Antimitotic activity of structurally simplified biaryl analogs of the anticancer agents colchicine and combretastatin A4

Article abstract of DOI:10.1016/j.bmcl.2014.10.090

Two substituted biaryl analogues of colchicine and combretastatin A4, readily available through a one-step, protecting group free Suzuki-Miyaura reaction were discovered to exhibit anticancer activity while simultaneously being of low cytotoxicity to noncancerous cell lines. The compounds were shown to initiate apoptosis selectively via a mechanism involving inhibition of tubulin polymerization.

Full text of DOI:10.1016/j.bmcl.2014.10.090

Accepted Manuscript
Antimitotic activity of structurally simplified biaryl analogs of the anticancer
agents colchicine and combretastatin A4
James McNulty, Sean van den Berg, Dennis Ma, Daniel Tarade, Seema Joshi,
Julia Church, Siyaram Pandey
PII:
S0960-894X(14)01161-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.10.090
BMCL 22145
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 September 2014
24 October 2014
28 October 2014
Please cite this article as: McNulty, J., Berg, S.v.d., Ma, D., Tarade, D., Joshi, S., Church, J., Pandey, S., Antimitotic
activity of structurally simplified biaryl analogs of the anticancer agents colchicine and combretastatin A4,
Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.10.090
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Antimitotic activity of structurally simplified biaryl analogs of
the anticancer agents colchicine and combretastatin A4
James McNulty,a,* Sean van den Berg,a Dennis Ma,b Daniel Tarade,b Seema Joshi,b Julia
Church,b Siyaram Pandey,b*
a Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ont., L8S 4M1, Canada
b Department of Biochemistry, University of Windsor, Windsor, Ont., Canada
This is where the receipt/accepted dates will go; Received Month XX, 2000; Accepted Month XX, 2000 [BMCL RECEIPT]
Abstract – Two substituted biaryl analogues of colchicine and combretastatin A4, readily available through a one-step, protecting group
free Suzuki-Miyaura reaction were discovered to exhibit anticancer activity while simultaneously being of low cytotoxicity to
noncancerous cell lines. The compounds were shown to initiate apoptosis selectively via a mechanism involving inhibition of tubulin
polymerization.
© 2014 Elsevier Science Ltd. All rights reserved.
Since their isolation from the African bush willow
Combretum caffrum by Pettit and co-workers in 1982,1
the combretastatin phenolic-stilbenes have attracted
considerable attention in view of the potent anticancer
activity demonstrated.2 Colchicine 1, as well as the
combretastatin 2-4 (see Figure 1) antimitotics share
obvious structural similarities and have been
collectively referred to as colchicinoids.2b Their potent
antimitotic activity is attributed to microtubule-
polymerization, acting at a site distinct from the vinca-
alkaloid tubulin destabilizing agents (vinblastine,
vincristine etc). Disruption of the microtubule assembly
process results in the induction of apoptosis in actively
dividing cells. The combretastatins are distinct in their
mode of activity from other tubulin-active agents, such
as paclitaxel (taxol) 5, that act directly on assembled
microtubules enhancing tubulin polymerization. Both
classes of tubulin-interactive compounds ultimately
interfere with the normal cellular vascalature2d resulting
in apoptosis induction. The combretastatins are also
highly distinctive by comparison with paclitaxel and
other taxoids in view of their relative structural
simplicity.
destabilization
through inhibition of tubulin
O
MeO
MeO
MeO
MeO
MeO
NH
OH
OH
MeO
O
Me
MeO
MeO
O
OR
OMe
OMe
OMe
3
Combretastatin A4 (R=H)
CA4 phosphate 4 (R=PO3Na2
The synthesis and biological evaluation of many
structural analogues of the combretastatins has been
carried out over the last two decades.2,3 As select
examples, Pettit and co-workers reported the synthesis
of phenstatin 6, its phosphate derivative and analogs
some of which exhibited nanomolar potencies to human
tumor cell lines.3d Chen and co-workers synthesized a
series of analogs containing a cyclopropylamide bridge
7 that showed micromolar activity to select human
cancer cell lines.3e Gurjar and co-workers synthesized a
series of analogs with hydroxycyclopentenone or
hydroxycyclopentenone oxime bridges based on 8,
examples of which exhibited nanomolar activity
towards human cell cancer lines (oral, larynx, ovary,
colon, lung, pancreas) and anti-tubulin activity of 1.75
Colchicine
1
Combretastatin A1
2
)
O
AcO
OH
O
OH
Bz
Ph
MeO
NH
O
NH Cl
MeO
MeO
O
O
MeO
MeO
MeO
H
O
O
OAc
OH
OH
OH
OMe
Bz
5
7
Paclitaxel
Phenstatin
O
6
OH
OH
OMe
R2
O
MeO
MeO
R1
MeO
MeO
MeO
MeO
OMe
OMe
OMe
OMe
OMe
10
8
9
Figure 1. Structures of colchicinoid antimitotics 1-4, paclitaxel 5 and a
selection of synthetic stilbenoid modifications 6 to10 .

