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 () was prepared by a standard chemical transformation from an extract, and 29 derivatives were synthesized through parent . 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 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 and its derivatives, Ca release function was affected, causing mitochondrial Ca overload, depolarisation of membrane potential. Remarkably, , , , and – induced mitophagy and ferroptosis. In summary, our results reveal that , , , and – holds great potential in developing anti-tumor agents for targeting TMBIM6.

中文翻译：

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13-oxyingenol dodecanoate 衍生物通过靶向 TMBIM6 作为潜在的抗 NSCLC 药物诱导线粒体自噬和铁死亡

巨大戟二萜类化合物因其广泛的生物活性和新颖的结构特征而继续引起人们的关注。为了进一步探索这类化合物作为抗肿瘤药物的潜力，通过标准化学转化从提取物中制备了13-oxyingenol dodecanoate ()，并通过母体合成了29种衍生物。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优越的抗非小细胞肺癌（NSCLC）细胞的细胞毒性效力。此外，TMBIM6被确定为使用ABPP靶标定位技术的关键细胞靶标，随后通过pull down、siRNA干扰、BLI和CETSA测定进行验证。 TMBIM6及其衍生物通过调节TMBIM6蛋白的功能，影响Ca释放功能，导致线粒体Ca超载，膜电位去极化。值得注意的是， 、 、 和 – 诱导线粒体自噬和铁死亡。总之，我们的结果表明 、 、 和 – 在开发针对 TMBIM6 的抗肿瘤药物方面具有巨大潜力。