Antiausterity Agents from Uvaria dac and Their Preferential Cytotoxic Activity against Human Pancreatic Cancer Cell Lines in a Nutrient-Deprived Condition

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• 作者：Suresh Awale ; Jun-ya Ueda ; Sirivan Athikomkulchai ; Sherif Abdelhamed ; Satoru Yokoyama ; Ikuo Saiki ; Ryuta Miyatake
• 刊名：Journal of Natural Products
• 出版年：2012
• 出版时间：June 22, 2012
• 年：2012
• 卷：75
• 期：6
• 页码：1177-1183
• 全文大小：384K
• 年卷期：v.75,no.6(June 22, 2012)
• ISSN：1520-6025

文摘

Human pancreatic cancer cell lines are known for their inherent tolerance to nutrition starvation, which enables them to survive under a hypovascular (austerity) tumor microenvironment. The search for agents that preferentially retard the survival of cancer cells under low nutrition conditions (antiausterity agent) is a novel approach to anticancer drug discovery. In this study, it was found that a dichloromethane extract of the stem of Uvaria dac preferentially inhibited PANC-1 human pancreatic cancer cells survival under nutrition-deprived conditions at a concentration of 10 渭g/mL. Workup of this bioactive extract led to the discovery of (+)-grandifloracin (8) as a potent antiausterity agent as evaluated in a panel of four human pancreatic cancer cell lines, PANC-1 (PC₅₀, 14.5 渭M), PSN-1 (PC₅₀, 32.6 渭M), MIA PaCa-2 (PC₅₀, 17.5 渭M), and KLM-1 (32.7 渭M). (+)-Grandifloracin (8) has been isolated from a natural source for the first time. Its absolute stereochemistry was established by single-crystal X-ray crystallography and circular dichroism spectroscopic analysis. In addition to this, seven other new highly oxygenated cyclohexene derivatives, named uvaridacanes A (1) and B (2), uvaridacols A鈥揇 (3, 4, 6, 7), and uvaridapoxide A (5), were also isolated and structurally characterized.