Synthesis and cytotoxic evaluation of combretafurans, potential scaffolds for dual-action antitumoral agents

Article abstract of DOI:10.1021/jm060621o

We have synthesized rigid analogues of combretastatin bearing a furan ring in place of the olefinic bridge. These compounds are cytotoxic at nanomolar concentrations in neuroblastoma cells, display a similar structure-activity relationship compared to com

Full text of DOI:10.1021/jm060621o

5372
J. Med. Chem. 2006, 49, 5372-5376
Brief Articles
Synthesis and Cytotoxic Evaluation of Combretafurans, Potential Scaffolds for Dual-Action
Antitumoral Agents
Tracey Pirali,†,‡ Sara Busacca,†,‡ Lorena Beltrami,† Daniela Imovilli,† Francesca Pagliai,† Gianluca Miglio,† Alberto Massarotti,†
Luisella Verotta,§ Gian Cesare Tron,*,† Giovanni Sorba,† and Armando A. Genazzani†
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and Drug and Food Biotechnology Center, UniVersita` degli
Studi del Piemonte Orientale “A. AVogadro”, Via BoVio 6, 28100 NoVara, Italy, and Dipartimento di Chimica Organica e Industriale,
UniVersita` degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
ReceiVed May 24, 2006
We have synthesized rigid analogues of combretastatin bearing a furan ring in place of the olefinic bridge.
These compounds are cytotoxic at nanomolar concentrations in neuroblastoma cells, display a similar
structure-activity relationship compared to combretastatin A4, and inhibit tubulin polymerization. We also
show that the furan ring can be further functionalized. Thus, it is possible that combretafurans could act as
scaffolds for the development of dual-action antitumoral agents.
Introduction
The neovasculature typical of solid tumors has recently
become a primary target for the development of new drugs,
and a number of the agents that have already entered clinical
trials disrupt the microtubule complex by interacting with
â-tubulin.1,2 Among the drugs that possess specificity for
Figure 1. Combretastatin A4 (1) and combretafurazan (2).
neovasculature and that interact with tubulin is combretastatin
A43,4 (CA-4) (1) (Figure 1), whose phosphate prodrug has
entered clinical trials.3 The structure-activity relationship of
CA-4 is well-characterized.3 In brief, the cis configuration of
the double bond is fundamental, as are the 3,4,5-trimethoxy
groups on ring A. The cis olefinic bridge is able to undergo
rapid cis-trans isomerization under the influence of heat, light,
and protic media. In light of this, and with the attempt to render
compounds more stable, a conspicuous number of cis-restricted
analogues have been synthesized and shown to retain similar
biological activity compared to combretastatin. Indeed, as one
would expect, some are even more potent.5,6 For example, we
have recently shown that substitution of the olefinic bridge with
a furazan ring gives analogues with an identical mechanism of
action and a modest increase in potency (e.g., 2).7 In the present
manuscript we decided to exploit this finding to generate
chimeric drugs that might bear a second functional group or
might bear a cell-targeting residue. If this were achieved, for
example, it could be conceivable to develop a chimeric drug
that targets both the vasculature and the surrounding tumoral
tissue (including the rim, which is thought to rely on the
vasculature from the surrounding healthy tissue)8,9 or to direct
the drug to a target different from the neovasculature (i.e., the
solid tumor itself or a hematologic tumor with the use of a
monoclonal antibody). Because of the impossibility of using
furazan itself, we opted to investigate whether furan, a substitut-
able ring, could also mimic the olefinic bridge. Indeed, the furan
ring might be considered a bioisosteric group of the furazan
ring with Grimm’s substitution between the nitrogen sp2 atom
and the carbon sp2 atom. Furthermore, furan rings can be easily
functionalized through electrophilic aromatic substitution, while
furazan rings are unable to undergo the same reaction.
In the present manuscript we show that combretafurans 7a,
8a, 8b, synthesized through an intramolecular aldolic condensa-
tion as the key step, are active and can be functionalized at the
2 and 5 positions, rendering them a putative novel scaffold for
designing a generation of dual-acting combretastatins.
Chemistry
The furan nucleus was prepared in the following manner.
