Awale Suresh, Okada Takahiro, Dibwe Dya Fita, Maruyama Takahiro, Takahara Satoyuki, Okada Takuya, Endo Satoshi, Toyooka Naoki
Division of Natural Drug Discovery, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan.
Bioorg Med Chem Lett. 2019 Jul 15;29(14):1779-1784. doi: 10.1016/j.bmcl.2019.05.010. Epub 2019 May 8.
Human pancreatic tumor cells have inherent ability to tolerate nutrition starvation which enables them to survive in the hypovascular tumor microenvironment. Discovery of agents that selectively inhibit the cancer cells' tolerance to nutrition starvation leading to cancer cell death is a new anti-austerity approach in anti-cancer drug discovery. A series of coumarins derivatives were synthesized and evaluated for their anti-austerity activity against PANC-1 human pancreatic cancer cell line. The compound 7-Hydroxy-2-oxo-2H-chromene-3-carboxylic acid (3-phenylpropyl)amide (2c) showed highly potent selective cytotoxicity against PANC-1 cells under nutrient-deprived conditions, with a PC value of 0.44 μM, without exhibiting toxicity in normal, nutrient-rich medium. Compound 2c caused dramatic alterations in PANC-1 cell morphology, leading to cell death. The compound 2c was found to inhibit PANC-1 cell migration and colony formation in a concentration-dependent manner. The compound 2c is a lead structure for the anti-austerity drug development against pancreatic cancer.
人胰腺肿瘤细胞具有耐受营养饥饿的内在能力，这使它们能够在低血管的肿瘤微环境中存活。发现能够选择性抑制癌细胞对营养饥饿的耐受性从而导致癌细胞死亡的药物，是抗癌药物研发中的一种新的抗营养匮乏方法。合成了一系列香豆素衍生物，并评估了它们对PANC-1人胰腺癌细胞系的抗营养匮乏活性。化合物7-羟基-2-氧代-2H-色烯-3-羧酸（3-苯丙基）酰胺（2c）在营养缺乏条件下对PANC-1细胞表现出高效的选择性细胞毒性，PC值为0.44μM，在正常的、营养丰富的培养基中不表现出毒性。化合物2c导致PANC-1细胞形态发生显著变化，从而导致细胞死亡。发现化合物2c以浓度依赖的方式抑制PANC-1细胞迁移和集落形成。化合物2c是用于开发抗胰腺癌抗营养匮乏药物的先导结构。
