title: Progesterone-adenine hybrids as bivalent inhibitors of P-glycoprotein-mediated multidrug efflux: design, synthesis, characterization and biological evaluation.
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.
authors.affiliation: Université de Lyon, Université Lyon 1, EA 4446 Biomolécules Cancer Chimiorésistances (B2C), ISPB-Faculté de Pharmacie, UMS 3453 Santé Lyon-Est, 8 Avenue Rockefeller, F-69373 Lyon Cedex 08, France.
authors.forename: Waël
authors.initials: W
authors.lastname: Zeinyeh
authors.forename: Zahia
authors.initials: Z
authors.lastname: Mahiout
authors.forename: Sylvie
authors.initials: S
authors.lastname: Radix
authors.forename: Thierry
authors.initials: T
authors.lastname: Lomberget
authors.forename: Axel
authors.initials: A
authors.lastname: Dumoulin
authors.forename: Roland
authors.initials: R
authors.lastname: Barret
authors.forename: Catherine
authors.initials: C
authors.lastname: Grenot
authors.forename: Luc
authors.initials: L
authors.lastname: Rocheblave
authors.forename: Eva-Laure
authors.initials: EL
authors.lastname: Matera
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.forename: Nadia
authors.initials: N
authors.lastname: Walchshofer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000225:Adenine / Q000737:chemistry*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D003630:Daunorubicin / Q000494:pharmacology; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D011374:Progesterone / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011374:Progesterone; D000225:Adenine; D003630:Daunorubicin