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M. Psurski et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4572–4576
G0/G1 phase, but they caused the highest cell death level (68% and
55%, respectively). Treatment with the compound 7 (c Log P = 3.56)
shows similar results in the phase cycle image and in a glutathione
were tested as racemic mixtures. It is interesting to investigate, if
there are some differences between the enantiomers and such ap-
proach could be helpful in the search of an appropriate mechanism
of action for isothiocyanates. The synthesis of such derivatives is in
progress.
level depletion as in case of
B (phenethyl isothiocyanate,
c Log P = 3.26).
The cell cycle and the reduced glutathione depletion level anal-
ysis suggests a possible correlation between the structure and the
mechanism of action of the synthesized compounds, thus hydro-
philic compounds like 2 (c Log P = 0.84) exhibit their antiprolifera-
tive activity mainly causing cell death, when hydrophobic
compounds like 12 (c Log P = 4.2) act through GSH depletion and
cell cycle arrest in the G0/G1 phase, but do not cause a massive cell
death. In fact, cell cycle arrest in G0/G1 is directly correlated with
the glutathione depletion which leads to a decrease of the redox
status of the cells. The redox model of cell proliferation (RMCP),
as described by Hoffman31 suggested that within normal cells
the cell cycle is stopped by a redox switch (towards the more oxi-
dative environment) in G0/G1 phase. The above described redox
switch helps to regulate proliferation via phosphorylation and
dephosphorylation of redox-sensitive regulatory proteins such as
the retinoblastoma protein (pRb). Due to metabolic and chromo-
somal changes the cancer cells do not possess such checkpoint,
and the redox switch does not occur, pRb cannot be dephosphoryl-
ated and the cells can proliferate easily. However, such redox
switch can be induced artificially, for example, by isothiocyanates,
and can lead to the cell cycle inhibition. Such phenomena can also
be observed for some dialkoxyphosphoryl isothiocyanates, espe-
cially for compound 12.
Supplementary data
Supplementary data (synthesis and experimental procedures
along with the full characterization for the compounds) associated
with this article can be found, in the online version, at doi:10.1016/
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