Differences in Antiproliferative Activity Between Salinomycin-AZT Conjugates Obtained via 'Click' and Esterification Reactions.

BACKGROUND: Pharmacophore hybridization by bioconjugation, in which two bioactive moieties are covalently linked, is one of the current strategies in drug discovery for the development of new compounds with improved affinity and efficacy relative to those of the parent molecules. Prompted by the idea that cancer cells may be effectively killed by 3'-azido-3'-deoxythymidine (AZT) and salinomycin (SAL) individually, we synthesized hybrids of these compounds. The development of this type of derivatives, which can easily penetrate the lipid-rich cell membranes and then undergo hydrolysis inside the cancer cells, is an important research area.

METHODS: Efficient methods for the synthesis of two new conjugates are presented. The first method is based on the 'click' chemistry and involves the copper(I) catalysed 1,3-dipolar Huisgen cycloaddition reaction. In the second method AZT as well as SAL are connected by the ester bond under mild reaction conditions. The in vitro anti-proliferative activity of both conjugates against several drugsensitive and drug-resistant cancer cell lines as well as toxicity against normal murine embryonic fibroblasts are also determined.

RESULTS: Our studies clearly showed that the hybrid obtained via esterification reaction (SAL-OAZT) seems to be attractive in the fight against neoplastic diseases because it helps to overcome a strong drug-resistance of the cancer cell lines examined at low micromolar concentrations. The anticancer activity of this hybrid is also connected with high selectivity indexes (low toxicity) against normal cells.On the other hand, the 'click' conjugate (SAL-AZT) is practically inactive against the drug-resistant cancer cell lines tested and weakly active against the drug-sensitive ones. Also no synergistic effect has been found between SAL and AZT against eight cancer cell lines studied.

CONCLUSION: All of our findings support a strategy to decrease the doxorubicin concentration in combination with SAL-O-AZT hybrid in order to reduce the toxicity of this drug, as recently demonstrated for SAL. The advantages of the SAL-O-AZT conjugate over SAL are better RI and SI parameters at similar IC50values.