Design, Synthesis and Evaluation of Hybrid Intracellularly Targeted Anticancer and Antimicrobial Agents

Aziz, Kiran

Abstract

One of the most important barriers to the success of anticancer therapy is the dysregulation of apoptotic pathways that limit effectiveness of current chemotherapy. A long-term objective seeks to exploit links between apoptosis and the functions of mitochondria to favour apoptosis and thus circumvent mechanisms of multi-drug resistance.
The specific aims of this research are the synthesis, characterisation and evaluation of a series of novel anthraquinone-based, tri-partite hybrid DCA-ciprofloxacin-TPP compounds to repurpose clinically useful antibiotics as non-genotoxic anticancer agents; and towards the design of dual anticancer and antibacterial agents.
These hybrid compounds consist of 3 components: ciprofloxacin (a broad-spectrum clinically useful 2nd generation fluoroquinolone antibiotic), dichloroacetate (DCA, a metabolic inhibitor of mitochondrial oxidation), and a triphenylphosphonium (TPP) cationic group, a hydrophobic carrier group with delocalised charge, capable of passing through mitochondrial membranes and accumulating in this organelle.
Dichloroacetate (DCA) is characterised as an apoptosis inducer in cancer cells; specifically, its clean mechanism of action to inhibit the critical mitochondrial enzyme pyruvate dehydrogenase kinase 2 (PDK2).
Four members of the series code-named Aq-Pip-DCA, Aq-Pip-Lys(TFA)-NH-TPP, Aq-Pip-Lys(Cp-TFA)-NH-TPP, and Aq-Pip-Lys(Cp-DCA)-NH-TPP hybrids showed good antibacterial activity. Ciprofloxacin (CIPRO) conjugate Aq-Pip-Lys(Cp-TFA)-NH-TPP was the most potent agent to inhibit bacterial growth in both sensitive (ATCC47055) and resistant (LIB213) strains of Escherichia coli (MIC 0.5 and 8 mg/L, respectively), and in Staphylococcus aureus both sensitive (82) and resistant (83) strains with MIC values 4 and 64 mg/L. In preliminary experiments, compounds from the series have shown cytotoxic activity against the resistant HCT15 colon carcinoma cell line at micromolar concentrations. Ciprofloxacin-TPP-DCA hybrids could provide multi-targeted leads for the design of biologically active agents with dual anticancer and antimicrobial activities.

• Thesis Type: Thesis
• Deposit Date: Aug 18, 2023
• Publicly Available Date: Aug 18, 2023
• DOI: https://doi.org/10.17869/enu.2023.3170314
• Award Date: Jul 5, 2023