Isocombretastatins A versus combretastatins A: The forgotten isoCA-4 isomer as a highly promising cytotoxic and antitubulin agent

Article abstract of DOI:10.1021/jm900321u

Herein is reported a convergent synthesis of isocombretastatins A, a novel class of potent antitubulin agents. These compounds having a 1,1-diarylethylene scaffold constitute the simplest isomers of natural Z-combretastatins A that are easy to synthesize

Full text of DOI:10.1021/jm900321u

4538 J. Med. Chem. 2009, 52, 4538–4542
DOI: 10.1021/jm900321u
Isocombretastatins A versus Combretastatins A: The Forgotten isoCA-4 Isomer as a Highly Promising
Cytotoxic and Antitubulin Agent
†
Samir Messaoudi, Bret Treguier, Abdallah Hamze, Olivier Provot, Jean-Franc-ois Peyrat, Jordi Rodrigo De Losada,
†
†
†
†
†
ꢀ
‡
‡
‡
‡
‡
†
ꢀ ^
Jian-Miao Liu, Jerome Bignon, Joanna Wdzieczak-Bakala, Sylviane Thoret, Joelle Dubois, Jean-Daniel Brion, and
,†
^
Mouad Alami*
†
ꢀ
ꢀ
ꢀ
Univ Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Therapeutique, Faculte de Pharmacie, 5 rue J.-B. Clement,
^
‡
Chatenay-Malabry F-92296, France, and Institut de Chimie des Substances Naturelles (ICSN), UPR 2301 CNRS, Avenue de la Terrasse,
F-91198 Gif-sur-Yvette, France
Received March 25, 2009
Herein is reported a convergent synthesis of isocombretastatins A, a novel class of potent antitubulin
agents. These compounds having a 1,1-diarylethylene scaffold constitute the simplest isomers of natural
Z-combretastatins A that are easy to synthesize without need to control the Z-olefin geometry. The
discovery of isoCA-4 with biological activities comparable to that of CA-4 represents a major progress
in this field.
Introduction
lossofpotency in the cytotoxicity assays(ED50=900 nM) and
CA-6 was essentially inactive. Furthermore, combretastatins
A-1 to A-4 were identified as potent inhibitors of tubulin
polymerization at the micromolar concentration (2-5 μM)
due to their ability to rapidly bind to tubulin at the colchicine
site. The recent interest in the anticancer potential of the
combretastatin A-series has gained momentum following the
observation that CA-4 and CA-1 induce rapid and reversible
vascular shutdown in established tumors in vivo, consistent with
an antivascular mechanism of action.7 The water-soluble pro-
drugs CA-4P and CA-1P have reached the most advanced stage
of preclinical development. Currently, CA4-P8 either as a single
agent or in combination therapy is undergoing several advanced
clinical trials worldwide for the treatment of age-related macular
degeneration (AMD) or anaplastic thyroid cancer.9
The relative simplicity of the 1,2-diarylethylene scaffold of
combretastatin A-series, along with their biological proper-
ties, resulted in extensive structure-activity relationship
(SAR) studies.10 In fact, over the past decade, the literature
search, with regard to combretastatins, has exploded, and just
for the last five years, more than 250 publications and 170
patents concern combretastatins, many of which show the
greatinterest in the discovery of new small molecules targeting
tubulin assembly.
In spite of these SAR studies and the impressive number of
analogues synthesized (>28000), only the CA-4 and CA-1
remain the most promising molecules as their prodrugs, CA-
4P and CA-1P, have a significant impact on the clinical
management of cancer.9
Despite their remarkable therapeutic interest, these
Z-natural stilbene compounds are prone to double-bond
isomerization during storage and administration, leading to
the E-isomer, which dramatically displayed a reduced inhibi-
tion of cancer cell growth and tubulin assembly.11 It should be
noted that the third isomer of the combretastatin A-series,
named isocombretastatins A (isoCA), has never been stu-
died despite the impressive number of synthetic analogues.
