Development of small-molecule P-gp inhibitors of the N-benzyl 1,4-dihydropyridine type: novel aspects in SAR and bioanalytical evaluation of multidrug resistance (MDR) reversal properties

Bioorg Med Chem. 2013 Jan 1;21(1):166-77. doi: 10.1016/j.bmc.2012.10.041. Epub 2012 Nov 3.

Abstract

Novel series of N-benzyl 1,4-dihydropyridines have been prepared by facile syntheses. All relevant substituents of the molecular scaffold have been varied. The resulting compounds were biologically evaluated as P-glycoprotein (P-gp) inhibitors. Substitutions of the N-benzyl residue favour biological activity beside respective 3-ester functions. Most active compounds were further evaluated as multidrug resistance (MDR) modulators to restore the cytotoxic properties of varying daunorubicin applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Daunorubicin / pharmacology
  • Dihydropyridines / chemistry*
  • Dihydropyridines / pharmacology*
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Mice
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Structure-Activity Relationship

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibiotics, Antineoplastic
  • Dihydropyridines
  • 1,4-dihydropyridine
  • Daunorubicin