2. Academic Validation
  3. Tumour-specific cytotoxicity and structure-activity relationships of novel 1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones

Tumour-specific cytotoxicity and structure-activity relationships of novel 1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones

  • Bioorg Med Chem. 2016 May 15;24(10):2206-14. doi: 10.1016/j.bmc.2016.03.056.
Mohammad Hossain 1,  Umashankar Das 2,  Naoki Umemura 3,  Hiroshi Sakagami 3,  Jan Balzarini 4,  Erik De Clercq 4,  Masami Kawase 5,  Jonathan R Dimmock 6
Affiliations

Affiliations

  • 1 Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.
  • 2 Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada. Electronic address: umashankar.das@usask.ca.
  • 3 Division of Pharmacology, Mekai University School of Dentistry, Saitama 350-0238, Japan.
  • 4 Rega Institute of Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
  • 5 Faculty of Pharmaceutical Sciences, Matsuyama University, Matsuyama, Ehime 790-8578, Japan.
  • 6 Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada. Electronic address: jr.dimmock@usask.ca.
PMID: 27073056 DOI: 10.1016/j.bmc.2016.03.056
Abstract

A series of 1-acyl-3,5-bis(benzylidene)-4-piperidones 3-7 were designed and synthesized as novel cytotoxic agents. These compounds displayed potent cytotoxic properties towards human Molt4/C8, CEM, HSC-2, HSC-3 and HSC-4 neoplasms and also to murine L1210 cells. The majority of the compounds have sub-micromolar or very low micromolar IC50 and CC50 values and are significantly more potent than the reference alkylating drug melphalan. Evaluation of these compounds against non-malignant HGF and HPLF cells revealed the tumour-specific toxicity. In particular, 3e emerged as a promising lead cytotoxic agent which caused Apoptosis and PARP1 cleavage in HSC-2 cells.

Keywords

4-Piperidone; Cytotoxicity; Structure–activity relationships; Tumour-specific toxicity; α,β-Unsaturated ketone.

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