Introduction
!The fruit of Melia toosendan Sieb. et Zucc. (Meliaceae), well-known as "Chuan-Lian-Zi" in Chinese, is an important traditional Chinese medicine (TCM) for the treatment of malaria, sting, stomachache, acute or chronic inflammations, and parasitosis [1][2][3], and possesses the property of "soothing liver-qi stagnation", indicating the neuroprotective potency according to TCM theory [4]. Pharmacological studies have demonstrated that toosendanin is an active component of "ChuanLian-Zi" as a selective presynaptic blocker, effective antibotulismic agent, and proliferation inhibitor of various human cancer cells [1,5]. In addition, "Chuan-Lian-Zi" is widely used as a botanical pesticide in agriculture due to the presence of limonoid-type triterpenoids [3,6]. Previous research has mainly focused on the limonoid-type triterpenoids of M. toosendan, from which more than 50 cases have been isolated [3,7,8]. However, there have been only a few investigations of lignans, another main component of "Chuan-Lian-Zi". Lignans as secondary metabolites derived from the shikimic acid pathway are widely distributed in plants and possess antitumor, antimitotic, antiviral, enzyme inhibitory, piscicidal, and antifungal activities [9][10][11]. Especially, it has been reported that lignans have neuroprotective activity in vitro and in vivo [12-15].Melatonin receptor type 1 (MT 1 ), a high-affinity G-protein-coupled receptor widely distributed in the brain, retina, cardiovascular system, immune system, reproductive system, kidneys, pancreas, and liver, is a very important target in the treatment of most melatonin-related nervous system diseases, including sleep disorders, depression, and anxiety syndromes [16][17][18]. Mediation on the activation of MT 1 is an effective therapy for these psychiatric problems, based on which several agonistic drugs (circadin, ramelteon, agomelatine, etc.) have been developed successfully, along with many potential candidates undergoing clinical trials [18]. In order to clarify the neuroprotective components of the entitled plant, the bioassay-guided investigation on the EtOAc part of the fruit of M. toosendan led to the isolation of seven new lignans (1-7; l " Fig. 1) and seventeen known ones (8-24; Fig. 1S, Supporting Information). Among them, compounds 8-23 were isolated from the fruits of M. toosendan for the first time. Their structural elucidation and biological evaluation are reported in this paper. (1-7), along with seventeen known compounds (8-24). The structures of the new compounds, involving four neo-lignans (1-4), two sesquilignans (5-6), and a norlignan (7), were elucidated based on extensive spectroscopic analyses (high-resolution electrospray ionization mass spectra, ultraviolet, infrared, one-dimensional and two-dimensional nuclear magnetic resonance). Compound 24 exhibited activity on melatonin receptor type 1 with an agonistic rate of 57.77 % at 1.02 mM according to the assay on HEK293 cell lines in vitro.
Results and Discussion
Supporting information available online at
