Synthesis and biological evaluation of RGD peptidomimetic-campthotecin conjugates with disulfide linkers

Conjugation of cytotoxic agents to targeting carriers (e.g. antibodies or small molecules) capable of selectively binding to tumor-specific antigens, is emerging as a successful strategy to overcome the drawbacks of traditional chemotherapy.[1] Being over-expressed by several human tumors, αvβ3 integrin can be considered as a suitable target for cancer therapy with small molecule-drug conjugates (SMDCs). The Arg-Gly-Asp (RGD) peptide sequence has been found to bind with high affinity to αvβ3 integrin: for these reasons, several RGD-bearing peptides and peptidomimetics have been investigated as promising carriers for the delivery of anticancer drugs.[2] The resulting SMDCs are able to release the anticancer agents upon cleavage of a linker, under the specific conditions of the tumor environment. Following this approach, our research group has recently developed two RGD-Paclitaxel conjugates containing dipeptide linkers that can be selectively cleaved by proteases.[3] Here, we report the development of new RGD conjugates containing the disulfide linker, which is stable in plasma but can be selectively cleaved by the reductants present in the cell. Two such RGD peptidomimetic-Campthotecin conjugates (compounds 2, 3) have been synthesized, and their ability to bind αvβ3 integrin has been evaluated. They exhibited high affinity for the αvβ3 integrin, with low-nanomolar IC50 values, comparable to that of the free ligand 1.[4] Further biological assays are in progress to evaluate the cytotoxicity of the new compounds against cancer cell lines expressing αvβ3 integrin at different levels.