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. (1st June 2021)

• Record Type: Journal Article
• Authors: Rasapalli, Sivappa; Sammeta, Vamshikrishna Reddy; Murphy, Zachary F.; Golen, James A.; Agama, Keli; Pommier, Yves; Savinov, Sergey N.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 41(2021)
• Publication Date: 2021-06-01
• Subjects: aza-Nazarov -- Quinazolinonyl enones -- Vasicinone -- uotonin A -- Topoisomerase I; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.127998
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.