2-Oxo-2-phenylethyl 2-phenylacetate derivatives (5a-d) were
prepared by reacting the salt of 3,4,5-trimethoxyphenylacetic
(3) acid with the corresponding monobromine derivative of ace-
tophenone (4a-d). The lactone ring was then prepared by an
intramolecular aldolic condensation starting from derivatives
5a-d (for similar approaches, see refs 10-12). Finally, the R,â
unsaturated lactone was treated with the reducing agent DIBAL-H
to give the desired furan derivatives (Scheme 1).
The formation of the desired unsaturated lactones 6a-d was
rather capricious, requiring a careful choice of the base and of
the reaction conditions because initial attempts failed to be
reproducible. Indeed, we were also able to separate, alongside
the desired unsaturated lactone, 3,4-diphenyl-2,5-furandione (9)
and 5-hydroxy-3,4-diphenyl-2(5H)-furanone derivatives (10)
(see Supporting Information for structures).13,14 It appeared quite
clear that the presence of molecular oxygen and the base used
played a pivotal role in directing the formation of the products.
For these reasons, we surveyed a series of bases that differed
for strength. Bases with a pKa lower than 13 (e.g., TEA, DIPEA,
* To whom correspondence should be addressed. Phone: +39-0321-
375857. Fax: +39-0321-375821. E-mail: tron@pharm.unipmn.it.
† Universita` degli Studi del Piemonte Orientale “A. Avogadro”.
‡ These authors contributed equally to the present work.
§ Universita` degli Studi di Milano.
10.1021/jm060621o CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/29/2006

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5373
Scheme 1a
a Reagents and conditions: (a) TEA, CH3CN; (b) KOH, 18-crown-6, CH3CN; (c) DIBALH, THF, -10 °C; (d) Zn, CH3COOH (8a); tosic acid, methanol
(8b).
Scheme 2a
DBU)11,15 failed to promote the cyclization, while bases with
pKa values higher than 16 (e.g., t-BuOK, NaH)12,16,17 favored
the deprotonation of the lactone, which subsequently reacted
with oxygen or other electrophilic sites present in the reaction
mixture. A good compromise was obtained by using finely
pulverized potassium hydroxide (pKa ≈ 15.7) and a catalytic
amount of 18-crown-6 ether in acetonitrile, previously degassed
in order to remove the presence of oxygen. The reaction had to
be carefully monitored to obtain higher yields. The reaction
1
mixture was monitored by H NMR, since separation in thin-
layer chromatography was unsatisfactory. Under these experi-
mental conditions, we were able to reproduce and scale up the
reaction successfully, obtaining the desired unsaturated lactone
in moderate to good yields (40-80%). The resulting lactone
was treated at low temperatures (-10 °C) with a solution of
DIBAL-H in dry THF, yielding, after acidic workup, the desired
combretafuran derivatives.18,19
a Reagents and conditions: (a) PCl3, DMF; (b) 2-(4-carboxybutanoyl-
)hydrazinium hydrochloride, EtOH/CH2Cl2.
The synthesis of combretafurans bearing a methoxy (7a), a
dioxolane ring (7b), a 4-methoxy-3-nitro (7c), or a 4-methoxy-
3-amino group (8a) on ring B is reported in Scheme 1.
The diastereoisomeric pair structures were assigned through
two NOESY experiments, optimized with a mixing time of 1.2
s. Cross-coupling of spatially related protons was clearly visible;
in 12 the aldehyde proton gave NOE with protons 2 and 6, while
the furan proton gave NOE with protons 2′ and 6′. In contrast,
in 13 the furan proton gave NOE with protons 2 and 6 and the
methoxy groups at 3 or 5, while the aldehydic proton gave NOE
with protons 2′ and 6′.
Last, the hydroxyl substituted combretafuran 8b was prepared
starting from the Mem-protected derivative 4d as outlined in
the same Scheme 1. Mem deprotection was successfully
accomplished using catalytic amounts of tosic acid in MeOH.
A very mild condition was necessary because furans undergo
hydrolysis to dicarbonylic compounds in an acidic environment.
