Tanzawaic Acid Derivatives from the Marine-Derived Penicillium steckii as Inhibitors of RANKL-Induced Osteoclastogenesis

Abstract

Seven new tanzawaic acid derivatives, steckwaic acids E–K (1–7), and one new benzene derivate (8), together with seven known tanzawaic acid analogues (9–16) were isolated from the marine algicolous fungus Penicillium steckii SCSIO 41040. The structures and absolute configurations of these new compounds (1–8) were determined by spectroscopic analyses, X-ray diffraction, and comparison of ECD spectra to calculations. Compounds 2, 10, and 15 inhibited lipopolysaccharide (LPS)-induced nuclear factor kappa-B (NF-κB) with IC50 values of 10.4, 18.6, and 15.2 μM, respectively. Compound 2 could suppress the receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophage cells (BMMCs). To the best of our knowledge, this is the first report of osteoclastogenesis inhibitory activity for tanzawaic acid derivatives.

Identifying Marine-Derived Tanzawaic Acid Derivatives as Novel Inhibitors against Osteoclastogenesis and Osteoporosis via Downregulation of NF-κB and NFATc1 Activation

“…Penicisteck acids E−H (1−4), with rare decalin ring-opening at A ring, are characterized by the presence of a benzene ring with a penta-2′,4′-dienoic acid at C-1 and another side chain at C- Marine natural products have been recently found to be a vital source of inhibitors of osteoclastogenesis. 14,19 All of these compounds isolated were then evaluated for their inhibitory effects against lipopolysaccharide (LPS)-induced NF-κB luciferase activities in RAW264.7 macrophages stably expressing the NF-κB luciferase reporter gene and against RANKLinduced osteoclastogenesis in bone marrow-derived macrophage cells (BMMCs) measured by TRAP assays. As a result, 23 TAs showed inhibition of LPS-induced NF-κB luciferase activities in NF-κB-Luc transfected RAW264.7 macrophages at 20 μM (***P < 0.001) (Figure 3).…”

“…BAY11-7082 was used as the positive control at a concentration of 5.00 μM. 6,[13][14][15][16]18,19,21,22,25,[28][29][30][31]35,38, and 39 suppressed LPS-induced NF-κB luciferase in a dose-dependent manner (Figure S6), with IC 50 values ranging from 12.37 to 26.29 μM (Table S7).…”

“…FO-1611 isolated from soil in 1993 and then designated as hynapenes A and B. , To the best of our knowledge, approximately 70 TAs (Figure S4, Supporting Information) with anti-inflammatory , and antimicrobial activities − have been reported, and marine fungi are the new source for TAs. In addition, TAs are found by our team to have antiosteoclast differentiation potential for the first time. , …”

“…Natural products are one of the most significant sources for the treatment of osteoporosis, and many of them were reported to have active antiosteoporosis potential via modulating the function of osteoclasts and osteoblasts . Marine microorganisms, especially marine fungi, have recently been proven to be prolific sources of biologically significant natural compounds. − We have identified a series of inhibitors against osteoclastogenesis with potential for treating osteoporosis from marine fungi, which indicates that it is an important resource for the discovery of novel leading antiosteoporosis compounds. − Tanzawaic acids (TAs), a decalin-type polyketide, were first discovered from cultures of the fungus Penicillium sp. FO-1611 isolated from soil in 1993 and then designated as hynapenes A and B. , To the best of our knowledge, approximately 70 TAs (Figure S4, Supporting Information) with anti-inflammatory , and antimicrobial activities − have been reported, and marine fungi are the new source for TAs.…”

“…In addition, TAs are found by our team to have antiosteoclast differentiation potential for the first time. 19,27 In the process of osteoclast differentiation inhibitors screening from marine microbial natural products, we conducted an in-depth exploration of TAs from the fungus Penicillium steckii and investigated the mechanism of their antiosteoclastogenesis activity (in vitro and in vivo) herein.…”