2. Academic Validation
  3. Synthesis and Biological Evaluation of Novel Olean-28,13β-lactams as Potential Antiprostate Cancer Agents

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

  • J Med Chem. 2015 Jun 11;58(11):4506-20. doi: 10.1021/jm5020023.
Yong Ai 1 2,  Yang Hu 1,  Fenghua Kang 1 2,  Yisheng Lai 1 2,  Yanju Jia 1,  Zhangjian Huang 1 2,  Sixun Peng 1 2,  Hui Ji 1,  Jide Tian 3,  Yihua Zhang 1 2
Affiliations

Affiliations

  • 1 †State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
  • 2 ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P. R. China.
  • 3 §Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, United States.
PMID: 25992974 DOI: 10.1021/jm5020023
Abstract

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.

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