The discovery of natural substances capable of interfering
with the assembly or disassembly of microtubules has drawn
much attention because microtubules are recognized as an
attractive pharmacological target for anticancer drugs.1,2
Natural substances that are able to modulate the microtubule
assembly can be broadly divided into two groups. In the first
one, paclitaxel, currently used in the treatment of ovarian and
breast cancer, is well-known to promote the polymerization of
microtubules, resulting in highly stable, nonfunctional as-
sembled microtubules.3 In contrast to taxanes, the vinca
alkaloids (e.g.; vincristine, vinblastine, etc.), dolastatins as
well as colchicine inhibit microtubule assembly.4 However, all
these complex molecules have limitations resulting from high
toxicity, difficulty of synthesis, and some of them become
rapidly prone to resistance phenomena.5 Among the large
class of natural substances known as inhibitors of tubulin
assembly, combretastatins A-1 to A-6, isolated from the
African willow tree Combretum caffrum, are currently the
simplest structures and have attracted the attention of many
medicinal chemists for the rational design of antitubulin
agents (Figure 1).6 The cell growth inhibition of combretas-
tatins of the series A-1 to A-6 was evaluated in vitro in a panel
of 60 human tumor cell lines.6c The most potent member of
these natural stilbenes family is CA-4 (GI50=3.2 nMa), while
CA-1 (GI50=16.2 nM) and CA-2 (GI50=31.6 nM), respec-
tively, were about one-fifth and one-tenth as potent as CA-4.
In another study,6b CA-3 was found to retain significant
growth cell inhibition against the murine P-388 lymphocytic
leukemia (ED50=26 nM), while CA-5 displayed a significant
*To whom correspondence should be addressed. Phone: 33(0)
1.46.83.58.87. Fax: 33(0)1.46.83.58.28. E-mail: mouad.alami@u-psud.
fr.
aAbbreviations: CA, combretastatin A; isoCA, isocombretastatin A; IC50, the
half maximal inhibitory concentration; GI50, the half maximal growth inhibitory
concentration; ED50, the half maximal effective dose concentration).
r
pubs.acs.org/jmc
Published on Web 06/16/2009
2009 American Chemical Society

Brief Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4539
Figure 1. Combretastatins A, synthetic tubulin assembly inhibitor phenstatin (1), and structures of the synthesized isocombretastatins A-1 to
A-5 (isoCA).
Scheme 1a
Table 1. Cytotoxicity of isoCA on the Human Cancer Cell Lines and
Antitubulin Activities
IC50 [nM]a
MDA-
MB231
ITP IC50
[μM]b
HCT116
K562
H1299
phenstatin
colchicine
CA-4
33
32
41
29
21
30
28
26
2.0
2.1
1.0
2.1
3.4
5.0
2.2
NAc
2.3
850
38
3.6
750
38
5.0
3.0
820
48
isoCA-1
isoCA-2
isoCA-3
isoCA-4
isoCA-5
2000
32
34
2.5
2800
52
5.0
3100
25
8
5.0
4.0
3000
5000
a IC50 is the concentration of compound needed to reduce cell growth
by 50% following 72 h cell treatment with the tested drug (average of
three experiments). b ITP=Inhibition of tubulin polymerization; IC50 is
the concentration of compound required to inhibit 50% of the rate of
microtubule assembly (average of three experiments). c Nonactive.
coupling with appropriate aryl halides 4, 5, and 10 furnished
after alkaline deprotection the desired isoCA-2 to isoCA-5 in
good yield (Scheme 1). It should be noted that isoCA-5 is
either the isomer of position of the CA-5 or its trans isomer
CA-6.
a Reagents and conditions: (a) TsNHNH2, EtOH, reflux. (b) ArX,
Pd2(dba)3, Xphos, tBuOLi, dioxane, 70 °C. (c) K2CO3, MeOH. (d) (i)
n-BuLi, THF, -78 °C then MeCHO; (ii) PCC, CH2Cl2, 20 °C.
