Progesterone-adenine hybrids as bivalent inhibitors of P-glycoprotein-mediated multidrug efflux: design, synthesis,
Waël Zeinyeh1, Zahia Mahiout, Sylvie Radix
1Université 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.
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.
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