Last, we decided, as proof of principle, to synthesize an acid-
labile hydrazone derivative of 13 to verify the potential of our
novel scaffold to yield 14 (Scheme 2).20
The products obtained were evaluated for cytotoxicity and
antitubulinic action (see Biological Results and Discussion) and
after establishment of their activity, the furan nucleus was
functionalized by introducing a formyl group. To avoid the
presence of two regioisomers, initial attempts were performed
using a new combretafuran bearing a methyl group at the 2
position (11) (see Supporting Information for structure). Un-
fortunately, this derivative appeared quite unstable and unsuit-
able for further derivatization. We next turned our attention to
7a, which, although 10 times less cytotoxic then 8b, presents
an easier synthetic accessibility. Formylation of 7a using the
Vilsmeier-Haack protocol (PCl3, DMF) afforded the two
regioisomers (12 and 13) in excellent yields. These were
subsequently separated by column chromatography and HPLC
(Scheme 2).
Biological Results and Discussion
To evaluate the cytotoxic nature of the synthesized com-
pounds, we used a neuroblastoma cell line (SH-SY5Y) that we
had previously characterized as sensitive to combretastatin A4.
We incubated increasing concentrations of 1 and its analogues
for 48 h to establish the IC50 for the cell death of each compound
(Table 1). Compound 1 yielded an IC50 of 1.6 ( 0.1 nM, a
value similar to the one reported previously in this model.7
Combretafuran 7a, which resembles combretastatin except for
the absence of the hydroxyl group on ring B, displayed an IC50
for cytotoxicity of 39 ( 8.9 nM, thereby demonstrating the
potent nature of this novel class of analogues. For combre-

5374 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Brief Articles
Table 1. Dose concentration Data of Combretastatin A4 (1) and
Combretafuran Analogues on SH-SY5Y Cell Linea
compd
IC50, nM
compd
IC50, nM
1
1.6 ( 0.10
39 ( 8.9
244.54 ( 150
5.1 ( 0.7
8b
12
13
14
2.9 ( 0.33
35.8 ( 20
231 ( 72
7a
7c
8a
1670 ( 783
a Values are the mean ( SEM of 8-23 determinations.
tafurans, the reported SAR for the meta position of ring B5 was
maintained, with the analogue bearing the hydroxyl group being
the most potent (8b, 2.9 ( 0.33 nM), the compound bearing
the amino group displaying a slightly superior IC50 (8a, 5.1 (
0.7 nM), and the analogue bearing the nitro group (7c)
displaying an IC50 between 100 nM and 1 µM. We also tested
7b, which presents a dioxolane moiety on ring B, but this
compound was inactive up to 1 µM. Therefore, combretafuran
8b that most closely resembles combretastatin displays just a
2-fold loss of cytotoxic action. To confirm a similar mechanism
of action, we performed the in vivo tubulin polymerization
assay.7,21 This assay relies on the incubation of high amounts
of inhibitor (50-fold the IC50) overnight and extraction of the
proteins in the presence of paclitaxel to freeze tubulin poly-
merization. Indeed, 7a, at 1.5 µM (50-fold the IC50) behaved
identically to 1 (50 nM, 50-fold the IC50; see Supporting
Information). To further confirm this, we evaluated whether 8b,
the compound that most closely resembles 1, behaved identically
to its parent compound in the in vivo tubulin polymerization
assay and in a cell cycle analysis, as one would expect. As
expected, 8b behaved identically to 1 (data not shown), while
paclitaxel exerted the opposite effect (see Supporting Informa-
tions) in the in vivo tubulin polymerization assay. It is well-
known that 1 induces a G2/M arrest of the cell cycle, and this
was confirmed in our experiments (Figure 2). Surprisingly, 8b
did not elicit any significant alteration of the cell cycle (Figure
3) (see Supporting Informations for numeric analysis). Similar
cell cycle profiles were obtained in cells treated with 7a (data
not shown). In summary, combretafurans are active as cytotoxic
agents and inhibit tubulin polymerization but does not appear
to share the G2/M block of combretastatin, thereby suggesting
a distinct mechanism of action, which may or may not rely on
tubulin.
Since the cytotoxic potency of these compounds was retained,
we therefore decided to investigate the properties of the
compounds bearing a formyl group in position 2 (12) or 5 (13)
of the furan ring. Both these compounds were cytotoxic, with
12 displaying an identical IC50 (35.8 ( 20 nM) and 13 showing
a loss of approximately 6.5-fold reduction (231 ( 72 nM)
compared to 7a (the reference compound, since it lacks the
hydroxyl group). In our hands, the dose response of combret-
astatin and combretafurans shows a Hill slope between 1 and
2. While this was retained for 12, the Hill slope for 11 was
reproducibly higher, suggesting that this compound possesses
a cytotoxic effect distinct from those of the other compounds.