Moreover, isoCA derivatives share a structural similarity with
phenstatin, a very strong anticancer substance serendipitously
discovered12 (Figure 1) and, therefore, could potentially be an
attractive class of compounds for cancer treatment.
Results and Discussion
The isocombretastatins A-1 to A-5 were evaluated for their
cytotoxic activities against four types of human cell lines,
human colon carcinoma HCT116 cells, chronic myelogenous
leukemia K562 cells, nonsmall lung human carcinoma H1299
cells, and human breast cancer MDA-MB231 cells. The
results of this study summarized in Table 1 demonstrated that
the newly synthesized isoCA-4 exhibited approximatively a
10-fold greater cytotoxic activity (nanomolar level) than that
of phenstatin and colchicine on the four tested cell lines.
Interestingly, isoCA-4 activity against the above cell lines is
comparable to the natural CA-415 isomer (2-5 nM). These
results suggest that switching an aromatic ring from the C2 to
the C1 position retained potent cytotoxicity and that, in this
series, the 1,1-ethylene bridge would be regarded as a bioisos-
tere16 of the Z-1,2-ethylene one. Next, other isocombretasta-
tins A were examined. Again, isoCA-2 and isoCA-3 showed
strong cytotoxicities (IC50 values of 32-48 nM and 8-52 nM,
respectively), which are comparable to their CA-2 and CA-3
parents.6 Inverting a MeO substituent by a OH group on
the aromatics led to a dramatic reduction in cytotoxicity
when isoCA-4 and isoCA-5 were compared. The isoCA-5
In our efforts to discover novel tubulin assembly inhibi-
tors,13 we hypothesized that isocombretastatins A with 1,1-
diarylethylene scaffold could be as active as those of natural
combretastatins A. Here, we report on synthesis of isocom-
bretastatins A-1 to A-5 (Figure 1) and the evaluation of their
biological properties. This study would bring additional
information on the importance of the carbonyl oxygen of
phenstatin to form crucial interactions at the colchicine site
when compared to isoCA. The potencies of newly synthesized
isoCA were examined for their capacity to inhibit cancer cell
growth and to act as potential antimitotic agents.
Chemistry. Because the CA-4 is the most active compound
of the combretastatin A-series, we first focused our attention
on the synthesis of isoCA-4. Thus, the reaction of N-tosylhy-
drazone14 (3), readily available from 2, with aryl iodide (4) in
the presence of Pd2(dba)3 and Xphos provided the resulting
coupling product, which was subsequently desilylated under
alkaline media to obtain the target isoCA-4 (Scheme 1). In
the same way, starting from hydrazones 3, 7, and 9, the

4540 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Messaoudi et al.
cytotoxicity is comparable to that of the CA-5 parent product
but is 1000-fold less important than isoCA-4.
displayed by isoCA-2 (3.4 μM), isoCA-3 (5.0 μM), and the less
cytotoxic isoCA-1 (2.1 μM).
As combretastatin A-series have been well documented to
interact with tubulin, isocombretastatins A-1 to A-5 were
evaluated for their antitubulin assembly activities (Table 1).
According to our assumption about the similarity between the
natural isomer CA-4 and isoCA-4, the latter showed an
inhibition of tubulin assembly in the same order of magnitude
(2.2 μM) than that exhibited by CA-4 (1.0 μM) or colchicine
(2.1 μM). More interestingly, the activity of isoCA-4 is
comparable with that of phenstatin (2.0 μM) despite the
absence of the carbonyl function that was suggested to play
a positive role for strong antitubulin activity.17 This trend was
also observed by the level of the inhibition of tubulin assembly
The effects of the most active agent isoCA-4 on cell cycle
distribution were analyzed in K562 cells cultured for 24 h in
the presence of increasing amounts of isoCA-4. The results
presented in Figure 2 demonstrate a dose-dependent increase
in the proportion of cells in G2/M phase and the simultaneous
decrease in the number of cells in S and G1 phases, suggesting
that isoCA-4 induces selectively arrested cell division in the
G2/M phase of the cell cycle.
