Chlorajaponols A–F, sesquiterpenoids from Chloranthus japonicus and their in vitro anti-inflammatory and anti-tumor activities

Abstract

Two new eudesmane sesquiterpenoids, chlorajaponols A–B (1–2), two new guaiane sesquiterpenoids, chlorajaponols C–D (3–4), a new germacrane sesquiterpenoid, chlorajaponol E (5), and a new lindenane sesquiterpenoid, chlorajaponol F (6), along with 8 known sesquiterpenoids and 6 known disesquiterpenoids, were isolated from the whole plant of Chloranthus japonicus. Their structures were established by extensive analysis of NMR spectroscopic data in combination with mass spectrometry. The structures of compounds 1–4 were confirmed by single crystal X-ray diffraction (CuKα radiation). The possible biogenetic pathways of compounds 1–6 were discussed. Chlorajaponol B (2) showed significant inhibition against nitric oxide (NO) release in LPS-induced RAW264.7 macrophages with the IC₅₀ value of 9.56 ± 0.71 μM, comparable to that of positive control amino guanidine (8.50 ± 0.35 μM). Shizukaol C (18) strongly suppressed the proliferation of three human tumor cell lines MGC803, HepG2, and HL-60 with IC₅₀ values of 4.60 ± 1.05 μM, 3.17 ± 0.66 μM, and 1.57 ± 0.27 μM, respectively.

Introduction

Natural products have been playing a highly important role in drug discovery and development process due to their unique structures and bioactivities [1]. Traditional medicinal plants are considered as a quite important source for discovering new lead compounds due to their definite medicinal records and long application in folk medicine [2]. Chloranthus species of the family Chloranthaceae are mainly distributed in tropical and warm regions in Asia, among which there are 13 species and 5 varietas in China [3]. In Chinese folk medicine, some Chloranthus plants have been long used to treat traumatic injury, blood stasis, and ringworm infection [4]. Previous investigations have revealed that sesquiterpenoids [5], especially eudesmane [6] and lindenane sesquiterpenes [7], [8], are major secondary metabolites of the genus Chloranthus. Some of these sesquiterpenoids showed diverse bioactivities, including cytotoxicity [9], anti-inflammatory [10], anti-HIV [11], and anti-fungal activities [6], as well as potent and selective potassium channel blocking activity [12].

Chloranthus japonicus Sieb., a perennial herbaceous plant of the genus Chloranthus, grows in shady places in the southern part of Korea, Japan, and China [3]. In Chinese folk medicine, this plant is commonly used for the treatment of traumatic injuries, rheumatic arthralgia, fractures, pulmonary tuberculosis, and neurasthenia [4]. Phytochemical investigations on this plant led to the isolation of a serial of interesting sesquiterpenoids and sesquiterpenoid oligomers [5], in which shizukaol B, cycloshizykaol A, and shizukaol F exhibited inhibition of the expression of cell adhesion molecules [13], while shizukaols B, C, F, and H had potent inhibition against HIV-1 [11]. Since our group has been long focusing on the discovery of bioactive natural products from medicinally important herbs in China [14], [15], these results inspired our great interest in exploring more secondary metabolites of C. japonicus and their bioactivities, and led to the isolation of two new eudesmane sesquiterpenoids, chlorajaponols A–B (1–2), two new guaiane sesquiterpenoids, chlorajaponols C–D (3–4), a new germacrane sesquiterpenoid, chlorajaponol E (5), and a new lindenane sesquiterpenoid, chlorajaponol F (6), along with 8 known sesquiterpenoids and 6 known disesquiterpenoids from the titled plant (Fig. 1). Herein, we describe the isolation, structural elucidation, in vitro anti-inflammatory and anti-tumor evaluation of these sesquiterpenoids.