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

被引：6

作者：

Rasapalli, Sivappa ^{[1
]}

Sammeta, Vamshikrishna Reddy ^{[1
]}

Murphy, Zachary F. ^{[1
]}

Golen, James A. ^{[1
]}

Agama, Keli ^{[2
,3
]}

Pommier, Yves ^{[2
,3
]}

Savinov, Sergey N. ^{[4
]}

机构：

[1] Univ Massachusetts Dartmouth, Dept Chem & Biochem, 285 Old Westport Rd, N Dartmouth, MA 02747 USA

[2] NCI, Ctr Canc Res, Dev Therapeut Branch, Bethesda, MD 20892 USA

[3] NCI, Ctr Canc Res, Lab Mol Pharmacol, Bethesda, MD 20892 USA

[4] UMass Amherst, Dept Biochem & Mol Biol, Amherst, MA 01003 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2021年 / 41卷

关键词：

aza-Nazarov; Quinazolinonyl enones; Vasicinone; uotonin A; Topoisomerase I; RING; DERIVATIVES; CYCLIZATION;

D O I：

10.1016/j.bmcl.2021.127998

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页数：4