The X-ray crystal structure of isoCA-4 depicted in
Figure 3A shows that the conformation of the 1,1-diarylethy-
lene scaffold is not planar and the planes of the two aromatic
rings are inclined toward each other (dihedral angle=68°). A
similar nonplanarity was observed in the case of the natural
substance CA-4.18 It seems that in combretastatin A-series,
switching the trimethoxyaryl nucleus from the C(1) to the C(2)
position of the ethylene bridge preserves the spatial relationship
of the two aromatic rings (cis-relationship) in the 1,1-diaryl-
ethylene scaffold and, therefore, possibly could explain similar
activities exhibited by these substances.
Adopting the conformation found in its X-ray crystal
structure, isoCA-4 was computer docked inside the colchicine
binding site. For this purpose, the X-ray structure of tubulin-
colchicine complex (Code PDB: 1sa0)19 was used. Figure 3B
shows the docking-derived superimposition of isoCA-4, CA-
4, phenstatin, and colchicine (blue, green, red, and orange,
respectively). As expected, isoCA-4, CA-4, and phenstatin
show a nice fitting between them and the colchicine X-ray
structure into the binding site (Figure 3B). As previously
reported for a set of colchicine site inhibitors,17 the trimethox-
yphenyl moieties occupy very similar Cartesian space. Hydro-
xyl and methoxy groups belonging to the rest of the system are
Figure 2. Effect of isoCA-4 on cell-cycle distribution in chronic
myelogenous leukemia K562 cells determined by flow cytometry
analysis. DNA content was assessed via propidium iodide staining.
Figure 3. (A) X-ray crystal structure of isoCA-4. (B) Putative binding mode of isoCA-4 (blue), CA-4 (green), phenstatin (red), and colchicine
(orange) in the colchicine binding site.
Figure 4. IsoCA-4 analogues 12 and 14 with a tri- and tetra-substituted double bonds.

Brief Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4541
also well fitted. Hydroxyl groups belong to CA-4, isoCA-4,
and phenstatin show a hydrogen bond with backbone of
Val181 as proposed by Nguyen et al.17
over MgSO4, and concentrated in vacuo to give a residue which
was purified by silica gel chromatography to yield isoCA. Purity
was determined by elemental analysis and HPLC; purity of key
target compounds isoCA-1 to isoCA-5 was >98%.
Because the 1,1-ethylene bridge appears to be a suitable
bioisosteric replacement for the Z-1,2-ethylene one in this
series, we attempted to extend this finding to other potent
antitubulin agents. We anticipated that substances 12 and 14
with a one-carbon sp2 bridge would be as active as their
known synthetic parent compounds 1120 and 1321 having a
tri- or tetra-substituted double-bond, respectively (Figure 4).
To this end, the synthetic strategy that allowed the prepara-
tion of 12 and 14 utilized a Wittig olefination of phenstatin
silyl ether intermediate12 with the appropriate ylides followed
by an O-desilylation step. The substances 12 and 14 were then
evaluated for their cytotoxic effects against HCT116 cell lines
and for tubulin polymerization inhibitory activity using CA-4
as reference compound (Figure 4). Diarylacrylonitrile 12
related to CC-507922 was tested as a mixture of E and Z
isomers (1/1) and was found to exhibit a high activity with an
IC50 of 3.0 nM (IC50 = 2.3 nM for CA-4) and difluorinated
substance 14 showed almost the same activity as the parent
compound 13 (H460 nonsmall cell lung carcinoma). Interest-
ingly, 12 and 14 displayed strong antitubulin activities with
IC50 of 4.3 and 2.5 μM, respectively. These results clearly
demonstrate that the modification made on the ethylene
bridge maintains cytotoxic and antitubulin polymeri-
zation activities and, consequently, validate our bioisosteric
replacements wherein a 1,1-ethylene moiety mimics a Z-1,2-
ethylene one.
Acknowledgment. We thank the CNRS for support of this
research and the ICSN for a doctoral fellowship to B.T.
