3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride: a lead tumor-specific cytotoxin which induces apoptosis and autophagy.
A number of N-4-(2-aminoethoxy)phenylcarbonyl derivatives of various 3,5-bis(benzylidene)-4-piperidones 2-5 demonstrated noteworthy cytotoxic potencies towards human HL-60 leukemic cells as well as human HSC-2 and HSC-4 squamous cell carcinomas. In general, toxicity towards HGF, HPC, and HPLF normal cells was substantially lower. The highest selective toxicity was noted when the terminal base is morpholine. Lead optimization was based on finding compounds which had (i) high cytotoxic potencies, (ii) a greater toxicity to neoplasms than normal cells, and (iii) drug-likeness based on the rule of five. From the biodata generated, 5a evolved as a promising lead compound for further development. The mode of action of 5a included the induction of apoptosis in HL-60 cells in which internucleosomal DNA fragmentation and activation of caspase-3 was noted. In addition, 5a caused autophagy in HSC-2 cells.
Das
Umashankar
U
Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5C9.
Sakagami
Hiroshi
H
Chu
Qing
Q
Wang
Qintao
Q
Kawase
Masami
M
Selvakumar
Ponniah
P
Sharma
Rajendra K
RK
Dimmock
Jonathan R
JR
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D018922:HL-60 Cells; D019073:HT29 Cells; D006801:Humans; D010881:Piperidones / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
C526290:3,5-bis(benzylidene)-4-piperidone; D000970:Antineoplastic Agents; D003603:Cytotoxins; D010881:Piperidones