Faculty of Arts and Science, Kyushu University.
Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of Toyama.
Biol Pharm Bull. 2023;46(10):1412-1420. doi: 10.1248/bpb.b23-00224.
Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-austerity strategy for eradicating pancreatic cancer cells in their microenvironment. In this study, we employed a chemical biology approach using the Ugi reaction to rapidly synthesize new anti-austerity agents and evaluate their structure-activity relationships. Out of seventeen Ugi adducts tested, Ugi adduct 11 exhibited the strongest anti-austerity activity, showing preferential cytotoxicity against PANC-1 pancreatic cancer cells with a PC value of 0.5 µM. Further biological investigation of Ugi adduct 11 revealed a dramatic alteration of cellular morphology, leading to PANC-1 cell death within 24 h under nutrient-deprived conditions. Furthermore, the R absolute configuration of 11 was found to significantly contribute to the preferential anti-austerity ability toward PANC-1, with a PC value of 0.2 µM. Mechanistically, Ugi adduct (R)-11 was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway preferentially under nutrition starvation conditions. Consequently, Ugi-adduct (R)-11 could be a promising candidate for drug development targeting pancreatic cancer based on the anti-austerity strategy. Our study also demonstrated that the Ugi reaction-based chemical engineering of natural product extracts can be used as a rapid method for discovering novel anti-austerity agents for combating pancreatic cancer.
胰腺癌细胞具有内在的耐受能力，可以在缺乏足够营养和氧气的乏血管肿瘤微环境中存活。开发针对这种营养饥饿耐受的抗癌药物是一种很有前途的抗营养剥夺策略，可以消灭肿瘤微环境中的胰腺癌细胞。在这项研究中，我们采用了一种化学生物学方法，使用 Ugi 反应快速合成新的抗营养剥夺剂，并评估它们的结构-活性关系。在测试的十七个 Ugi 加合物中，Ugi 加合物 11 表现出最强的抗营养剥夺活性，对 PANC-1 胰腺癌细胞表现出优先的细胞毒性，PC 值为 0.5µM。对 Ugi 加合物 11 的进一步生物学研究表明，细胞形态发生了显著改变，导致在营养剥夺条件下，PANC-1 细胞在 24 小时内死亡。此外，发现 11 的 R 绝对构型对 PANC-1 的优先抗营养剥夺能力有显著贡献，PC 值为 0.2µM。在机制上，发现 Ugi 加合物 (R)-11 在营养饥饿条件下优先抑制磷脂酰肌醇 3-激酶 (PI3K)/蛋白激酶 B (Akt)/哺乳动物雷帕霉素靶蛋白 (mTOR)信号通路。因此，Ugi 加合物 (R)-11 可能是一种很有前途的候选药物，可用于基于抗营养剥夺策略开发针对胰腺癌的药物。我们的研究还表明，基于 Ugi 反应的天然产物提取物的化学工程可以作为发现新型抗营养剥夺剂以对抗胰腺癌的快速方法。
