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.
Supramolecular control of singlet oxygen generation is
incredibly
valuable for several fields with broad applications and thus still
challenging. However, macrocyclic inclusion complexes inherently restrict
the interaction of photosensitizers with surrounding oxygen in the
media. To circumvent this issue, we turned our attention in this work
to acyclic cucurbituril-like containers and uncover their properties
as supramolecular hosts for photosensitizers with extraordinary control
of their photophysics, including singlet oxygen generation. Thermodynamic
and photophysical studies were carried out showing that these acyclic
containers compare very favorably to benchmark macrocycles such as
cucurbiturils and cyclodextrins in terms of their binding affinities
and supramolecular control of singlet oxygen generation. Acyclic container
with terminal naphthalene walls offers a similar cavity to cucurbit[7]uril
and the same carbonyl-lined portals for a tight binding of phenothiazinium
dye methylene blue and stabilizing its singlet and triplet excited
states. Thus, generation of singlet oxygen for this container is higher
than for other macrocycles and even higher than the free photosensitizer.
While the acyclic container with smaller terminal benzene walls, stacks
over the dye through sulfur−π and π–π
interactions deactivating the singlet and triplet excited states,
thus showing the lowest generation of singlet oxygen out of all of
the studied systems. Due to the great water solubility and biocompatibility
of these systems, they possess great potential for novel applications
in photocatalysis, synthesis, and biomedical fields, among others.
A new toluidine blue-myristic acid photosensitizer derivate (TBOMyr) was investigated as a design molecule to bind simultaneously to cucurbit[7]uril (CB[7]) and human serum albumin (HSA) with the aim of constructing...
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