C. V. Do et al. / Bioorg. Med. Chem. Lett. 26 (2016) 174–180
175
X
of the 3,4,5-trimethoxystyrene unit on these sulfur (benzo)hetero-
cycles at different 2 and 3 positions (Fig. 1, compounds 2).
Moreover, in parallel to our work, Alami and co-workers have
described the preparation of isoCA-4 derivatives with substituted
benzofurans 3a (Y = O) and indole 3b (Y = NR0) (Fig. 1) using a pal-
ladium-catalyzed coupling/ring closure domino reaction.26
So, the second goal of the present study was to assess the effect
of the grafting of the 2-[1-(3,4,5-trimethoxy-phenyl)-vinyl] unit on
sulfur heterocycles, at both positions 2 and 3, so extending the
knowledge of the structure–activity relationships of this family
(Fig. 1, compounds 4).
The key step of our synthetic strategy to these new isoCA-4
derivatives 4 relied on the preparation of the methylene group
by water elimination on methyl diarylcarbinols 6: these com-
pounds could be in turn obtained by trapping the appropriate aryl
lithium species with 3,4,5-trimethoxyacetophenone 7a (R0 = Me) or
after addition of methyl magnesium iodide onto the diarylketo
derivatives 5 (Fig. 2).
MeO
MeO
OH
MeO
MeO
R
A
B
A
B
OMe
OMe
OMe
OMe
CA-4:
R = OH
isoCA-4:
X = CH2
X = O
CA-4P:
R = OPO3Na2
phenstatin:
AVE8062: R = NH-serinol,HCl
O
OMe
OH
MeO
MeO
3
O
OMe
BNC105
MeO
MeO
2
Y
2
OMe
OMe
Y
OMe
Since the first synthesis of phenstatin,23 the preparation of
biaryl keto derivatives were usually based on the addition of the
aryl lithium onto an amide, derived from a benzoic acid. Recently,
an alternative process which was described by Rigo and co-work-
ers27 and Petrov et al.28 used an acylation process of a benzoic acid
on the appropriate aromatic substrate, in Eaton’s reagent (P2O5 in
MeSO3H).
In our synthetic approach, those compounds 5 could be pre-
pared by the addition of the (benzo)thiophene lithium reagent,
generated at the appropriate 2- or 3-position, onto 3,4,5-tri-
methoxy benzaldehyde 7b (R0 = H), followed by an oxidation step
of the obtained alcohol (Fig. 2).29 By this way, the isosteric replace-
ment of the exocyclic CH2 in compounds 4 by an oxygen atom
(phenstatin analogs 5) could also be investigated.30
For the present study, in the thiophene series, 2- and 3-lithio
species were prepared using halogen/lithium exchange with
n-BuLi on commercially available 2- and 3-bromothiophene. The
corresponding aryl lithium intermediate was then trapped by
3,4,5-trimethoxy acetophenone 7a to obtain 6a,b. These tertiary
alcohols were submitted to an acid-catalyzed dehydration and
the target compounds 4a,b were isolated with good yields over
these two steps (Scheme 1).31
For the preparation of benzoheterocyclic derivatives, 2- and
3-lithio reagents were obtained after deprotonation of benzo[b]
thiophene itself or by bromine/lithium exchange on its 3-bromo
derivative 832 (Scheme 2).
MeO
3
1
Y = O, S, NR'
MeO
X
3
3
2
2
OMe
S
S
MeO
MeO
OMe
4
5
OMe X = CH2
X = O
2
Figure 1. Combretastatin A-4 and its soluble derivatives, synthetic methylene and
keto tubulin-targeting compounds.
Despite these potent activities, solubility parameters had to be
improved and this was achieved with the preparation of several
derivatives, having a phosphate group (R = OPO3Na2, fosbretabu-
lin10,11) or an aminoalcohol side chain (R = NH-serinol hydrochlo-
ride salt, ombrabulin12). These compounds, which demonstrated
Vascular Targeting or Disrupting properties,13 actually undergo
clinical evaluations for the treatment of various cancers but also
diseases associated to vascularization disorders.14
Nevertheless, these compounds, known to interact with the col-
chicine binding site of tubulin,15 were reported to isomerize
in vivo,16 thus leading to the less active trans isomers.17 While this
isomerization is not deleterious for the development of CA-4
derivatives as anticancer drugs (as shown by fosbretabulin and
ombrabulin), the discovery of new tubulin-targeting agents based
on this structure that also avoid the Z to E isomerization still
remains a stimulating challenge.18
After addition of aldehyde 7b, alcohols 9a,b (Scheme 2) were
isolated and further oxidized into ketones 5a,b using MnO2 in ace-
tonitrile (Scheme 3). These carbonyl compounds were thereafter
Besides the addition of a substituent onto the double bond,19
one of the solutions to block this isomerization was to replace it
by an (hetero)cycle20 or by designing iso methylene derivatives,
so-called isocombretastatins (e.g., isoCA-4, Fig. 1).21,22 Other
research groups also developed the isosteric version of isoCA-4,
i.e., phenstatin23 derivatives, and those ketones have also shown
interesting tubulin-targeting properties. Based on this 3,4,5-
trimethoxybenzophenone scaffold, several heterocyclic analogs
were developed, including indoles,24a benzo[b]thiophenes24b or
benzofurans such as BNC10524c (Fig. 1) which is currently undergo-
ing clinical trials.
Our initial strategy for the development of new tubulin-target-
ing molecules aimed to evaluate the effect of the replacement of
the B ring with different benzoheterocycles, attached to position
2, leading to compounds 1 (Fig. 1). This preliminary work demon-
strated that the most active compound possessed a benzo[b]thio-
phene ring (Y = S).25 One of the objectives of the present Letter
was to evaluate the importance of the vicinal aromatic ring (thio-
phene versus benzo[b]thiophene) but also the effect of the grafting
HO Me
3
3
MeO
MeO
MeO
MeO
2
2
S
S
6
4
OMe
OMe
OMe
OMe
R'=Me
R'=H
O
O
MeO
MeO
3
R'
MeO
MeO
2
S
7
5
+
Li
3
or
Li
2
S
S
Figure 2. Synthetic strategy to iso methylene derivatives 4.