Xylodon flaviporus-Derived Drimane Sesquiterpenoids That Inhibit Osteoclast Differentiation

Abstract

The presence of excessive osteoclasts is a major factor in skeletal diseases. The present study aimed to discover osteoclast differentiation inhibitors from the basidiomycete Xylodon flaviporus. Seven new drimane sesquiterpenoids (1–7) and 7-ketoisodrimenin-5-ene (8) were obtained and characterized by various spectroscopic methods. The isolated compounds were evaluated for their inhibitory effects against receptor activator of nuclear factor-kappa-B ligand-induced osteoclastogenesis in mouse bone marrow macrophages. Compounds 1, 3, and 6 showed potent activities with IC50 values of 1.6, 0.9, and 2.1 μM, respectively, while 4, 5, and 7 exhibited relatively weak activities with IC50 values of 10.7, 10.1, and 8.5 μM, respectively.

Chemical Diversity and Biosynthesis of Drimane‐Type Sesquiterpenes in the Fungal Kingdom

“…Benzoic acid can also form esters at the C‐1 position, as in polymorphine B ( 63 ), which was isolated from Xylaria polymorpha and exhibited anti‐acetylcholinesterase and α‐glucosidase inhibitory activities [34] . Additional DTS‐esters, such as xylodonin derivatives ( 64 – 66 ), presenting similar structures but possessing a p ‐coumaroyl or cinnamoyl moiety, have been found to inhibit the osteoclastogenesis and thus are promising therapeutics for treating osteoclast‐related diseases such as osteoporosis [35] . From a biosynthetic perspective, the mechanisms of ester bond formation and acetylation on the DTS backbone have been proposed in A. oryzae , [11] where a nonribosomal peptide synthetase (NRPS), AstA, should be responsible for the AMP‐esterification and transferring of benzoic acid to form 1 and 2 , and the acetyl transferase AstG promotes O ‐acetylation at position C‐15 to form 6 and 7 (Figure 1), a similar mechanism for compounds 53 – 66 was hypothesized.…”

“…[23] Slightly different structures could be obtained by the condensation of C-11 aldehyde with C-12 hydroxy group or carboxylic acid, which would result in different ring variations, as observed in 35-38 [20a,24] and 39-41. [25] Among them, pereniporin A (35) was isolated together with 25 and also showed plant growth inhibitor activity, [23] while 6-epi-pereniporin A from Perenniporia maackiae exhibited anticancer property. [24a] Concerning their potential biosynthesis, in A. calidoustus, a multistep cytochrome P450 (DrtD) and a FADbinding oxidoreductase (DrtC) were solely responsible for subsequent hydroxylations and oxidations that led to the lactone ring formation.…”

Taxonomic evaluation of Xylodon (Hymenochaetales, Basidiomycota) in Korea and sequence verification of the corresponding species in GenBank

“…flaviporus has potential bioremediation abilities to degrade organic pollutants such as polycyclic aromatic hydrocarbons ( Lee et al, 2014 ). In addition to their enzymatic abilities, the compounds of X. flaviporus also have medicinal effects, inhibiting RANKL-stimulated osteoclastogenesis ( Kwon et al, 2019 ).…”

Stereoselective Synthesis of Xylodonin A and 22-Hydroxyxylodonin A and Discovery of Analogues with Cytotoxic Activity

“…Xylodonin A ( 1 ) and 22-hydroxyxylodonin A ( 2 ) were selected as synthetic targets because of their complex isolation procedures and low yields from natural sources, which have limited further investigation of their cytotoxic effects . Xylodonin A ( 1 ) and 22-hydroxyxylodonin A ( 2 ), isolated from Xylodon flaviporus , potently inhibited receptor activator of nuclear factor-kappa-B ligand (RANKL) . Both 1 and 2 belong to a growing family of drimane-type sesquiterpenoids, including 1-hydroxyxylodonin A, xylodonin B, ustusoic acid A, ustusoic acid B, etc. − …”

“…Xylodonin A ( 1 ) and 22-hydroxyxylodonin A ( 2 ), isolated from Xylodon flaviporus , potently inhibited receptor activator of nuclear factor-kappa-B ligand (RANKL) . Both 1 and 2 belong to a growing family of drimane-type sesquiterpenoids, including 1-hydroxyxylodonin A, xylodonin B, ustusoic acid A, ustusoic acid B, etc. − …”