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

[Display omitted] 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 (7...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2021-06, Vol.41, p.127998-127998, Article 127998
Main Authors: Rasapalli, Sivappa, Sammeta, Vamshikrishna Reddy, Murphy, Zachary F., Golen, James A., Agama, Keli, Pommier, Yves, Savinov, Sergey N.
Format: Article
Language:English
Subjects:
aza-Nazarov
Quinazolinonyl enones
Topoisomerase I
uotonin A
Vasicinone
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2021.127998