Carbonic Anhydrase inhibitors bearing organotelluride moieties as novel agents for antitumor therapy

Abstract

Solid tumors are mainly characterized by a specific hypoxic microenvironment which makes them particularly challenging to treat. The Carbonic Anhydrase IX (CA IX) is one of the major enzymes implicated in the regulation and maintaining of such conditions and therefore its targeting represents a winning approach in recent tumor targeted therapy. In our search for an innovative combination therapy, we attained the synthesis of selective CA IX inhibitors which are also used for cell specific delivery of cytotoxic organotellurium scaffolds. We investigated compounds 5b, 7b and 7c for their redox properties by means of radical species scavenging and lipid peroxidation inhibitory capacity, as well as intracellular (reactive oxygen species) ROS production in both normal and cancer cell lines. Subsequently, compounds were evaluated as possible free radical generators by ESR spectrometry showing to cause or promote the formation of free radicals. These results accounted for a novel, potent, and selective CA IX inhibitor (i.e. 7c, K_i = 32 nM) with high cytotoxic effect against malignant melanoma (MeWo) and hepatocellular carcinoma (HepG2) cells over normal fibroblasts (NHDF) through ROS-independent mechanisms. The preliminary data gives support to employ organotellurium moieties as useful pharmacological tools for further development in the oncological field.

Keywords: Carbonic anhydrase; Metalloenzymes; Organotelluride; ROS; Tumor.