Chemical diversity, medicinal potentialities, biosynthesis, and pharmacokinetics of anthraquinones and their congeners derived from marine fungi: a comprehensive update

Abstract

Marine fungi receive excessive attention as prolific producers of structurally unique secondary metabolites, offering promising potential as substitutes or conjugates for current therapeutics, whereas existing research has only scratched the surface in terms of secondary metabolite diversity and potential industrial applications as only a small share of bioactive natural products have been identified from marine-derived fungi thus far. Anthraquinones derived from filamentous fungi are a distinct large group of polyketides containing compounds which feature a common 9,10-dioxoanthracene core, while their derivatives are generated through enzymatic reactions such as methylation, oxidation, or dimerization to produce a large variety of anthraquinone derivatives. A considerable number of reported anthraquinones and their derivatives have shown significant biological activities as well as highly economical, commercial, and biomedical potentialities such as anticancer, antimicrobial, antioxidant, and anti-inflammatory activities. Accordingly, and in this context, this review comprehensively covers the state-of-art over 20 years of about 208 structurally diverse anthraquinones and their derivatives isolated from different species of marine-derived fungal genera along with their reported bioactivity wherever applicable. Also, in this manuscript, we will present in brief recent insights centred on their experimentally proved biosynthetic routes. Moreover, all reported compounds were extensively investigated for their in-silico drug-likeness and pharmacokinetics properties which intriguingly highlighted a list of 20 anthraquinone-containing compounds that could be considered as potential drug lead scaffolds.

Fig. 1. General biosynthetic pathway of anthraquinones in fungi. (A) domain architecture of the non-reducing polyketide synthase. (B) Biosynthetic pathways of the anthraquinones emodin (14) and endocrocin. The isotope labelling pattern is shown black bold lines and the polyketide starter unit is indicated in red.

Fig. 2. Chemical structures of compounds 1–10.

Fig. 3. Chemical structures of compounds 11–44.

Fig. 4. Chemical structures of compounds 45–80.

Fig. 5. Chemical structures of compounds 81–98.

Fig. 6. Chemical structures of compounds 99–113.

Fig. 7. Chemical structures of compounds 114–130.

Fig. 8. Chemical structures of compounds 131–142.

Fig. 9. Chemical structures of compounds 143–155.

Fig. 10. Chemical structures of compounds 156–163.

Fig. 11. Chemical structures of compounds 164–170.

Fig. 12. Chemical structures of compounds 171–177.

Fig. 13. Chemical structures of compounds 178–183.

Fig. 14. Chemical structures of compounds 184–208.

Fig. 15. Distribution of molecular weight (M_wt), fraction of sp³ carbons (FCsp³), number of rotatable bonds (RB), topological polar surface area (TPSA), lipophilicity (log P), solubility (log S) according to the species. Comparison between the values of FCsp³ and M_wt, log P and M_wt, TPSA and M_wt, log S and M_wt, log P and log S, and log S and TPSA. NIG: Nigrospora sp., ASP: Aspergillus sp., PEN: Penicillium sp., STE: Stemphylium sp., ALT: Alternaria sp., TRI: Trichoderma sp., EUR: Eurotium sp., FUS: Fusarium sp., ENG: Engyodontium album, SPO: Sporendonema casei, and OTH: other marine fungi.

Fig. 16. Heatmap of the compliance with rules of drug-likeness according to the classes. LIP: Lipinski, GHO: Ghoose, VEB: Veber, EGA: Agan and MUE: Muegge. NIG: Nigrospora sp., ASP: Aspergillus sp., PEN: Penicillium sp., STE: Stemphylium sp., ALT: Alternaria sp., TRI: Trichoderma sp., EUR: Eurotium sp., FUS: Fusarium sp., ENG: Engyodontium album, SPO: Sporendonema casei, and OTH: other marine fungi.

Fig. 17. Distribution and total anthraquinones and their derivatives isolated from different species of marine-derived fungi.

Fig. 18. Total biological activities of various anthraquinones and their derivatives isolated from different species of marine-derived fungi.

Mohamed Sebak

Fatma Molham

Claudio Greco

Mohamed A. Tammam

Mansour Sobeh

Amr El-Demerdash