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

• Published in: Journal of medicinal chemistry 2015-06, Vol.58 (11), p.4506-4520
• Main Authors: Ai, Yong, Hu, Yang, Kang, Fenghua, Lai, Yisheng, Jia, Yanju, Huang, Zhangjian, Peng, Sixun, Ji, Hui, Tian, Jide, Zhang, Yihua
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle - drug effects; Cell Membrane Permeability - drug effects; Cell Proliferation - drug effects; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Ether-A-Go-Go Potassium Channels - metabolism; Humans; Lactams - chemistry; Lactams - pharmacology; Male; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Models, Molecular; Molecular Structure; Patch-Clamp Techniques; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Rats; Signal Transduction - drug effects; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5020023

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.