Terminal Cyclohexane-Type Meroterpenoids from the Fruiting Bodies of Ganoderma cochlear

Abstract

Eleven new cyclohexane-type meroterpenoids (1, 3–5, 7, 8, 11–15) and four known similar meroterpenoids (2, 6, 9, and 10) were isolated from Ganoderma cochlear. Their structures and absolute configurations at stereogenic centers were elucidated by using HRESIMS, NMR spectroscopy and computational methods. In addition, the structure of the known meroterpenoid, cochlearol G (2), was revised, and the absolute configurations at the stereogenic centers of known meroterpenoids 9 and 10 were determined. All the isolated meroterpenoids were evaluated for their activities against renal fibrosis and triple negative breast cancer, and their insulin resistance. The results of the renal fibrosis study showed that meroterpenoid 11 inhibits over-expression of fibronectin, collagen I and α-SMA. Results of the wound healing study revealed that 4, 6 and 8 significantly inhibit migration of BT549 cells. Observations made in Western blotting experiments showed that 6 decreases the levels of TWIST1 and ZEB1, and increases the level of E-cadherin. Finally, meroterpenoids 7, 9, 11, and 15 significantly up-regulate p-AMPK protein expression in normal L6 myotubes cells.

Anti-Fibrotic Potential of Tomentosenol A, a Constituent of Cerumen from the Australian Native Stingless Bee, Tetragonula carbonaria

“…Agents that interfere with the TGF-β 1 signalling pathway may provide anti-fibrotic benefit by inhibiting myofibroblast differentiation and collagen production [ 3 ]. This has been reported previously for small molecule meroterpenoids, petchiether A [ 24 ] and ganodercin M [ 25 ], isolated from the fruiting body of fungi, Ganoderma petchii and G. cochlear . The effect of Compound 1 on NFF-myofibroblast differentiation was examined by stimulating cells with TGF-β 1 (10 ng/mL) and immunostaining for α-SMA.…”

“…TGF-β 1 is known to induce NFF-myofibroblast differentiation via the activation of both Smad- and non–Smad dependent cell signalling pathways [ 28 , 29 ]. A recent study investigating the anti-fibrotic effects of the meroterpenoid, ganodercin M, found no effect on Smad2/3 phosphorylation in TGF-β 1 –stimulated rat renal proximal tubular cells (NRK-52E cells), suggesting a Smad-independent mechanism [ 25 ]. The precise mechanisms by which Compound 1 elicits its anti-fibrotic responses remain to be elucidated.…”

Structural diversity, hypothetical biosynthesis, chemical synthesis, and biological activity ofGanodermameroterpenoids

“…Given that the cyclohexane ring of compounds 42–45 (ref. 46 and 47) is present between C-6′ and C-11′, we deduce their possible biosynthetic pathways as follows: (1) the epoxidation of Δ 10′,11′ ; (2) C-6′ attacks C-11′ to form cation of C-7′; (3) deprotonation at C-6′, C-15′, and C-8′ respectively leads to the generation of derivatives 42–45 (Fig. 9).…”

“…Similarly, since C-8′ is still an allylic position, thus, the six-membered carbon ring of compounds 48–55 (ref. 46) could be formed from fornicin D ( 13 ) by a series of free radical reactions, with allylic oxidation leading to the formation of the hydroxyls at C-8′ and C-9′ (Fig. 11).…”

“…In addition, C-1′ could form an ester ring with C-14′ leading to the generation of ganotheaecoloids G/H ( 65 ), and I ( 66 ). 46 Additionally, the generation of (−)-ganotheaecoloids A and B ( 67 and 68 ) 46 (Fig. 13) from G. theaecoloum could be due to the decarboxylation (C-14′) and dehydration (C-1 and C-2′).…”