Abstract：
Ingenol diterpenoids continue to attract the attention for their extensive biological activity and novel structural features. To further explore this type of compound as anti-tumor agent, 13-oxyingenol dodecanoate (13-OD) was prepared by a standard chemical transformation from an Euphorbia kansui extract, and 29 derivatives were synthesized through parent 13-OD. Their inhibition activities against different types of cancer were screened and some derivatives showed superior anti-non-small cell lung cancer (NSCLC) cells cytotoxic potencies than oxaliplatin. In addition, TMBIM6 was identified as a crucial cellular target of 13-OD using ABPP target angling technique, and subsequently was verified by pull down, siRNA interference, BLI and CETSA assays. With modulating the function of TMBIM6 protein by 13-OD and its derivatives, Ca2+ release function was affected, causing mitochondrial Ca2+ overload, depolarisation of membrane potential. Remarkably, 13-OD, B6, A2, and A10-2 induced mitophagy and ferroptosis. In summary, our results reveal that 13-OD, B6, A2, and A10-2 holds great potential in developing anti-tumor agents for targeting TMBIM6.
摘要：
芬诺二萜以其广泛的生物活性和新颖的结构特征而不断受到关注。为进一步探索该类化合物作为抗肿瘤剂,13-氧ingenol十二烷酸酯（13-OD）是通过标准化学转化从大黄甘遂提取物中制备的，和29个衍生物通过母体13-OD合成。筛选了它们对不同类型癌症的抑制活性，一些衍生物显示出比奥沙利铂更高的抗非小细胞肺癌（NSCLC）细胞毒性。此外,TMBIM6被鉴定为13-OD的关键细胞靶标，使用ABPP靶标成角度技术，随后通过下拉验证，siRNA干扰,BLI和CETSA测定。通过13-OD及其衍生物调节TMBIM6蛋白的功能,Ca2+释放功能受到影响,导致线粒体Ca2+超负荷,膜电位去极化。值得注意的是,13-OD,B6、A2和A10-2诱导有丝分裂和铁凋亡。总之,我们的结果表明，13-OD，B6，A2和A10-2在开发靶向TMBIM6的抗肿瘤剂方面具有巨大潜力。
