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 IC50