Protopanoxadiol is a key active ingredient derived from Panax ginseng that is well-known to exhibit anti-tumor activity. Previous research focused on the natural protopanaxadiol derivative AD-1 has demonstrated that it possesses broad spectrum anti-tumor activities in vitro and in vivo. However, its limited activity, selectivity, and cell permeability have impeded its therapeutic application. Herein, a series of novel AD-1 derivatives were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking AD-1 at the C-3 and C-12 positions with pomalidomide through linkers of alkyl chain of differing lengths to achieve the goal of improving the efficacy of the parent compound. Among these synthesized PROTACs, the representative compound A05 exhibited the most potent anti-proliferative activity against A549 cells. Furthermore, mechanistic studies revealed that compound A05 was able to suppress MDM2 expression, disrupt interactions between p53 and MDM2 and readily induce apoptotic death via the mitochondrial apoptosis pathway. Moreover, the in vivo assays revealed that compound A05 exhibited both anti-proliferative and anti-metastatic activities in the zebrafish tumor xenograft model with A549 cells. Together, our findings suggest that AD-1 based PROTACs associated with the degradation of MDM2 may have promising effects for the treatment of lung cancer and this work provide a foundation for future efforts to develop novel anti-tumor agents from natural products.

Protopoxadiol 是从人参中提取的一种关键活性成分，众所周知，它具有抗肿瘤活性。之前针对天然原人参二醇衍生物 AD-1 的研究表明，它在体外和体内都具有广谱抗肿瘤活性。然而，其有限的活性、选择性和细胞渗透性阻碍了其治疗应用。在此，基于蛋白水解靶向嵌合体（PROTAC）技术，通过不同长度的烷基链连接剂将AD-1的C-3和C-12位与泊马度胺连接起来，设计合成了一系列新型AD-1衍生物。达到提高母体药效的目的。在这些合成的 PROTAC 中，代表性化合物A05对 A549 细胞表现出最强的抗增殖活性。此外，机理研究表明，化合物A05能够抑制 MDM2 表达，破坏 p53 和 MDM2 之间的相互作用，并容易通过线粒体凋亡途径诱导细胞凋亡。此外，体内试验表明化合物A05在 A549 细胞的斑马鱼肿瘤异种移植模型中表现出抗增殖和抗转移活性。总之，我们的研究结果表明，与 MDM2 降解相关的基于 AD-1 的 PROTAC 可能对肺癌的治疗具有良好的效果，这项工作为未来从天然产物中开发新型抗肿瘤药物的努力奠定了基础。