M. G. Banwell et al. / Bioorg. Med. Chem. Lett. 16 (2006) 181–185
183
products was achieved using TBAF and thereby
affording the remaining target analogues, namely phe-
nols 10 (93%) and 12 (82%), respectively. The spectral
data obtained on each of compounds 5–12 were con-
sistent with the assigned structures and each member
of the relevant enantiomeric pair displayed optical
rotations of essentially the same magnitude but oppo-
site sign. The R-configured materials were laevorotatory
in each case.
followed by oxidative cyclization of this material using
VOF3 and TFA then gave target 1419 in 56% yield.
Each of compounds 5–12 was screened, at eight different
concentrations, against a panel of nineteen human and
other cancer cell lines as listed in Table 1.20 An authentic
sample of natural product 2 was also tested against the
same panel. As a consequence it became clear that the
monoseco-analogues (6, 8, 10, and 12) of cryptopleurine
(2) are ca. three orders of magnitude less cytotoxic than
the parent compound while the related cis-stilbenes
show essentially no toxicity whatsoever. Furthermore,
the configuration (R vs S) at the single stereogenic center
within these analogues has essentially no impact on
activity. Clearly, then, the scission of the C8c–C15 bond
within the title natural products leads to derivatives with
dramatically reduced cytotoxicity profiles. The phe-
nanthrenes 13 and 14 also proved to be only weakly
cytotoxic.
The reaction sequence (Scheme 2) leading to the trim-
ethoxyphenanthrene 13 started with the condensation
of the commercially available aldehyde 26 and arylacetic
acid 27 under conditions defined by Oishi and Kurosa-
wa.15 The resulting a-arylcinnamic acid 28 (45%) was
decarboxylated by heating with copper(II) sulfate in
refluxing quinoline16 and the major product of the reac-
tion was the cis-stilbene 29 (70%), although this was
accompanied by small amounts (5%) of the correspond-
ing trans-isomer. Attempts to convert the former prod-
uct into the target phenanthrene 13 by treating it with
LiepaÕs reagent then TFA only resulted in the formation
of the trans-stilbene observed in the previous step. How-
ever, when an ether/dichloromethane solution of com-
pound 29 containing catalytic amounts of iodine was
irradiated with light from a medium-pressure mercury
vapor lamp17 the desired phenanthrene 1318 could be
obtained in 51% yield. The preparation of the N,N-
dimethylaminomethyl derivative, 14, of phenanthrene
13 involved initial conversion of the acid 28 into the cor-
responding N,N-dimethylamide 30 (68%) under stan-
dard conditions. LiAlH4-promoted reduction of the
latter compound to the corresponding amine 31 (74%)
The anti-angiogenic properties of compounds 5–14
were determined in an in vitro assay using rat aorta
blood vessel fragments.21 Unfortunately, solubility
problems prevented analogous testing of cryptopleu-
rine itself. Nevertheless, the results shown in Table 2
indicate that most of the analogues 5–12 completely
inhibited blood vessel growth at 100 lg/mL. Even
more significantly, compounds 6 and 8 also completely
inhibited blood vessel growth at the 10 lg/mL level,
while several others were still able to inhibit growth
by more than 50% at the 1 lg/mL level. It is worth
noting that every single one of these analogues of
alkaloids 1 and 2 is more active, at least at the
100 lg/mL level, than PI-88, a polysulfated oligosac-
charide which exhibits anti-angiogenic properties in vi-
vo and which is now in clinical development as an
agent for the treatment of certain cancers.22 A further
important facet of these results is that the phenanth-
renes seem to be more active than the corresponding
cis-stilbenes, while chirality has little or no impact
on the anti-angiogenic properties of the title ana-
logues. In addition, those phenanthrenes incorporating
a free hydroxy group are slightly less active than their
methoxy counterparts, perhaps because of a reduction
in their lipophilic properties. Interestingly, the phenan-
threne and aminomethyl subunits associated with
compounds 5–12 both seem to be making important
contributions to their anti-angiogenic properties as
judged by the test results observed for the simpler
analogues 13 and 14.
OMe
MeO
OMe
MeO
CHO
Ac2O,
Et3N
26
+
CO2H
CO2H
MeO
28
MeO
27
CuSO4,
quinoline
(COCl)2
then HNMe2
OMe
OMe
MeO
MeO
I2, hν
N
13
The origins of the significant anti-angiogenic proper-
ties of compounds 5–14 have not been established
thus far. However, the capacity of certain combretast-
atin A4 derivatives/analogues to act as vascular target-
ing agents, by binding to tubulin in newly formed
endothelial cells lining the tumor vasculature,23 sug-
gests this mode of action may be involved in the pres-
ent case. This situation, coupled with the considerable
interest in the possibility of separating any cytotoxic
activity of combretastatin-type compounds from
their ability to effect vascular shutdown,8,23b serves
to highlight the therapeutic potential of C8c–C15
O
MeO
MeO
OMe
30
29
LiAlH4
MeO
MeO
VOF3
thenTFA
N
14
31
Scheme 2.
Banwell, Martin G.
