Design and Synthesis of Functionalized Thiosemicarbazone Analogues as Potential Anti-metastatic Agents

Metastasis is often the ultimate cause of death among cancer patients. An emerging target in the treatment of metastasis is cathepsin L which facilitates the degradation of the extracellular matrix thereby providing a pathway for the movement of cancer cells to secondary locations in the body from the primary tumor. A variety of potent small-molecule cathepsin L inhibitors bearing the thiosemicarbazone moiety have been discovered through the collaboration of the Pinney Research Group and Trawick Research Group at Baylor University. A compound known as KGP94 is among the more potent inhibitors discovered and has been re-synthesized for further studies. The majority of thiosemicarbazone containing inhibitors of cathepsin L are asymmetrical and prone to isomerization about the imine bond of the thiosemicarbazone functional group. Since isomerization may interfere with the ability of these compounds to inhibit cathespin L, a series of symmetrical thiosemicarbazone analogues was prepared and evaluated as inhibitors of cathepsin L.