Triphenylphosphonium (TPP) conjugates of 1,2,3-triazolyl nucleoside analogues. Synthesis, cytotoxicity and antimicrobial activity

Abstract

A series of new triphenylphosphonium (TPP) conjugates of 1,2,3-triazolyl nucleoside analogues were synthesised by coupling with 8-bromooctyl or 10-bromodecyl triphenylphosphonium bromide and evaluated in vitro for cytotoxicity against human cancer and normal cells and antimicrobial activity against Gram-positive cells, including methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative bacteria and pathogenic yeasts. In these TPP conjugates, the TPP cation was attached via an octyl or decyl linker to the N3 atom of the heterocyclic fragment (uracil, thymine, 6-methyluracil, quinazoline-2,4-dione) and its N1 atom was attached via a methyl or butyl linker with a 1,2,3-triazolylribofuranosyl moiety. Lead compounds possessing a decyl linker between the heterocyclic fragment and the TPP cation showed high cytotoxicity against HuTu-80 cancer cells (IC₅₀ = 0.5 μM) with a selectivity index >10. The lead compounds were found to induce apoptosis in HuTu-80 cancer cells via the mitochondrial pathway and to arrest the cell cycle of HuTu-80 cells in the G1 phase. Molecular docking modelling indicates that the lead compounds bind to the active site (BH3 domain) of the anti-apoptotic protein Bcl-2. Lead compounds with high anticancer specificity were also shown to be very active against S. aureus (MIC and MIC are 0.25–0.5 μM) and good efficacy against MRSA strains (MIC and MIC are 7.8–15.6 μM). In relation to bacteria, the lead compounds have a membranotropic effect due to a significant decrease in the potential of the cytoplasmic membrane.