The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, 300350, People's Republic of China.
The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, 300350, People's Republic of China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine, Tianjin, 300457, People's Republic of China.
Eur J Med Chem. 2018 May 10;151:601-627. doi: 10.1016/j.ejmech.2018.03.078. Epub 2018 Mar 29.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor and resistant to most therapies. Pancreatic cancer stem cells (PCSCs) had critical role in regulating PDAC progression, metastasis, and drug resistance. Therefore, targeting PCSCs is considered to be a promising strategy for treatment of PDAC. However, there is no effective drug that can selectively ablate PCSCs. A series of twenty rakicidin A analogues were synthesized via a combinatorial strategy and evaluated for their anti-PDAC activities, and the structure-activity relationship was also discussed. Compound 32g was prepared in 14 linear steps with 5.05% overall yield, which is much more efficient than our previously reported total synthesis of rakicidin A (19 linear steps with 0.19% yield). In a highly metastatic pancreatic cancer cell line ASPC-1, compound 32g showed about 4 times higher potency (IC = 0.022 μM) than rakicidin A (IC = 0.082 μM) at hypoxia condition, and 12 folds of hypoxia selectivity (IC = 0.27 μM at nomoxia condition). In contrast, the activity of adriamycin in the same hypoxic condition decreased. The percentage of PCSCs (with CD24CD44ESA biomarker), activity of ALDH, and the number of tumorspheres in PANC-1 cells were greatly reduced after treatment of 32g. More importantly, the tumor-initiating frequency was reduced by 19 folds after the treatment of 32g, which is better than that of rakicidin A (reduction of 4.7 folds).
胰腺导管腺癌（PDAC）是一种高度侵袭性的恶性肿瘤，对大多数治疗方法具有耐药性。胰腺癌细胞干细胞（PCSCs）在调节 PDAC 的进展、转移和耐药性方面起着关键作用。因此，靶向 PCSCs 被认为是治疗 PDAC 的一种有前途的策略。然而，目前还没有能够选择性地消灭 PCSCs 的有效药物。通过组合策略合成了一系列 20 种雷卡汀 A 类似物，并对其抗 PDAC 活性进行了评价，还讨论了构效关系。化合物 32g 通过 14 步线性反应制备，总收率为 5.05%，比我们之前报道的雷卡汀 A 的总合成（19 步线性反应，收率为 0.19%）效率更高。在高转移性胰腺癌细胞系 ASPC-1 中，化合物 32g 在缺氧条件下的活性比雷卡汀 A（IC=0.082μM）高约 4 倍（IC=0.022μM），缺氧选择性为 12 倍（IC=0.27μM 在常氧条件下）。相比之下，阿霉素在相同缺氧条件下的活性降低。经 32g 处理后，PANC-1 细胞中具有 CD24CD44ESA 生物标志物的 PCSCs（比例）、ALDH 活性和肿瘤球数量都大大减少。更重要的是，32g 处理后肿瘤起始频率降低了 19 倍，优于雷卡汀 A（降低 4.7 倍）。
