Anti-Osteoclastogenic and Antibacterial Effects of Chlorinated Polyketides from the Beibu Gulf Coral-Derived Fungus Aspergillus unguis GXIMD 02505.

Yanting Zhang,Chenghai Gao,Shuai Peng,Bingyao Huang,Xiaowei Luo,Yonghong Liu,Yanhui Tan,Kai Liu,Zhichao Li,Xinming Liu

doi:10.3390/md20030178

Abstract

One new depsidone derivative, aspergillusidone H (3), along with seven known biosynthetically related chlorinated polyketides, were obtained from the Beibu Gulf coral-derived fungus Aspergillus unguis GXIMD 02505. Their structures were determined by comprehensive physicochemical and spectroscopic data interpretation. Notably, the X-ray crystal structure of 2 and the previously unknown absolute configuration of 8, assigned by ECD calculations, are described here for the first time. Compounds 1–5, 7 and 8 exhibited inhibition of lipopolysaccharide (LPS)-induced NF-κB in RAW 264.7 macrophages at 20 μM. In addition, the two potent inhibitors (2 and 7) dose-dependently suppressed RANKL-induced osteoclast differentiation without any evidence of cytotoxicity in bone marrow macrophages cells (BMMs). This is the first report of osteoclastogenesis inhibitory activity for the metabolites of these kinds. Besides, compounds 1, 2, 4, and 6–8 showed inhibitory activity against marine biofilm-forming bacteria, methicillin-resistant Staphylococcus aureus, Microbulbifer variabilis, Marinobacterium jannaschii, and Vibrio pelagius, with their MIC values ranging from 2 to 64 μg/mL. These findings provide a basis for further development of chlorinated polyketides as potential inhibitors of osteoclast differentiation and/or for use as anti-fouling agents.

Highlights

Bone is a rigid, yet dynamic, organ that provides maximal strength with minimal mass, supporting the human body and producing indispensable red and white blood cells [1]
The whole extract was performed on the repeated column chromatography involving silica gel, reversed-phase silica gel C18, and semipreparative high performance liquid chromatography (HPLC)
The HPLC-DAD-guided purification resulted in the discovery of eight chlorinated aromatic polyketides, including two diphenyl ethers (1 and 2), four depsidones (3–6), one depside (7), and one related block (8)

Summary

Introduction

Bone is a rigid, yet dynamic, organ that provides maximal strength with minimal mass, supporting the human body and producing indispensable red and white blood cells [1]. Normal bone homeostasis is known to be regulated and maintained by two bone remodeling metabolic processes, bone resorption by osteoclasts and bone formation by osteoblasts [2]. Osteoporosis, postmenopausal osteoporosis, will pose severe worldwide concern to public health and economic development [3]. The development of therapeutic agents to treat osteoporosis is urgently needed. The differentiation of the osteoclast is modulated by two critical factors, the macrophage colony stimulation factor (M-CSF) and the receptor activator of the nuclear factor kappa-B (NF-κB) ligand (RANKL). RANKL signaling pathways have been recently proposed as key targets for inhibiting osteoclast differentiation and bone resorption [4]. Many efforts have been recently devoted to the discovery of lead compounds from natural sources that target RANKL-induced osteoclast differentiation for attenuating enhanced bone resorption and bone loss [5]

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Conclusion