近日,国际著名杂志《自然—化学生物学》Nature Chemical Biology杂志在线刊登了德国研究人员的最新研究成果“Natural product–inspired cascade synthesis yields modulators of centrosome integrity,”,文章中,研究者开发出了一种能够有效合成仿天然分子的方法,利用该方法合成的分子具有控制细胞有丝分裂的作用,这有助于科学家了解细胞常规功能以及癌症的变化。
受到吲哚类生物碱这种天然物结构的启发,Kamal Kumar,Herbert Waldmann和其他研究人员发明的合成方法可在“一锅法”中产生12种不同反应,其合成的高复杂多环化合物可在分子6处位置发生结构变化。
研究人员将合成得到的26种分子进行测试,看是否能对细胞产生效果。结果发现,和吲哚类生物碱一样,这些分子确实对有丝分裂产生了影响。目前已知核仁磷酸蛋白与癌症发生有关,但其具体作用却仍是未知,这些分子也许能为我们了解核仁磷酸蛋白在正常细胞与染病细胞中的功能提供有价值的帮助。(生物谷Bioon.com)
doi:10.1038/nchembio.758
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Natural product–inspired cascade synthesis yields modulators of centrosome integrity
Heiko Dückert, Verena Pries, Vivek Khedkar, Sascha Menninger, Hanna Bruss, Alexander W Bird, Zoltan Maliga, Andreas Brockmeyer, Petra Janning, Anthony Hyman, Stefan Grimme, Markus Schürmann, Hans Preut, Katja Hübel, Slava Ziegler, Kamal Kumar & Herbert Waldmann
In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, met by the scaffolds of natural products selected in evolution. The synthesis of natural product–inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10–30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1.