近日，國(guó)際著名雜志《自然—化學(xué)生物學(xué)》Nature Chemical Biology雜志在線刊登了德國(guó)研究人員的最新研究成果“Natural product–inspired cascade synthesis yields modulators of centrosome integrity,，”,，文章中，研究者開(kāi)發(fā)出了一種能夠有效合成仿天然分子的方法,，利用該方法合成的分子具有控制細(xì)胞有絲分裂的作用,，這有助于科學(xué)家了解細(xì)胞常規(guī)功能以及癌癥的變化。
受到吲哚類生物堿這種天然物結(jié)構(gòu)的啟發(fā),，Kamal Kumar,，Herbert Waldmann和其他研究人員發(fā)明的合成方法可在“一鍋法”中產(chǎn)生12種不同反應(yīng)，其合成的高復(fù)雜多環(huán)化合物可在分子6處位置發(fā)生結(jié)構(gòu)變化,。
研究人員將合成得到的26種分子進(jìn)行測(cè)試,，看是否能對(duì)細(xì)胞產(chǎn)生效果。結(jié)果發(fā)現(xiàn),，和吲哚類生物堿一樣,，這些分子確實(shí)對(duì)有絲分裂產(chǎn)生了影響。目前已知核仁磷酸蛋白與癌癥發(fā)生有關(guān)，但其具體作用卻仍是未知,，這些分子也許能為我們了解核仁磷酸蛋白在正常細(xì)胞與染病細(xì)胞中的功能提供有價(jià)值的幫助。（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.
