Re-Engineering of Yohimbine's Biological Activity through Ring Distortion: Identification and Structure-Activity Relationships of a New Class of Antiplasmodial Agents.
Re-Engineering of Yohimbine's Biological Activity through Ring Distortion: Identification and Structure-Activity Relationships of a New Class of Antiplasmodial Agents.
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通过环扭曲重新设计育亨宾的生物活性：一类新型抗疟原虫的鉴定和结构-活性关系。
DOI：
10.1021/acsinfecdis.9b00380
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发表时间：
2020
影响因子：
5.3
通讯作者：
Huigens3rd,RobertW
中科院分区：
文献类型：
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作者：
Paciaroni,NicholasG;Perry2nd,DavidL;Norwood4th,VerrillM;Murillo-Solano,Claribel;Collins,Jennifer;Tenneti,Srinivasarao;Chakrabarti,Debopam;Huigens3rd,RobertW
精选的天然产物是环状扭曲的理想起点，或通过短的合成路径戏剧性地改变固有的复杂分子，以产生一系列具有不同骨架结构的新型化合物。我们的环扭曲方法的一个主要目标是重新设计吲哚生物碱的生物活性，以确定在对人类健康和药物具有重要意义的领域具有不同生物活性的新化合物。在这项研究中，我们通过环重排和环裂解合成途径对吲哚生物碱育亨宾的生物活性进行了重新设计，以发现新的一系列抗疟原虫药物。一种新化合物Y7j对抗氯喹恶性疟原虫Dd2细胞(EC_(50)=0.33μM)有较好的抑制作用，而对HepG2细胞(EC_(50)和GT；40μM)无细胞毒作用。合成了一系列类似物以获得构效关系，我们了解到Y7j的两个苄基都是活性所必需的，通过改变苄基上的取代模式可以实现抗疟原虫活性的微调。这项研究展示了环扭曲的潜力，以推动新的发现和改变化学生物学和药物发现的范式。
Select natural products are ideal starting points for ring distortion, or the dramatic altering of inherently complex molecules through short synthetic pathways, to generate an array of novel compounds with diverse skeletal architectures. A major goal of our ring distortion approach is to re-engineer the biological activity of indole alkaloids to identify new compounds with diverse biological activities in areas of significance to human health and medicine. In this study, we re-engineered the biological activity of the indole alkaloid yohimbine through ring rearrangement and ring cleavage synthesis pathways to discover new series of antiplasmodial agents. One new compound,Y7j, was found to demonstrate good potency against chloroquine-resistantPlasmodium falciparumDd2 cells (EC50= 0.33 μM) without eliciting cytotoxicity against HepG2 cells (EC50> 40 μM).Y7jdemonstrated stage-specific action against parasites at the late ring/trophozoite stage. A series of analogues was synthesized to gain structure–activity relationship insights, and we learned that both benzyl groups ofY7jare required for activity and fine-tuning of antiplasmodial activities could be accomplished by changing substitution patterns on the benzyl moieties. This study demonstrates the potential for ring distortion to drive new discoveries and change paradigms in chemical biology and drug discovery.