µM.3f Flynn and co-workers synthesized a series of
combretastatin A4 (CA-4) indenone derivatives 9 that
showed tubulin inhibition properties but no cytotoxicity
to MCF-7 breast cancer cells,3g while Pinney et al.
synthesized a library of benzosuberene analogs 10 that
showed nM activity to some cancer cell lines.3h
Br
MeO
MeO
MeO
MeO
Pd(OAc)2
+
OH
B
OR
OH
Pr3P, CsCO3
PhMe
OMe
OMe
O
OR2
R1
OR1
11
12
R1=H, R2=Me
R1=Me, R2=H
These varied structure-activity studies have allowed
development of a relatively clear view of the anticancer
pharmacophore, outlined in Figure 2. Three preferred
embodiments (circled) include a 3,4,5-trimethoxyaryl
motif in ring-A, a cis-configured stilbene or analog
Figure 3. Suzuki-Miyaura cross coupling as a direct synthesis of biaryl
analogs 11 and 12.
As part of our research program investigating the
apoptosis-inducing activity of natural products and
structural analogs,7 we have amassed a large collection
of variously substituted biaryl8 and stilbenoid9
derivatives. Compounds 11 and 12 were prepared8 as
part of this program (McMaster) and included in a
library consisting of 600 compounds, which was
screened blind (Windsor) against an osteocarcoma cell
line (U-2 OS). Each of the compounds was tested at a
concentration of 10 µM for 48 hours. Compounds that
significantly reduced the proliferation of these cancer
cells were further studied allowing identification of four
efficient inducers of apoptosis. Two of these
compounds were positive controls (pancratistatin and
narciclasine) randomly seeded in the library, while the
other two compounds proved to be the biaryl derivatives
11 and 12. The two compounds were readily accessed
on scale-up of the original synthesis8 and were readily
prepared in one step, without requirement of phenol
protection, using a standard Suzuki-Miyaura cross-
coupling reaction (Figure 3). As a result, large amounts
of 11 and 12 were prepared for further study.
thereof linking ring-A to
a
3,4-substituted
methoxyphenol as ring-B.2b Small deviations from these
requirements often result in total loss of apoptosis-
inducing and anticancer activity. Currently, CA-4 3 and
its disodium-phosphate prodrug 4 are the most
investigated compounds in the series having advanced
to Phase II and III clinical trials in a variety of human
cancers4a as well as treatment of diabetic retinopathy,4b
the most common cause of blindness, in view of the
potent vascular disrupting activity demonstrated.
cis-stilbenoid or analog
trimethoxy-
arene
OMe
MeO
MeO
MeO
MeO
MeO
MeO
HO
A
B
MeO
MeO
OR2
OR
OR1
13
OMe
3,4-methoxy-
phenol
11 R1=H, R2=Me
12
R1=Me, R2=H
Combretastatin A4 pharmacophore
Figure 2. Depiction of the 3-component combretastatin A4
pharmacophore and reduction to simplified biaryl analogs 11 and 12.
Screening of analogs 11 and 12 for anti-proliferative
properties was conducted in leukemia and osteocarcoma
cell lines, as well as in noncancerous colon epithelial
cells (Table. 1). The half-maximal inhibitory
concentration (IC50) was calculated for CA-4 and the
biarly analogs and in each cell line, without exception,
CA-4 had an IC50 at least two orders of magnitude
lower than that of analogues 11 and 12.
In view of the structural requirements of the CA-4
pharmacophore and the biaryl linkage found within
colchicine 1, we postulated that complete removal of the
double bond and re-connection of the two aryl rings as
direct biaryl derivatives, leading to structures 11 and 12
(Figure 2), might lead to structurally simplified analogs
retaining anticancer activity. We recently disclosed that
the styryl-double bond in the anticancer natural product
narciclasine was detrimental to further development of
this compound due to the interaction of human
cytochrome P450 enzymes at this site.5 Removal of the
double bond, as in CA4 analogues 11 and 12, could also
lead to more metabolically stable analogs. A successful
outcome of this biaryl strategy is not obvious given that
many biaryl natural products are known in particular
being commonly found as antifungal phytoalexins in
plants of the Rosaceae family. The closest examples
recorded include biaryl compounds such as 13 (Scheme
2), which were reported to be devoid of anticancer
activity.6 Nonetheless, we considered pursuit of 11 and
12 worthwhile given the known peculiarities of the
combretastatin A4 pharmacophore.
Table 1. IC50 values of structures 11, 12, and CA-4 were determined at
the 48 hour time point in several cancerous and noncancerous cell lines.
MV-4-11 = myelocytic leukemia; E6-1 = acute T-cell leukemia; Saos-2
& U-2 OS = osteocarcoma; NCM460 = normal colon epithelial cells.
Values are represented as mean of quadruplicates SD of three
independent trials.

