通过一锅偶氮-Nazarov-Friedlander 序列设计和合成 C-芳基角型芦竹素及其拓扑异构酶 I 抑制研究以及 C-芳基玉叶金花素和芦竹素。
Design and synthesis of C-aryl angular luotonins via a one-pot aza-Nazarov-Friedlander sequence and their Topo-I inhibition studies along with C-aryl vasicinones and luotonins.
机构信息
University of Massachusetts Dartmouth, Department of Chemistry and Biochemistry, 285 Old Westport Rd, North Dartmouth, MA 02747, USA.
University of Massachusetts Dartmouth, Department of Chemistry and Biochemistry, 285 Old Westport Rd, North Dartmouth, MA 02747, USA.
出版信息
Bioorg Med Chem Lett. 2021 Jun 1;41:127998. doi: 10.1016/j.bmcl.2021.127998. Epub 2021 Mar 30.
Abstract
A facile one-pot synthesis of C-ring substituted angular luotonins has been realized via a methanesulfonic acid mediated aza-Nazarov-Friedlander condensation sequence on quinazolinonyl enones. Topoisomerase I (topo-I) inhibition studies revealed that the angular luotonin library (7a-7l) and their regioisomeric analogs (linear luotonins, 8a-8l) are weak negative modulators, compared to camptothecin. These results would fare well for the design of topo-I-inert luotonins for non-oncological applications such as anti-fungal and insecticide lead developments. Surprisingly, the tricyclic vasicinones (9h, 9i, and 9j) showed better topo-I inhibition compared to pentacyclic C-aryl luotonins providing a novel pharmacophore for further explorations.
摘要
通过在喹唑啉酮烯酮上进行甲磺酸介导的氮杂-Nazarov-Friedlander 缩合反应，实现了 C-环取代的角型卢酮的简便一锅合成。拓扑异构酶 I（topo-I）抑制研究表明，与喜树碱相比，角型卢酮文库（7a-7l）及其区域异构体类似物（线性卢酮，8a-8l）是弱负调节剂。这些结果非常适合设计拓扑异构酶 I 惰性卢酮，用于非肿瘤学应用，如抗真菌和杀虫剂先导物的开发。令人惊讶的是，与五环 C-芳基卢酮相比，三环 vasicinones（9h、9i 和 9j）显示出更好的 topo-I 抑制作用，为进一步探索提供了新的药效团。
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Design and synthesis of C-aryl angular luotonins via a one-pot aza-Nazarov-Friedlander sequence and their Topo-I inhibition studies along with C-aryl vasicinones and luotonins.通过一锅偶氮-Nazarov-Friedlander 序列设计和合成 C-芳基角型芦竹素及其拓扑异构酶 I 抑制研究以及 C-芳基玉叶金花素和芦竹素。
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