Cytotoxic derivatives of dichloroacetic acid and some metal complexes

Abstract

This study outlines a number of studies of dichloroacetic acid (DCA) and some of its derivatives. Although DCA has low cytotoxic potencies, various structural modifications are described which result in potent cytotoxins. In particular, hybrid molecules created from DCA and other bioactive molecules whose modes of action differ from DCA are particularly promising as candidate anticancer agents. Considerable emphasis in this review is placed on various series of compounds that incorporate both platinum and DCA into their structures. In addition, the importance of the formulation of some of the bioactive compounds described herein is revealed.

Reprogramming Energy Metabolism with Synthesized PDK Inhibitors Based on Dichloroacetate Derivatives and Targeted Delivery Systems for Enhanced Cancer Therapy

“…In recent years, PDK inhibitors have been developed with different structures. − Among them, N -aryl dichloroacetamide derivatives exhibit good antiproliferative activity and potential PDK inhibition. ,,− However, their potencies are still unsatisfactory. Considering the hydrophobicity of PDK binding pockets and its nearby region, optimization efforts focused on enhancement of the hydrogen bonding, hydrophobicity, and molecular flexibility.…”

“…To address this limitation, many researchers attempted to chemically modify DCA and obtain more effective anticancer agents (Figure ). DCA was conjugated with organelle-targeted groups, Pt coordination compounds, or polymers . However, similar to other PDK inhibitors, DCA derivatives still suffer from limited activity in vitro and/or in vivo and lack mechanism discussion and targeted delivery.…”

“…Hydrogen bonding, hydrophobicity, and molecular flexibility may contribute to the activity of PDK inhibitors. − Hydrophobic derivatives of N -aryl dichloroacetamide that were obtained by adding substituents at different positions on the phenyl ring exhibit good antiproliferative activity and potential inhibition of PDK. ,,− Unfortunately, satisfactory potencies are not observed, and structural modifications are necessary. Owing to the hydrophobicity of PDK binding pockets and its nearby regions, the alkyl linkers of different lengths between phenyl ring and DCA was considered to differentially enhance hydrophobic interactions between small molecules and PDK .…”

All-in-One Pyruvate Dehydrogenase Kinase Inhibitor for Tracking, Targeting, and Enhanced Efficacy

“…This inherent anionic charge limits the accumulation of DCA across the hyperpolarized mitochondrial membrane leading to a rapid clearance of the small DCA molecules in vivo before reaching the tumor cells, making it unsuitable for crossing the cell membrane and entering the mitochondria through passive diffusion. 12,17 In order to introduce physiologically relevant DCA doses and to engineer the anionic form of DCA to partition across the inner mitochondrial membrane (IMM) to access PDK1, our group developed a DCA-based prodrug, Mito-DCA, 12 which has three DCA groups and a triphenylphosphonium (TPP) cation to utilize mitochondrial membrane potential (Δψ m ) to partition into the mitochondrial matrix of cells resulting in substantially lower minimum effective dosage. Mito-DCA has the ability to selectively alter metabolism in cancer cells by inhibiting glycolysis and overall ATP production to reduce the cancer cell proliferation.…”

“…Limited stability of DCA in the biological environment and the inherent anionic charge of ionized DCA molecules are considered as the possible factors that significantly affect its therapeutic outcomes. This inherent anionic charge limits the accumulation of DCA across the hyperpolarized mitochondrial membrane leading to a rapid clearance of the small DCA molecules in vivo before reaching the tumor cells, making it unsuitable for crossing the cell membrane and entering the mitochondria through passive diffusion. , …”