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 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.