[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity.
[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity.
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DOI：
10.1021/jacsau.2c00435
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发表时间：
2022-11-28
期刊：
影响因子：
8
通讯作者：
Fuchter, Matthew J
中科院分区：
文献类型：
--
作者：
Rushworth, James L;Thawani, Aditya R;Fajardo-Ruiz, Elena;Meiring, Joyce C M;Heise, Constanze;White, Andrew J P;Akhmanova, Anna;Brandt, Jochen R;Thorn-Seshold, Oliver;Fuchter, Matthew J
螺烯是具有独特共轭螺旋结构的高兴趣合成目标，已发现重要的技术应用。尽管有这种兴趣，螺旋烯在化学生物学中的影响有限。在这里，我们公开了一种一流的抗有丝分裂螺旋菌素1(HA-1)，其中螺旋菌烯支架作为已知的抗有丝分裂药物秋水仙碱的结构模拟物。合成通过Pd催化的顺序偶联反应和PtCl2催化的π-Lewis酸环异构化进行。在无细胞和活细胞检测中，均发现HA-1可阻断微管聚合。这不仅证明了将螺旋烯用作针对蛋白质靶标的生物活性支架的可行性，而且表明螺旋烯作为联芳基或顺式二苯乙烯的异构体--本身就是常见的药物和天然产物支架--具有更广泛的潜力。总体而言，这项研究进一步支持了螺旋烯在一系列化学生物应用中的未来机会。
Helicenes are high interest synthetic targets with unique conjugated helical structures that have found important technological applications. Despite this interest, helicenes have had limited impact in chemical biology. Herein, we disclose a first-in-class antimitotic helicene, helistatin 1 (HA-1), where the helicene scaffold acts as a structural mimic of colchicine, a known antimitotic drug. The synthesis proceeds via sequential Pd-catalyzed coupling reactions and a π-Lewis acid cycloisomerization mediated by PtCl2. HA-1 was found to block microtubule polymerization in both cell-free and live cell assays. Not only does this demonstrate the feasibility of using helicenes as bioactive scaffolds against protein targets, but also suggests wider potential for the use of helicenes as isosteres of biaryls or cis-stilbenes—themselves common drug and natural product scaffolds. Overall, this study further supports future opportunities for helicenes for a range of chemical biological applications.