The asmarines are a family of cytotoxic natural products whose mechanism of action is unknown. Here, we used chemical synthesis to reverse engineer the asmarines and understand the functions of their individual components. We found that the potent asmarine analog “delmarine” arrested the mammalian cell cycle in the G1 phase and that both cell cycle arrest and cytotoxicity were rescued by cotreatment with ferric and ferrous salts. Cellular iron deprivation was clearly indicated by changes in iron-responsive protein markers, and cytotoxicity occurred independently of radical oxygen species (ROS) production. Chemical synthesis allowed for annotation of the distinct structural motifs required for these effects, especially the unusual diazepine, which we found enforced an iron-binding tautomer without distortion of the NCNO dihedral angle out of plane. With this information and a correlation of cytotoxicity with logP, we could replace the diazepine by lipophilic group appendage to N9, which avoided steric clash with the N6-alkyl required to access the aminopyridine. This study transformed the asmarines, scarce marine metabolites, into easily synthesized, modular chemotypes that may complement or succeed iron-selective binders in clinical trials and use.

中文翻译：

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细胞毒性天青碱生物碱的作用机理

阿马替林是一类细胞毒性天然产物，其作用机理尚不清楚。在这里，我们使用化学合成对阿玛琳进行逆向工程，并了解其各个组成部分的功能。我们发现强效的蓝绿色类似物“ delmarine”将哺乳动物细胞周期阻滞在G1期，并且细胞周期阻滞和细胞毒性均通过与铁盐和亚铁盐共同处理而得以挽救。铁反应蛋白标记物的变化清楚地表明了细胞铁的剥夺，并且细胞毒性的发生与自由基氧物质（ROS）的产生无关。化学合成可以注释这些作用所需的独特结构基序，特别是不寻常的二氮杂pine，我们发现该二氮enforce可以形成铁结合互变异构体，而NCNO二面角不在平面内变形。有了这些信息，并将其与logP的细胞毒性相关联，我们可以用N9的亲脂基团取代二氮卓，从而避免了与使用氨基吡啶所需的N6-烷基发生空间冲突。这项研究将稀有的海洋代谢物阿玛替林转变为易于合成的模块化化学型，可以在临床试验和使用中补充或替代铁选择性结合剂。