Rational design, synthesis and characterization of potent, drug-like monomeric Smac mimetics as pro-apoptotic anticancer agents

A set of phenyl-substituted Smac mimetics/IAP inhibitor analogues of lead compound 2a was synthesized, aiming to retain its strong cell-free potency while increasing its bioavailability. Seventeen compounds 2b-r were prepared and characterized in vitro, using cell-free and cellular assays. Among them, the p-CF3 substituted analogue 2m showed the best permeability through cell membranes, and was selected for further in vitro and in vivo studies due to its strong, sub-micromolar cellular potency.