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

Mohammad Hossain; Umashankar Das; Naoki Umemura; Hiroshi Sakagami; Jan Balzarini; Erik De Clercq; Masami Kawase; Jonathan R Dimmock

doi:10.1016/j.bmc.2016.03.056

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. Epub 2016 Mar 30.

Authors

Mohammad Hossain¹, Umashankar Das², Naoki Umemura³, Hiroshi Sakagami³, Jan Balzarini⁴, Erik De Clercq⁴, Masami Kawase⁵, Jonathan R Dimmock⁶

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Cell Line
Cell Line, Tumor
Cell Survival / drug effects
Drug Screening Assays, Antitumor
Humans
Mice
Neoplasms / drug therapy
Piperidones / chemistry*
Piperidones / pharmacology*
Structure-Activity Relationship

Substances

3,5-bis(benzylidene)-4-piperidone
Antineoplastic Agents
Piperidones

Grants and funding

CIHR/Canada