Despite the lower potency of biaryls 11 and 12, both
compounds still possessed strong anticancer properties,
clearly exhibited in the Saos-2 osteocarcoma cell line
and the leukemia cells lines, MV-4-11 and E6-1. In
these cells lines, while CA-4 possessed a lower IC50
value, all three compounds, including 11 and 12,
reduced the proliferation of the cancer cells to the same
low level (Figure 4). This is important when considering
the lack of anti-proliferative properties exhibited in the
noncancerous NCM460 cells. With doses as large as 20
µM not bringing the proliferation of the cells below
50%, it may be concluded that all compounds tested
were effective at reducing the proliferation of cancer
cells selectively in the in-vitro model used.
The one outlier appeared to be the U-2 OS cell line, in
which 11 and 12 appeared to have little effect when
considering that its IC50 was above 20 µM, while CA-4
retained its typically low IC50 value. However, at a
range consistent with the other reported IC50 values
(2.5-5.0 µM), 11 and 12 succeeded at reducing the
proliferation of the U-2 OS osteocarcoma cells to
approximately 60% (Figure 4). It was because of this
reduction in proliferation that compounds 11 and 12
were first identified in the blind screen. In the same
dose range of 2.5-5.0 µM, C-A4 reduced cell
proliferation to approximately 30%, suggesting that the
large difference in IC50 values did not mirror a similarly
disproportionate difference in overall anticancer activity
towards the U-2 OS osteocarcoma cell line.
The ability of 11 and 12 to induce apoptosis in cancer
cells was evaluated and compared to that of CA-4
(Figure 5). Apoptotic induction was monitored by
observing phosphatidylserine externalization, which is a
characteristic feature of apoptosis that leads to
identification and consumption of apoptotic cells by
surrounding macrophages.10 To do so, Annexin V, a
molecule with natural affinity for phosphatidylserine,
conjugated to Alexa Fluor 488 (green fluorescent probe)
was utilized. Additionally, propidium iodide (red
fluorescent probe) uptake by cells with permeabalized
membranes (i.e. necrotic cells) was monitored. Cell
populations exhibiting green and/or red fluorescence
were quantified using image-based cytometry.
Paralleling the data obtained with the proliferation
screen, CA-4 was effective at inducing apoptosis at
lower doses than both 11 and 12. This was the case with
both Saos-2 osteocarcoma cell line and the MV-4-11
leukemia cell line. However, at higher doses, 11 and 12
approached the level of activity seen with CA-4,
particularly structure 12, which at 5.0 µM in both the
Saos-2 and MV-4-11 cancer cells matched the
anticancer activity witnessed with CA-4 at the same
dose. Lastly, and most importantly, all three treatments
did not cause an increase in apoptotic/necrotic cell
populations in the noncancerous model (NCM460 cells)
studied.
It was also seen that the levels of apoptotic cells
(those exhibiting green fluorescence above base levels
observed in the control) exceeded the levels of necrotic
cells (those exhibiting red fluorescence above basal
levels). Cells that exhibited elevated red and green
fluorescence were considered both apoptotic and
necrotic. Overall, the data suggested that treatment with
11, 12, and CA-4 resulted in cell suicide that progressed
towards necrosis in our in-vitro model that lacked
macrophages.
Figure 4. Dose-response curves of 11, 12, and combretastatin A4 at 48
hours in various cancerous and noncancerous cell lines. Values are
represented as mean of quadruplicates SD of three independent trials.

