Deoxycholic acid derivatives as inhibitors of P-glycoprotein-mediated multidrug efflux

Steroids. 2016 Dec:116:5-12. doi: 10.1016/j.steroids.2016.09.017. Epub 2016 Sep 30.

Abstract

Deoxycholic acid derivatives were designed as P-glycoprotein (Pgp, ABCB1) inhibitors. Thus the synthesis and the biological activity of methyl deoxycholate derivatives 5-10 and their ether analogs 15-20 have been reported. The potency of these compounds to modulate Pgp-mediated MDR was evaluated through daunorubicin accumulation and potentiation of doxorubicin cytotoxicity in K562/R7 multidrug resistant cells overexpressing Pgp. In parallel, their intrinsic toxicity was appreciated on K562 sensitive cells. Methyl 12α-[(2R or 2S) tetrahydro-2H-pyran-2-yloxy]-3-oxo-5β-cholan-24-oate 9b has shown a good efficiency as a Pgp inhibitor and a low intrinsic toxicity. Therefore, this derivative constitutes a new lead compound which can be used as a starting point to improve the design of non-toxic Pgp modulators.

Keywords: Deoxycholic acid derivatives; Multidrug resistance; P-glycoprotein inhibitors.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Daunorubicin / metabolism*
  • Deoxycholic Acid / analogs & derivatives*
  • Deoxycholic Acid / chemistry
  • Deoxycholic Acid / pharmacology*
  • Doxorubicin / metabolism*
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Humans
  • K562 Cells

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Deoxycholic Acid
  • Doxorubicin
  • Daunorubicin