Synthesis and Cytotoxic Activity of Lepidilines A–D: Comparison with Some 4,5-Diphenyl Analogues and Related Imidazole-2-thiones

A straightforward
access to 2-unsubstituted imidazole N-oxides with
subsequent deoxygenation by treatment with Raney-nickel
followed by N-benzylation opens up a convenient route
to lepidilines A and C. Both imidazolium salts were used to generate
in situ the corresponding imidazol-2-ylidenes, which smoothly reacted
with elemental sulfur, yielding imidazole-2-thiones. These reactions
were performed either under classical conditions in pyridine solutions
or mechanochemically using solid Cs2CO3 as a
base. The structure of lepidiline C was unambiguously confirmed by
X-ray analysis of its hexafluorophosphate. An analogous protocol toward
lepidilines B and D and their 4,5-diphenyl analogues is less efficient
due to observed instability of the key precursors, i.e., the respective
2-methylimidazole N-oxides. Comparison of cytotoxic
activity against HL-60 and MCF-7 cell lines of all lepidilines, as
well as their selected structural analogues (e.g., 4,5-diphenyl derivatives
and PF6 salts), revealed slightly more potent activity
of the 2-methylated series, irrespectively of the type of counterion
present in the imidazolium salt. Remarkably, the well-known 1,3-diadamantylimidazolium
bromide (the “Arduengo salt”), known as the precursor
of the first, shelf-stable NHC representative, and its adamantyloxy
analogue displayed the most significant cytotoxic activity in the
studied series.