The
formation of inclusion complexes between drugs and macrocycles
has proven to be an effective strategy to increase solubilization
and stabilization of the drug, while in several cases improving their
biological activity. In this context, we explored the formation of
an inclusion complex between chemotherapeutic drug Melphalan (Mel)
and cucurbit[7]uril (CB[7]), and studied its effect on Mel alkylating
activity, hydrolysis, and cytotoxicity. The formation of the inclusion
complex (Mel@CB[7]) was proven by absorption and fluorescence spectroscopy,
NMR, docking studies, and molecular dynamics simulations. The binding
constant for Mel and CB[7] was fairly high at pH 1 ((1.7 ± 0.7)
× 106 M–1), whereas no binding was
observed at neutral pH. The Mel@CB[7] complex showed a slightly decreased
alkylating activity, whereas the cytotoxicity on the HL-60 cell line
was maintained. The formation of the complex did not protect Mel from
hydrolysis, and this result is discussed based on the simulated structure
for the complex.
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