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

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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► Progesterone–adenine hybrids as bivalent inhibitors of Pgp-mediated multidrug efflux.
► Design to target simultaneously the ATP-site and the steroid-binding site of Pgp.
► The attachment point and the nature of the linker play a fairly crucial role.
► C20-hybrid with hexamethylene linker enhances daunorubicin accumulation by 30%.