To strengthen these data, we performed immunocytochemistry
with an antitubulin antibody to visualize the disruption of the
cytoskeleton with these drugs. Indeed, 1, 8b, and 13 at the IC50
concentration for 24 h induced a disruption of the cytoskeleton
that brought cells to round up, while 12 did not induce any
change in tubulin organization (see Supporting Information).
Surprisingly, both compounds were able to induce tubulin
depolymerization in the in vivo polymerization assay (see
Supporting Information). As a proof of principle, to explore
the potential of the furan ring to act as scaffold, thereby allowing
the generation of chimeric drugs, mutual prodrugs, or targeted
Figure 2. Cell cycle analysis of neuroblastoma cells treated for 16 h
with the indicated compounds at the IC50 concentration. Graphs are
representative of at least three experiments that yielded similar results.
compounds, we functionalized this position with a hydrazonic
linker. It is well-known that these linkers are highly stable at
physiological pH but undergo rapid hydrolysis at pH 5.5.20
Because of our perplexity on the mode of action of 12, we
decided to develop 13. This modification (14) was cytotoxic,
although a 7-fold loss of activity compared to 13 (1.6 ( 0.7
µM) was observed. Indeed, 14 elicited an effect identical to
that of 1 in the tubulin assay (i.e., depolymerization of tubulin;
see Supporting Information).
Conclusions
The series of compounds we have synthesized are cytotoxic
and inhibit tubulin polymerization. The potential potency of
these compounds can be derived from the fact that 8b, which
resembles 1 except for the furan ring in place of the olefinic
bridge, displays a cytotoxic potential of comparable strength.
Further modifications, such as the addition of the formyl moiety,
yield a moderate loss of potency. Considering the fact that these
compounds are for designing scaffolds for chimeric or mutual
prodrugs, a loss of potency might be regarded as beneficial. In
fact, chimeric or mutual prodrugs rely on the fact that the two
drugs should be balanced in potency to allow both actions to
take place. The potency of 1 (low nanomolar) makes it difficult
therefore to generate well-balanced hybrids, while 13 might
allow for the use of a less potent drug (indeed, most drugs used
in clinical settings at present). Indeed, one initial attempt by us
to generate hybrids has failed for this very reason.22 Furthermore,
substitutions of the meta position on ring B with a hydroxyl or
a nitro will also allow for a dynamic range of activity. All these
compounds do not appear to interfere with the cell cycle, raising

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5375
solution was diluted with ether and the oganic layer was washed
with water (×1) and brine (×1). After drying over sodium sulfate
and evaporation of the solvent, the crude furan was purified by
column chromatography using 8:2 PE/EtOAc as eluant to obtain
7a as a pale-yellow solid (1.2 g, 76%).
the question of which is the cytotoxic mechanism of action of
these drugs. Indeed, it has been previously shown that some
combretastatin analogues can maintain cytotoxic potential while
losing antitubulin activity.5 Whether this is the case here is
unclear, since we are able to see an effect on tubulin poly-
merization. It will nonetheless be interesting to explore further
whether these drugs retain their angiotoxic potential or whether
their in vivo pattern of activity will be radically modified.
4-(4-Methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-2-furalde-
hyde (12) and 3-(4-Methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-
2-furaldehyde (13). PCl3 (147 µL, 232 mg, 1.69 mmol, 1.1 equiv)
was slowly added to dry DMF (3 mL), maintaning the temperature
below 30 °C. The solution became rapidly red. 3-(4-Methoxyphe-
nyl)-4-(3,4,5-trimethoxyphenyl)furan (522 mg, 1.53 mmol, 1 equiv),
dissolved in dry DMF (5 mL), was carefully added, and the resulting
solution was heated at 60 °C for 1 h, worked up by dilution with
EtOAc, and washed with water (×1). The water phase was extracted
thrice with EtOAc. The combined organic phases were then washed
with brine (×1) and dried over sodium sulfate. After evaporation,
the crude mixture was purified by column cromatography using as
eluant 8:2 PE/EtOAc. The mixture obtained was further purified
by HPLC (HiCHROM Kromasil silica, 250 mm × 21.2 mm × 10
µm; 7:3 PE/EtOAc; 6 mL/min; λ ) 254 nm) to give 12 (185 mg,
32.7%) and 13 (191 mg, 33.7%) as yellowish solids.
