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 analogs of lead compd. I [R = H] was synthesized, aiming to retain its strong cell-free potency while increasing its bioavailability. Seventeen compds. were prepd. and characterized in vitro, using cell-free and cellular assays. Among them, I [R = CF3] 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