An Amino-Benzosuberene Analogue That Inhibits Tubulin Assembly and Demonstrates Remarkable Cytotoxicity.
An Amino-Benzosuberene Analogue That Inhibits Tubulin Assembly and Demonstrates Remarkable Cytotoxicity.
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一种氨基苯并芘烯类似物，可抑制微管蛋白组装并表现出显着的细胞毒性。
DOI：
10.1039/c2md00318j
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Pinney,KevinG
中科院分区：
文献类型：
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作者：
Tanpure,RajendraP;George,ClintonS;Sriram,Madhavi;Strecker,TracyE;Tidmore,JustinK;Hamel,Ernest;Charlton-Sevcik,AmandaK;Chaplin,DavidJ;Trawick,MaryLynn;Pinney,KevinG
最近发现的一种基于苯并亚苯烯的小分子苯酚对某些人类癌细胞具有显著的皮摩尔细胞毒性，并能强烈抑制微管蛋白聚合（1-2 μM），这启发了人们设计和合成各种结构多样的苯并亚苯烯衍生物。建立了一条高效的功能化苯并亚苯醚合成路线。该方法利用了Wittig反应，然后是选择性烯烃还原和闭合环环形成核心苯并酮结构。该合成路线有利于制备4-硝基-1-（3′，4′，5′-三甲氧基苯基）苯并亚苯二烯衍生物及其相应的4-氨基类似物，收率较高。4-氨基类似物是一种强的微管蛋白聚合抑制剂（1.2 μM），显示出对人类癌细胞系的细胞毒性增强（例如，对SK-OV-3卵巢癌的GI50 = 33 pM），并且显示出浓度依赖性，破坏由人脐静脉内皮细胞形成的预先建立的毛细血管样小管网络。
The recent discovery of a small-molecule benzosuberene-based phenol that demonstrates remarkable picomolar cytotoxicity against selected human cancer cell lines and strongly inhibits tubulin polymerization (1–2 μM) inspired the design and synthesis of a variety of new, structurally diverse benzosuberene derivatives. An efficient synthetic route to functionalized benzosuberenes was developed. This methodology utilized a Wittig reaction, followed by a selective alkene reduction and ring-closing cyclization to form the core benzosuberone structure. This synthetic route facilitated the preparation of a 4-nitro-1-(3′,4′,5′-trimethoxyphenyl) benzosuberene derivative and its corresponding 4-amino analogue in good yield. The 4-amino analogue was a strong inhibitor of tubulin polymerization (1.2 μM), demonstrated enhanced cytotoxicity against the human cancer cell lines examined (GI50 = 33 pM against SK-OV-3 ovarian cancer, for example), and exhibited a concentration dependent disruption of a pre-established capillary-like network of tubules formed from human umbilical vein endothelial cells.