,Bochuan Yuan,Peter Proksch,Dong Liu,Wenhan Lin

doi:10.3389/fchem.2018.00314

Abstract

3,5-Dimethylorsellinic acid (DMOA) derived meroterpenoids comprise an unique class of natural products with diverse scaffolds and with a broad spectrum of bioactivities. Bioinformatics analysis of the gene clusters in association with the qRT-PCR detection of the amplification of two key genes led to speculate that the sponge associated fungus Penicillium brasilianum WZXY-m122-9 is a potential producer of meroterpenoids. Chromatographic separation of the EtOAc extract of this fungal strain on a large-scale fermentation resulted in the isolation of six new DMOA-related meroterpenoids with trivial names of brasilianoids A–F (1-6), together with preaustinoid D and preaustinoid A2. The structures were determined by extensive analyses of spectroscopic data, including the X-ray diffraction and the ECD data for configurational assignment. Brasilianoids A and F showed an unprecedented skeleton with a γ-lactone in ring A, while brasilianoids B–C featured a 7/6/6/5/5 pentacyclic ring system finding in nature for the first time. The biosynthetic relationship among the isolated compounds was postulated. Compound 1 significantly stimulated the expression of filaggrin and caspase-14 in HaCaT cells in dose-dependent manner, while compounds 2 and 3 showed moderate inhibition against NO production in LPS-induced RAW 264.7 macrophages.

Highlights

The fungal meroterpenoids as the fascinating hybrid natural products are widely distributed in marine environments with diverse molecular architectures, that are assembled by terpene moieties with other precursors such as polyketide unit by various biosynthetic pathways (Iida et al, 2008; Silva et al, 2011; Guo et al, 2012; Qi et al, 2017)
The 13C NMR and DEPT spectra exhibited a total of 26 carbon resonances (Table 2), which were classified into six methyl, five methylene, four methine, and eleven quaternary carbons involving two ketones and two ester carbonyl carbons
We reported P. brasilianum WZXY-m1229 to be obtained from a marine sponge for the first time

Summary

Introduction

The fungal meroterpenoids as the fascinating hybrid natural products are widely distributed in marine environments with diverse molecular architectures, that are assembled by terpene moieties with other precursors such as polyketide unit by various biosynthetic pathways (Iida et al, 2008; Silva et al, 2011; Guo et al, 2012; Qi et al, 2017). Fumigatonin and novofumigatonin are an additional subtype containing highly oxidized and complicatedly condensed ring system (Okuyama et al, 2008; Rank et al, 2008) These meroterpenoids have been reported to possess a range of biological activities (Rank et al, 2008; Zhang et al, 2012). Fungal strains of P. brasilianum are mostly isolated from terrestrial sources They produced diverse metabolite scaffolds including meroterpenenes, polyketides, alkaloids, and cyclopeptides (Bazioli et al, 2017). QRT-PCR detection showed that prenyltransferase gene (PM-122-9_1376) and terpene cyclase gene (PM-122-9_1374) in clusters A and B were highly expressed These findings suggested WZXYm122-9 strain to be a potential producer of terpenoids. Chromatographic separation of the EtOAc extract of the cultured fungus on a large scale resulted in the isolation of eight meroterpenoids, including six new compounds namely brasilianoids A-F (1-6) and known analogues preaustinoids D (7) and A2 (8) (Figure 2)

Methods

Results

Discussion

Conclusion