5-(2-{-[3-(4-Methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-2-
furyl]methylidene}hydrazino)-5-oxopentanoic Acid (14). To a
solution of 13 (106 mg, 0.288 mmol, 1 equiv) in ethanol (2 mL;
some drops of dry CH2Cl2 were added to improve the solubility of
the product), 2-(4-carboxybutanoyl)hydrazinium hydrochloride
(105.4 mg, 0.58 mmol, 2 equiv) was added. The mixture was stirred
at room temperature for 1 h, and the solvent was evaporated. The
crude product was purified by column chromatography, using 5:5
PE/EtOAc and EtOAc as eluant to give 14 (E/Z, 5:1mixture) as a
yellow solid (50 mg, 35%).
Experimental Section
Chemistry. Commercially available reagents and solvents were
used without further purification and were purchased from Fluka-
Aldrich or Lancaster. Dichloromethane was dried by distillation
from P2O5 and stored on activated molecular sieves (4 Å).
Acetonitrile was dried on CaH and stored on activated molecular
sieves (4 Å). Tetrahydrofuran (THF) and diethyl ether were distilled
immediately before use from Na/benzophenone under a slight
positive atmosphere of N2. Dimethylformamide (DMF) was purified
by distillation at reduced pressure, collecting the fraction having a
bp of 76 °C at 39 mmHg and storing it on activated molecular
sieves (4 Å). When needed, the reactions were performed in flame-
or oven-dried glassware under a positive pressure of dry N2.
Melting points were determined in an open glass capillary with
a Stuart scientific SMP3 apparatus and are uncorrected. All the
compounds were checked by IR (FT-IR Thermo Nicolet Avatar),
1H and 13C NMR (JEOL ECP, 300 MHz), and mass spectrometry
(Thermo Finningan LCQ-deca XP-plus), with the instrument being
equipped with an ESI source and an ion trap detector. NOE
experiments were performed on a Bruker Avance 500 MHz
instrument equipped with a 5 mm QNP multinuclear probe.
Chemical shifts are reported in part per million (ppm). Column
chromatography was performed on silica gel (Merck Kieselgel 70-
230 mesh ASTM) using the indicated eluants. Thin-layer chroma-
tography (TLC) was carried out on 5 cm × 20 cm plates with a
layer thickness of 0.25 mm (Merck silica gel 60 F254). When
necessary, they were developed with KMnO4. HPLC was carried
out on Jasco Borwin HERCULE lite apparatus. Elemental Analysis
(C, H, N) of the target compounds were performed by Universita`
dell’Insubria (Como, Italy) and are within (0.4% of the calculated
values unless otherwise noted. Compounds 4b,23 1-(3-hydroxy-4-
methoxyphenyl)-1-ethanone,24 2-bromo-1-(3-hydroxy-4-methoxy-
phenyl)-1-ethanone,25 and 2-(4-carboxybutanoyl)hydrazinium hy-
drochloride26 were synthesized as reported in the literature.
2-(4-Methoxyphenyl)-2-oxoethyl 2-(3,4,5-Trimethoxyphenyl)-
acetate (5a). To a cooled (0 °C) solution of trimethoxyphenylacetic
acid (5 g, 0.022 mol, 1 equiv) in CH3CN (50 mL), TEA (3.1 mL,
2.2 g, 0.022 mol, 1 equiv) and 2-bromo-1-(4-methoxyphenyl)-1-
ethanone (4a) (5 g, 0.002 mol, 1 equiv) were added. The resulting
solution was stirred for 4 h at 0 °C, worked up by dilution with
EtOAc and washed sequentially with 2 N HCl (×1), saturated
aqueous NaHCO3 (×2), and brine (×1). The organic layer was dried
over sodium sulfate. Filtration and evaporation of the solvent gave
5a as white solid, which was used directly without further
purification (6.8 g, 83%).
Acknowledgment. Financial support from Universita` del
Piemonte Orientale and Regione Piemonte is gratefully ac-
knowledged.
Supporting Information Available: Synthesis procedures of
1
all other compounds, their characterization (mp, IR, MS, and H
and 13C NMR data), structures of 9-11, elemental analysis results
of all target compounds, concentration response curves for the target
compounds, representative results of the in vivo polymerization
assay, and immunocytochemistry of tubulin in treated cells. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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