title: Synthesis and Biological Evaluation of Novel Olean-28,13β-lactams as Potential Antiprostate Cancer Agents.
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.
authors.affiliation: †State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.|‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ai
authors.affiliation: †State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: †State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.|‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Kang
authors.affiliation: †State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.|‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
authors.affiliation: †State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Yanju
authors.initials: Y
authors.lastname: Jia
authors.affiliation: †State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.|‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.affiliation: †State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.|‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.affiliation: †State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.affiliation: §Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, United States.
authors.forename: Jide
authors.initials: J
authors.lastname: Tian
authors.affiliation: †State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.|‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D007769:Lactams