化学
天然产物
去肽
人口
表型筛选
癌细胞
基因
计算生物学
组合化学
立体化学
生物化学
癌症
遗传学
表型
生物
社会学
人口学
作者
Nikolaj L. Villadsen,Kristian M. Jacobsen,Ulrik Bering Keiding,Esben Thybo Weibel,Bjørn Christiansen,Thomas Vosegaard,Morten Bjerring,Frank Jensen,Mogens Johannsen,Thomas Tørring,Thomas B. Poulsen
出处
期刊:Nature Chemistry
[Springer Nature]
日期:2016-11-21
卷期号:9 (3): 264-272
被引量:51
摘要
Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration. Discrepancies between the spectroscopic signatures of the synthetic compounds with that originally reported for the BE-43547 members stimulated us to re-isolate the natural product from a BE-43547-producing microorganism during which we elucidated the biosynthetic gene clusters for the BE-43547 family as well as for all other known APD-CLDs. Our studies underline the exciting possibilities for the further development of the anticancer activities of these natural products. Anti-proliferative compounds that display enhanced toxicity in a low-oxygen (hypoxic) environment may be used to eradicate aggressive and therapy-resistant cancer cells. Now, a promising lead structure has been identified in the BE-43547-class of depsipeptide natural products.
科研通智能强力驱动
Strongly Powered by AbleSci AI