Polyketides from Marine-Derived Aspergillus porosus: Challenges and Opportunities for Determining Absolute Configuration

Abstract

Fungal natural products have inspired and enabled countless modern therapeutics. During a survey of the secondary metabolites of endophytic fungi, we found that Aspergillus porosus produces new polyketides with interesting structural features named porosuphenols A−D (1, 2, 3a, and 3b). The structural elucidation of these metabolites was performed with 1D and 2D NMR techniques, Mosher ester analysis, J-based conformational analysis, and isotope exchange studies. The absolute configuration of these compounds was determined using typical approaches including comparative analysis of experimental NMR and electronic circular dichroism spectra with DFT calculations. However, these efforts did not provide conclusive results for porosuphenol A (1). To resolve this issue, we applied a strategy in which NMR data guide the conformer search. Herein are presented the structure elucidation of porosuphenols A−D as a case study in the challenges and opportunities for determination of absolute configuration. Lastly, bioassay-guided fractionation of cytotoxic fractions resulted in the additional isolation of pimarane diterpenes, sphaeropsidin A (4), and aspergiloid E (5).

Australian bush medicines harbour diverse microbial endophytes with broad‐spectrum antibacterial activity

“…Eurotiales are prolific producers of specialized metabolites and hundreds of NRPs and PKs have been isolated from this order, including the antibiotic penicillin (Toghueo and Boyom 2020). Recently, Aspergillus porosus an endophyte isolated from Fucus vesiculosus (brown alga) was found to produce porosuphenols; PKs with antimicrobial activity (Neuhaus et al 2019). Likewise, Tolypocladium sp.…”

Natural Polypropionates in 1999–2020: An Overview of Chemical and Biological Diversity

“…Ten carbon homocyclic PPs were obtained from microorganisms including fungi, actinomycetes and myxobacteria (Figure 4). Porosuphenols A-C (19)(20)(21) were isolated from a marine-derived Aspergillus porosus [18], and asperolan (22) was isolated from a Garcinia preussii endophytic fungus Aspergillus japonicus [19]. The absolute configuration of 19 was established using NMR data guided conformer searching and electrostatic circular dichroism (ECD) calculations.…”

“…The quantitative structure-activity relationship (QSAR) analysis suggested that the terminal hydrophilic functional group as well as an opposing hydrophobic chain would play an important role in MptpB inhibition activities [10]. Another marine-derived fungus A. porosus produced three new PPs porosuphenols A-C (19-21) and a hydrogenated benzopyran derivative porosuphenol D 103 (Figure 14) [18]. Though a series of conformation analysis was adapted to solve the stereochemistry of 19 and 20, the attempts to assign the absolute configuration of 21 and 103 were unsuccessful.…”

Antibiotics from Extremophilic Micromycetes

“…Substituted resorcinol B (245) showed pronounced cytotoxicity against several cell lines, whereas resorcinol A (244) was almost inactive (GI 50 > 50 μM). New polyketidic metabolites, porosulfenols A-D (234, 235, 237a,b) were obtained from the culture liquid of the Aspergillus porosus strain of marine origin [209]. Two latter compounds are in a dynamic equilibrium under ambient conditions (linear 237a and cyclic 237b forms).…”

“…26; the noted fragments are highlighted in red). Separation of toxic fractions of the culture liquid extract of the marine Aspergillus porosus strain [209] led to the release of the known phytotoxin, sphaeropsidin A (401) [272,273], which recently attracted interest as a cytotoxic agent [274]. Interestingly, the second isolated analog, which is very similar in structure to the known aspergiloid E (400) [273], has a significantly lower activity.…”