Synthesis and Biological Evaluation of Novel Olean-28,13β-lactams as Potential Antiprostate Cancer Agents

γ-Lactam is an important structural
motif in a large number of biologically active natural products and
synthetic small pharmaceutical molecules. However, there is currently
no effective approach to construct γ-lactam ring directly from
natural rigid polycyclic amides. Herein, we report a facile methodology
for synthesis of a new group of olean-28,13β-lactams (10a–j) from their corresponding amides,
promoted by an easily available reagent 2,3-dichloro-5,6-dicyanobenzo­quinone
(DDQ), through an intramolecular dehydrogenative C–N coupling
reaction via a radical ion mechanism. Biological evaluation indicated
that the most active lactam 10h displayed potent antiproliferative
activity against human cancer cells but 13.84- to 16.92-fold less
inhibitory activity on noncancer cells in vitro. In addition, 10h significantly inhibited the growth of implanted prostate
cancer in vivo. Furthermore, 10h induced cell cycle arrest
and apoptosis and down-regulated the AKT/mTOR signaling in DU-145
cells. Finally, 10h was more stable in rat plasma and
human liver microsomes than CDDO-Me and had little hERG channel inhibitory
activity. Collectively, 10h may be a potential antiprostate
cancer agent for further investigation.