1-[3-(2-Hydroxyethylsulfanyl)propanoyl]-3,5-bis(benzylidene)-4-piperidones: A novel cluster of P-glycoprotein dependent multidrug resistance modulators

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1319-21. doi: 10.1016/j.bmcl.2016.01.005. Epub 2016 Jan 5.

Abstract

A series of 1-[3-(2-hydroxyethylsulfanyl)propanoyl]-3,5-bis(benzylidene)-4-piperidones 4a-e display promising P-glycoprotein dependent multidrug resistance (MDR) revertant properties and are significantly more potent than a reference drug verapamil when evaluated against L-5178Y MDR lymphoma cells. These dienones may be referred to as dual agents having both MDR revertant properties and tumour-selective cytotoxicity. In particular, 3,5-bis(4-chlorobenzylidene)-1-[3-(2-hydroxyethylsulfanyl]propanoyl-4-piperidone 4d emerged as a lead molecule for further development based on its MDR revertant properties, cytotoxic potencies and tumour-selective toxicity. The structure-activity relationships reveal important structural requirements for further designing of potent MDR revertants.

Keywords: 3,5-Bis(benzylidene)-4-piperidones; MDR revertants; P-glycoprotein; Selective cytotoxicity; Structure–activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Humans
  • Mice
  • Piperidones / chemical synthesis
  • Piperidones / chemistry*
  • Piperidones / metabolism
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • 3,5-bis(benzylidene)-4-piperidone
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Piperidones