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