presumably leading to the witnessed apoptosis. The
potential advantage of analogs 11 and 12 are their
simplicity, even in comparison to CA-4. Lacking the
connecting stilbene group, 11 and 12 are expected to be
less sensitive to cytochrome P450. Additionally, the
conformation of the two aryl rings should be more
stable and less prone to conformational change, as there
is not an ethylene linker, isomerization of which from
active Z-isomer to inactive E-isomer has been shown to
abolish cytotoxic effects.11 In fact, much research has
been focused on attempting to alter the cis-stilbenoid
pharmacophore in order to lock in a cis configuration,
thus producing a more stable linker between the two
rings. Recent examples include the replacement of the
ethylene linker with a N-acylhydrazone scaffold12 or
pyridine ring.13 While the two sets of CA-4 analogs
show promise, as several of the synthesized compounds
possess potent cytotoxic effects, they are relatively
complicated structures. While it is true that 11 and 12
exhibit significantly less cytotoxicity in cancer cells,
they are simpler structures that are easily synthesized
and may possess similar stability, although it remains to
be confirmed.
research extends the work on 1,1-diarylethylene analogs
of CA-4 but now provides further evidence that
effective CA-4 analogs can be discovered with linkers
of less than two carbons. The new antimitotics 11 and
12
demonstrate
that
simple
vascalature
disrupting/apoptosis-inducing agents can be derived
from directly coupled biaryl derivatives based on the
CA-4 pharmacophore. In conclusion, simplified biaryl
structures may now be added to the growing arsenal of
colchicinoid vasculature disrupting agents in the pursuit
of potent, selective anticancer agents.
Acknowledgements
We thank NSERC and McMaster University for
financial support of this work. We gratefully
acknowledge the Vanier Canada Graduate Scholarship
to Dennis Ma.
Supplementary data
Experimental procedures and characterization data are
provided.
Additionally, the lack of cytotoxic effects in the
nanomolar range for 11 and 12 may not be a large
detriment as higher doses can be used moving forward
as doses up to 20 µM were well tolerated in the
noncancerous cells studied. However, to confirm the
selectivity of 11 and 12, further noncancerous cell lines
need to be screened. To further evaluate the selectivity
of 11 and 12, they could also be tested in colon cancer
cell lines, which would be a direct counterpart to the
noncancerous colon cells (NCM460) tested.
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The most significant aspect of this research, perhaps,
is the potential for a paradigm shift, as far as the
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