Progesterone-adenine hybrids as bivalent inhibitors of P-glycoprotein-mediated multidrug efflux: design, synthesis, characterization and biological evaluation

Steroids. 2012 Oct;77(12):1177-91. doi: 10.1016/j.steroids.2012.07.010. Epub 2012 Jul 31.

Abstract

Bivalent ligands were designed on the basis of the described close proximity of the ATP-site and the putative steroid-binding site of P-glycoprotein (ABCB1). The syntheses of 19 progesterone-adenine hybrids are described. Their abilities to inhibit P-glycoprotein-mediated daunorubicin efflux in K562/R7 human leukemic cells overexpressing P-glycoprotein were evaluated versus progesterone. The hybrid with a hexamethylene linker chain showed the best inhibitory potency. The efficiency of these progesterone-adenine hybrids depends on two main factors: (i) the nature of the linker and (ii) its attachment point on the steroid skeleton.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adenine / chemistry*
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Daunorubicin / pharmacology
  • Drug Design*
  • Drug Resistance, Multiple / drug effects*
  • Humans
  • Progesterone / chemical synthesis
  • Progesterone / chemistry*
  • Progesterone / pharmacology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Progesterone
  • Adenine
  • Daunorubicin