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The Mosaic of Rottlerin: The Sequel

Rottlerin (1) is a potent protein kinase C δ inhibitor that possesses a wide range of biological activities. However, the potential of this molecule to be developed as a drug has been restricted by its limited availability. We report herein a gram scale quantity synthesis of rottlerin in a five-step...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2019-05, Vol.82 (5), p.1190-1199
Main Authors: Hong, Kenneth K. C, Ho, Kitty K. K, Bhadbhade, Mohan, Ball, Graham E, Black, David StC, Kumar, Naresh
Format: Article
Language:English
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Summary:Rottlerin (1) is a potent protein kinase C δ inhibitor that possesses a wide range of biological activities. However, the potential of this molecule to be developed as a drug has been restricted by its limited availability. We report herein a gram scale quantity synthesis of rottlerin in a five-step synthetic route that can be completed within 2 days. The methodology was extended by the reaction of the key aminochromene intermediate (15) with various electron-rich arenes, forming novel unsymmetrical methylene-bridged compounds. The X-ray crystal structure revealed the boomerang shape of this kind of molecule for the first time. The direct transformation of rottlerin (1) into the natural product, isorottlerin (35), was observed for the first time, and we named this transformation the “isorottlerin change”. In addition, the antibacterial activities of rottlerin (1) and new rottlerin analogues 32–34 were examined against Staphylococcus aureus. The compounds showed MIC values as low as 2.0 μM, which were comparable to the clinically used antibiotic gentamicin.
ISSN:0163-3864
1520-6025
DOI:10.1021/acs.jnatprod.8b00917