Supporting Information Available: Typical experimental pro-
cedure, analytical data, crystallographic information files (CIF),
1
modeling programs, H, 13C NMR, and MS data of new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) Alami, M.; Brion, J.-D.; Provot, O.; Peyrat, J.-F.; Messaoudi, S.;
Hamze, A.; Giraud, A.; Bignon, J.; Bakala, J.; Liu, J.-M. IsoCA-4
and analogues thereof as potent cytotoxic agents inhibiting tubulin
polymerization. Patent WO 122620 A1, 2008.
(2) Hadfield, J. A.; Ducki, S.; Hirst, N.; McGown, A. T. Tubulin and
microtubules as targets for anticancer drugs. Prog. Cell Cycle Res.
2003, 5, 309–325.
(3) Schiff, P. B.; Fant, J.; Horwitz, S. B. Promotion of microtubule
assembly in vitro by taxol. Nature 1979, 277, 665–667.
(4) Bhattacharayya, B.; Panda, D.; Gupta, S.; Banerjee, M. Antimi-
totic activity of colchicine and the structural basis for its inter-
action with tubulin. Med. Res. Rev. 2008, 28, 155–183.
(5) Jordan, M. A. Mechanism of action of antitumor drugs that
interact with microtubules and tubulin. Curr. Med. Chem. Antic-
ancer Agents 2002, 1, 1–17.
(6) (a) Pettit, G. R.; Singh, S. B.; Niven, M. L.; Hamel, E.; Schmidt,
J. M. Isolation, structure, and synthesis of combretastatins A-1 and
B-1, potent new inhibitors of microtubule assembly, derived from
Combretum caffrum. J. Nat. Prod. 1987, 50, 119–131. (b) Pettit,
G. R.; Singh, S. B. Isolation, structure, and synthesis of com-
bretastatin A-2, A-3, and B-2. Can. J. Chem. 1987, 65, 2390–2396.
(c) Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.;
Schmidt, J. M.; Hogan, F. Antineoplastic agents. 291. Isolation
and synthesis of combretastatins A-4, A-5, and A-6. J. Med. Chem.
1995, 38, 1666–1672.
(7) Tozer, G. M.; Kanthou, C.; Parkins, C. S.; Hill, S. A. The biology
of the combretastatins as tumour vascular targeting agents. Int. J.
Exp. Pathol. 2002, 83, 21–38.
(8) Siemann, D. W.; Chaplin, D. J.; Walicke, P. A. A review and
update of the current status of the vasculature-disabling agent
combretastatin-A4 phosphate (CA4P). Expert Opin. Investig.
Drugs 2009, 18, 189–197.
(9) (a) Patterson, D. M.; Rustin, G. J. S. Combretastatin A-4 phos-
phate. Drugs Future 2007, 32, 1025–1032. (b) Lippert, J. W.
Vascular disrupting agents. Bioorg. Med. Chem. 2007, 15, 605–615.
(10) Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.; Dusacca, S.;
Genazzani, A. A. Medicinal chemistry of combretastatin A4:
present and future directions. J. Med. Chem. 2006, 49, 3033–3044.
(11) Pettit, G. R.; Toki, B.; Herald, D. L.; Boyd, M. R.; Hamel, E.;
Pettit, R. K.; Chapuis, G. C. Antineoplastic Agents. Asymmetric
Hydroxylation of trans-Combretastatin A-4. J. Med. Chem. 1999,
42, 1459–1465.
(12) Pettit, G. R.; Toki, B.; Herald, D. L.; Verdier-Pinard, P.; Boyd,
M. R.; Hamel, E.; Pettit, R. K. Antineoplastic agents. 379. Syn-
thesis of phenstatin phosphate. J. Med. Chem. 1998, 41, 1688–1695.
(13) (a) Provot, O.; Giraud, A.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
Synthetic approach to enyne and enediyne analogues of anticancer
agents. Tetrahedron Lett. 2005, 46, 8547–8550. (b) Mousset, C.;
Giraud, A.; Provot, O.; Hamze, A.; Bignon, J.; Liu, J. M.; Thoret,
S.; Dubois, J.; Brion, J.-D.; Alami, M. Synthesis and antitumor
activity of benzils related to combretastatin A-4. Bioorg. Med.
