新天然活性间苯三酚偶联萜类化合物的发现与研究

Cancer is one of the major diseases imperiling human. It is widely accepted that c-Met plays an important role in triggering multiple steps of cancer invasive growth including scattering, migration, invasion, branching morphogenesis. In light of the important role of HGF/c-Met signaling in cancer progression and metastases, this signaling axis has become one of the most promising therapeutic targets in anti-cancer drugs discovery. Recently, in our chemical and biological efforts on the genus Eucalyptus, several complex phloroglucinol-coupled terpenoids, including a new compound with a new carbon skeleton, were isolated from two Eucalyptus species in our lab. Among them, the compound with new carbon skeleton, markedly inhibited HGF-induced c-Met phosphorylation in a dose-dependent manner, and strongly inhibited HGF-stimulated cell metastatic phenotype in vitro. For the inspiring pioneer studies, the chemical and biological investigations on three plants of the genus Eucalyptus (E. globules, E. camaldulensis var. Pendula, and E. robusta), were proposed by the applicant in order to discovery the new natural compounds with significant bioactivities, especially the HGF/c-Met Axis inhibition activity. Furthermore, the terminal aim is to develop them to be new antitumor medicine leads or drug candidates.

癌症是严重危害人类健康的重大疾病。在肿瘤的发生、发展和转移过程中，受体酪氨酸激酶c-Met起到了枢纽的作用，抑制它就可以抑制多个肿瘤靶点发挥的效应。目前，阻断HGF/c-Met的信号转导已成为抗肿瘤药物研究的一个热点。最近，我们在研究桉属植物化学成分和生物活性的过程中，首次从两种国产桉属植物中发现数个结构复杂的间苯三酚偶联萜类化合物，其中1个新化合物具有新的碳骨架。该化合物以剂量依赖方式，特异性阻断肝细胞生长因子（HGF）介导的c-Met活化，并能强烈抑制由HGF激活c-Met介导的细胞转移表型。为此，本申请拟在前期研究的基础上，对3种桉属（植物蓝桉、垂枝赤桉和桉）进行系统的化学活性和生物活性研究，以期发现结构新颖、具有显著生物活性的天然化合物，特别是具有HGF/c-Met信号转导抑制活性的化合物，并希望最终发展成新型抗肿瘤药物先导结构或药物候选物。

本项目完成了3种桉属药用植物 (蓝桉、桉和垂枝赤桉) 的化学成分和生物活性研究，共获得化合物100多个，其中新化合物38个。实际非本人承担所获得的化合物主要为间苯三酚偶联萜类化合物，其次是间苯三酚偶联黄酮类以及木脂素类化合物，另有少量香豆素、黄酮、脂肪酸类化合物。对分离得到的化合物进行了广泛的生物活性研究，发现活性化合物30个，其中有13个化合物具有抗肿瘤活性，包括对人肺癌细胞A549细胞中的HGF/c-Met信号转导的抑制作用、对LPS介导的NF-κB激酶活性的抑制作用、对人白血病细胞HL-60增殖的抑制作用；有26个化合物对蛋白酪氨酸磷酸酶1B (PTP1B)有抑制活性, 其IC50值所处的范围区间是0.58～14.07µM。该项目的部分研究结果已发表论文1篇 (J Nat Prod, 2016, 79, 1365-1372), 还3篇论文在整理发表之中。