Abstract
Two new phenone derivatives penicophenones A (1) and B (2), a new cyclic tetrapeptide penicopeptide A (3), and five known compounds were isolated from the culture broth of Penicillium commune, an endophytic fungus derived from Vitis vinifera. Compounds 1–3 were elucidated by extensive spectroscopic analyses including 1D and 2D NMR and HRESIMS. The absolute configurations of 1 and 3 were determined by comparing its ECD with related molecules and modified Marfey’s analysis, respectively. Penicophenone A (1) possesses a rare benzannulated 6,6-spiroketal moiety, which is a new member of the unusual structural class with peniphenone A as the representative. Compound 3 exhibited significant inhibition activities against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in vitro and showed strong binding affinity to 11β-HSD1. Moreover, compound 3 treatments decreased the lipid droplet accumulation associate with the inhibition of 11β-HSD1 expression in differentiate-induced 3T3-L1 preadipocytes. Furthermore, the molecular docking demonstrated that compound 3 coordinated in the active site of 11β-HSD1 is essential for the ability of diminishing the enzyme activity.
Highlights
To explore the 11β-HSD1 inhibitory activities of compounds 1–8 in vitro, recombinant human 11β-HSD1 protein was incubated with various concentrations of compounds and the enzymatic activity was tested using HPLC-MS/MS (Fig. 3)
To further examine the 11β-HSD1 inhibitory effects of compound 3, we examined the anti-adipogenic effect of compound 3 during the differentiation of 3T3-L1 cells
The possible mechanism may be that compound 3 is more accessible to the active site of 11β-HSD1 to exert selective inhibition effects, which is indicated by MST assay (Kd = 82.1 ± 5.01 μM)
Summary
To explore the 11β-HSD1 inhibitory activities of compounds 1–8 in vitro, recombinant human 11β-HSD1 protein was incubated with various concentrations of compounds and the enzymatic activity (cortisone to cortisol) was tested using HPLC-MS/MS (Fig. 3) Among these compounds tested, compound 3 showed strong inhibitory effect against human 11β-HSD1, with an IC50 value of 9.07 ± 0.61 μM (Table 3). Several small molecule inhibitors of 11β-HSD1 were discovered from NPs, such as glycyrrhetinic acid, carbenoxolone, gossypol, and estradiol These NPs often showed low specificity in the inhibition of 11β-HSD1 with serious side effects. The possible mechanism may be that compound 3 is more accessible to the active site of 11β-HSD1 to exert selective inhibition effects, which is indicated by MST assay (Kd = 82.1 ± 5.01 μM). The novel structure of compound 3 combined with its significant inhibitory activities of 11β-HSD1 reported in this study may greatly promote the studies of 11β-HSD1 inhibitors from natural products, and further investigations on the mechanism and structure-function relationships for developing more excellent agents are necessary
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