Synthesis and In Vitro Evaluation of the Anticancer Effect of Novel Phosphonium Vindoline Derivatives

The Vinca alkaloid vindoline was coupled at position 17 with several trisubstituted phosphine derivatives and their in vitro anticancer activities on 60 human tumor cell lines (NCI60) were investigated. This phosphonium-type ionic side chain is beneficial because it allows therapeutic molecules to pass through the cell membrane. Thus, the candidates coupled to it can exert their activities in the mitochondria. The coupling of vindoline with the trisubstituted phosphines was achieved through flexible or rigid linkers. Instead of the ionic phosphonium structural part, a neutral moiety, namely the triphenylmethyl group, was also added to the side chain, being sterically similar but without a charge and phosphorus atom. In addition, the triphenylphosphine element was also built at position 10 of vindoline. Most of the derivatives showed low micromolar growth inhibition (GI50) values against most cell lines. Among them, conjugate 9e was outstanding: it exhibited nanomolar anticancer activity on the RPMI-8226 leukemia cell line (GI50 = 20.0 nM). Compound 9g elicited cell cycle disturbance and apoptosis on A2780 ovary cancer cells and inhibited their migration at subantiproliferative concentrations. The selectivity of the conjugates was determined by their effects on non-tumor Chinese hamster ovary (CHO) cells in the CellTiter-Glo Luminescent Cell Viability Assay. Compound 9e showed an estimated half-maximal inhibitory concentration (IC50) value of 1.36 mu M, suggesting good selectivity on cancer cells. These results open new perspectives of novel phosphonium-based vindoline derivatives as anticancer compounds.