Department of Pharmacy, Daqing Campus of Harbin Medical University, Daqing Hi-Tech Development Zone, Xinyang Road, Daqing 163319, China.
Graduate School of Science and Technology, Faculty of Engineering, Niigata University, Ikarashi, 2-8050, Niigata 950-2181, Japan.
Bioorg Chem. 2021 Mar;108:104642. doi: 10.1016/j.bioorg.2021.104642. Epub 2021 Jan 12.
Tuberiferin, 6-epi-tuberifelin, dehydrobrachylaenolide and two series of eudesmanolides, eudesmane-12,6 α-lactones and eudesmane-12,6β-lactones, were synthesized for the studies of the structure-activity relationships to explore novel anti-inflammatory, anti-cancer and crop disease prevention agents. The anti-inflammatory activities were tested by the inhibitory on the induction of inter-cellular adhesion molecule (ICAM-1), the permeation of leucocyte into inflammatory air pouch of murine, the killing function of cytotoxic T-lymphocytes (CTL), production of IL-1; The anti-cancer activities were established on the cytotoxic activities to six kinds of cell lines (P388, CCRF-CEM, VA-13, HepG2, QG-56, and WI-38). Results showed that Dehydrobrachylaenolide (an exo-endo cross conjugated dienone and α-methylene γ-lactone) was the most effective compound inhibiting ICAM-1 (IC 3.0 μM) and the cell line VA-13 (IC 0.45 μM); Compound 20 with an α-bromo-ketone moiety embraced the most potent inhibitory activity towards the permeation of leucocyte into inflammatory air pouches of murine in vivo (inhibitory ratio 54% at 10 mg); Compound 25 with an α-bromo-ketone and α-methylene trans-γ-lactone) showed the most significant inhibitory activity on the killing function of CTL (IC 18 μM), as well as the cell lines of CCRF-CEM (IC 1.1 μM) and P388 (IC 1.21 μM) ; Tuberiferin (an α,β-unsaturated ketone and α- methylene γ-lactone) was on the top effective inhibitory on the production of IL-1; Compounds 19 with an α-bromo-ketone and α-methylene cis-γ-lactone exhibited the most potent inhibitory of QG-56 (IC 12.5 μM); Compound 29 with an α-bromo-α,β-unsaturated ketone and α-methylene γ-lactone) showed significant inhibitory for HepG2 (IC 1.23 μM) , though potently inhibited WI 38 (IC 0.31 μM) as well. A conclusion may be reached that the α-Methylene γ-lactone moiety, exo-endo cross conjugated dienone moiety, and α-bromo-ketone withα-methylene moiety might be essential for eudesmanolides in the expression of their anti-inflammatory, anti-tumour biological activities. Similarly, the above mentioned key moieties are also responsible for the preventive activity of crop disease controlling.
为了研究结构-活性关系，寻找新型抗炎、抗癌和作物病害防治药物，我们合成了 6-表-薯蓣萜、去氢齿孔酸内酯和两类倍半萜内酯，即桉烷-12，6α-内酰胺和桉烷-12，6β-内酰胺。抗炎活性通过抑制细胞间黏附分子（ICAM-1）诱导、白细胞渗透到鼠类炎症性气囊、细胞毒性 T 淋巴细胞（CTL）杀伤功能、白细胞介素-1（IL-1）产生来检测；抗癌活性通过对 6 种细胞系（P388、CCRF-CEM、VA-13、HepG2、QG-56 和 WI-38）的细胞毒性来建立。结果表明，去氢齿孔酸内酯（外-内共轭二烯酮和α-亚甲基γ-内酰胺）是抑制 ICAM-1（IC3.0μM）和细胞系 VA-13（IC0.45μM）活性最强的化合物；具有α-溴酮部分的化合物 20 对体内白细胞渗透到炎症性气囊的抑制活性最强（10mg 时抑制率为 54%）；具有α-溴酮和α-亚甲基反式-γ-内酰胺的化合物 25 对 CTL 杀伤功能的抑制活性最强（IC18μM），对 CCRF-CEM（IC1.1μM）和 P388（IC1.21μM）细胞系也有显著抑制作用；薯蓣萜（α，β-不饱和酮和α-亚甲基γ-内酰胺）对白细胞介素-1 的产生有最强的抑制作用；具有α-溴酮和α-亚甲基顺式-γ-内酰胺的化合物 19 对 QG-56（IC12.5μM）的抑制作用最强；具有α-溴-α，β-不饱和酮和α-亚甲基γ-内酰胺的化合物 29 对 HepG2（IC1.23μM）的抑制作用显著，对 WI 38（IC0.31μM）也有很强的抑制作用。可以得出结论，α-亚甲基γ-内酰胺部分、外-内共轭二烯酮部分和含α-亚甲基的α-溴酮部分可能是桉烷型倍半萜内酯发挥抗炎、抗肿瘤生物活性所必需的。同样，上述关键部分也负责防治作物病害。