From the data gathered on the ability of 11 and 12 to
halt cancer proliferation and induce cell death, it was
clearly discerned that structure 12 is a more effective
anticancer compound than 11, considering that both
compounds did not have a deleterious impact on the
noncancerous NCM460 cells. Not only did 12 have a
lower IC50 in all of the cancerous cell lines tested for
which a concrete IC50 value could be obtained, it was
also more effective at inducing apoptosis. This evidence
suggests that phenyl substitution in ring-B of the biaryl
having the hydoxyl group in the para position and the
methoxy group in the meta position, is more effective
than the reverse constitution. This evidence is in accord
with the body of knowledge obtained around the CA-4
pharmacophore, the structure of which most closely
overlaps with the biaryl 12. These data illuminate the
subtleties of this new biaryl apoptosis-inducing
pharmacophore, particularly given the inactivity of
many known biaryl derivatives such as 13,6 for further
development of leads in the series.11
Finally, we wished to obtain evidence that the primary
mechanism of action of CA-4, that of mitotic
suppression via inhibition of tubulin polymerization,
was still present with 11 and 12 (Figure. 6). Using an in
vitro assay, microtubule polymerization was monitored
kinetically for one hour, either in the presence of
DMSO vehicle control or studied compound. The extent
of microtubule polymerization was determined
fluorometrically based on the incorporation of a
fluorescent reporter. Tubulin polymerization was
completely abolished by 3 µM CA-4, in a manner
similar to positive control colchicine. Conversely, 3 µM
11 had no impact on tubulin dynamics and 3 µM 12 had
only a moderate effect. With 10 µM of 11, a similarly
moderate effect was noticed while 10 µM of 12 was
almost as effective as the lower dose of CA-4. Thus, a
clear relationship between the anticancer effect and
impact on tubulin dynamics was discerned. 11 was least
effective at inhibiting tubulin polymerization and
similarly, was least effective at inhibiting cancer
proliferation and inducing apoptosis. 12 was more
effective than 11 at both the inhibition of tubulin
polymerization and the induction of cell death in cancer
cells. Lastly, CA-4 was the most effective at halting
tubulin polymerization and causing the cancer cells to
commit suicide. Thus, a correlation can be drawn
between the ability of these colchicinoids to disrupt
tubulin dynamics and cause cell death.
Figure 6. Tubulin polymerization in vitro was inhibited by the
colchicinoid combretastatin A4, as well as novel biaryl analogs 11 and
12. RFU = relative fluorescent units. Values are represented as mean of
duplicates SEM of three independent trials. * p < 0.05 vs. control; **
p < 0.005 vs. control; *** p < 0.0005 vs. control.
Although the novel biaryl analogues are less effective,
with a sufficient dose it can be seen that at least 12 was
able to completely abolish tubulin polymerization,
Figure 5. Apoptotic induction was selectively induced by 11, 12, and
CA-4 at 48 hours. Values are represented as mean SD of three
independent trials.

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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Antimitotic activity of structurally
simplified biaryl analogs of the
anticancer agents colchicine and
combretastatin-A4
James McNulty, Sean van den Berg, Dennis Ma,
Daniel Tarade, Seema Joshi, Julia Church,
Siyaram Pandey,
Two substituted biaryl analogues of colchicine and
combretastatin A4, readily available through
a one-step,
protecting group free Suzuki-Miyaura reaction were discovered
to exhibit anticancer activity while simultaneously being of low
cytotoxicity to noncancerous cell lines. The compounds were
shown to initiate apoptosis selectively via a mechanism involving
inhibition of tubulin polymerization.
Graphical abstract
O
MeO
MeO
MeO
NH
MeO
Me
MeO
MeO
O
MeO
OH
OMe
O
OH
OMe
Combretastatin A4
OMe
OMe
Colchicine
Simplified biaryl pharmacophore