Design, synthesis, and cytotoxicity of bifunctional anticancer agents targeted to mitochondria

Kamel, Mohamad Ali

Abstract

One of the major challenges of cancer chemotherapy is multidrug resistance (MDR) leading to failure and drug withdrawal. A major factor in drug resistance is the overexpression of transmembrane P-gp protein efflux pumps in cancer cell membranes that leads to low intracellular concentrations of drug. Motivated by either absent or low presence and activity of P-gp in mitochondrial membranes, the aim of this research is to design and develop novel candidate drugs that are delivered selectively to the mitochondria of cancer cells by exploiting the significant difference in mitochondrial membrane potential compared to normal cells.

A novel series of hybrid anthracenediones as potential anticancer agents that target and inhibit the unique properties of mitochondria in cancer cells has been synthesised and characterised by chemical, chromatographic and physical methods (HRMS and NMR). Bifunctional members of the series possess a lipophilic triphenylphosphonium (TPP) delocalised cation as a mitochondrial targeting vector and incorporate a cytotoxic dichloroacetic acid (DCA) moiety capable of inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase 2 (PDK2).

Several new compounds from the series are actively cytotoxic in the sensitive MCF-7 breast carcinoma cell line and notably, retain their activity (equitoxic) in the (high) P-gp expressing HCT-15 colon carcinoma cell line resistant to clinically used drugs.

Confocal microscopy studies demonstrate that active compounds are taken up by cancer cells and rapidly accumulate in the mitochondria, avoiding the cell nucleus, thereby demonstrating proof of principle.

Compounds (MK39 and MK44) amongst the anthracenedione-TPP-DCA hybrids have the potential to be efficiently delivered to tumour cells and provide lead candidates. The potential for circumvention of MDR, and improving the therapeutic index, should improve efficacy and limit systemic side effects in patients, compared with current chemotherapy.

• Thesis Type: Thesis
• Deposit Date: Aug 21, 2023
• Publicly Available Date: Aug 21, 2023
• DOI: https://doi.org/10.17869/enu.2023.3175207
• Award Date: Jul 5, 2023