Synthesis and biological evaluation of dual action cyclo-RGD/SMAC mimetic conjugates targeting a(v)beta(3)/a(v)beta(5) integrins and IAP proteins

The rational design, synthesis and in vitro biological evaluation of dual action conjugates 11-13, containing a tumour targeting, integrin a(v)beta(3)/a(v)beta(5) ligand portion and a pro-apoptotic SMAC mimetic portion (cyclo-RGD/SMAC mimetic conjugates) are reported. The binding strength of the two separate units is generally maintained by these dual action conjugates. In particular, the connection between the separate units (anchor points on each unit; nature, length and stability of the linker) influences the activity of each portion against its molecular targets (integrins a(v)beta(3)/a(v)beta(5) for cyclo-RGD, IAP proteins for SMAC mimetics). Each conjugate portion tolerates different substitutions while preserving the binding affinity for each target.