Chem. Lett. 2008, 18, 3266–3271.
Conclusion
In the present study, we have described the synthesis and
identification of active 1,1-diarylethylenes, named isocombre-
tastatins A, with strong anticancer activities. These com-
pounds, in contrast to their parent 1,2-diarylethylene
derivatives, are easy to synthesize without the need to control
the olefin geometry and constitute the simplest isomers of
natural combretastatins A. The most active agent, isoCA-4,
shares a striking structural similarity with phenstatin and
displayed a 10-fold better cytotoxic activity (2 nM). More-
over, isoCA-4 appears to elicit its cytotoxicity in a fashion
similar to CA-4, via inhibition of tubulin polymerization,
which then leads to cell cycle arrest in G2/M.1
As the replacement of the 1,2-ethylene by the 1,1-ethylene
bridge resulted in retention of biological activities, our results
may encourage the use of this scaffold in future structure-
activity relationship studies. All of this data make these
compounds worthy of further in vitro and in vivo investiga-
tion. The design of other antitumor agents based on the above
findings is currently underway; the results of synthetic and
biological studies will be reported in due course.
Experimental Section
Procedure for the synthesis of isoCA-1 to isoCA-5. To a
dioxane (6 mL) solution of N-tosylhydrazone (0.42 mmol),
tBuOLi (84 mg, 1.05 mmol), Pd2dba3 (44 mg, 0.042 mmol),
and X-Phos (40 mg, 0.084 mmol) was added the aryl halide
(0.42 mmol) in dioxane (1 mL). The mixture was stirred at 75 °C
for 5 h. CH2Cl2 (10 mL) was addedtothe cooledmixtureandthen
filtered over a pad of celite. After concentration, the residue
was dissolved in MeOH (3 mL), K2CO3 (116.0 mg, 0.84 mmol)
was added, and stirring was continued for 2 h. Water (10 mL) was
added and the aqueous phase was extracted with Et2O (3 Â
10 mL). The organic phase was washed with brine (15 mL), dried
ꢀ
(14) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. N-Tosylhydrazones
as reagents for cross-coupling reactions: a route to polysubstituted
olefins. Angew. Chem., Int. Ed. 2007, 46, 5587–5590.
(15) Giraud, A.; Provot, O.; Hamze, A.; Brion, J. D.; Alami, M. One-
pot hydrosilylation-protodesilylation of functionalized diarylalk-
ynes: a highly selective access to Z-stilbenes. Application to the
synthesis of combretastatin A-4. Tetrahedron Lett. 2008, 49, 1107–
1110.
(16) Patani, G. A.; LaVoie, E. J. Bioisosterism: a rational approach in
drug design. Chem. Rev. 1996, 96, 3147–3176.

4542 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Messaoudi et al.
(17) Nguyen, T. L.; McGrath, C.; Hermone, A. R.; Burnett, J. C.;
Zaharevitz, D. W.; Day, B. W.; Wipf, P.; Hamel, E.; Gussio, R. A
common pharmacophore for a diverse set of colchicine site inhibi-
tors using a structure-based approach. J. Med. Chem. 2005, 48,
6107–6116.
Novel combretastatin analogues effective against murine solid
tumors: design and structure-activity relationships. J. Med. Chem.
1998, 41, 3022–3032.
(21) Alloatti, D.; Giannini, G.; Cabri, W.; Lustrati, I.; Marzi, M.;
Ciacci, A.; Gallo, G.; Tinti, M. O.; Marcellini, M.; Riccioni, T.;
Guglielmi, M. B.; Carminati, P.; Pisano, C. Synthesis and biologi-
cal activity of fluorinated combretastatin analogues. J. Med. Chem.
2008, 51, 2708–2721.
ꢀ
(18) Lara-Ochoa, F.; Espinosa-Perez, G. A new synthesis of combre-
tastatins A-4 and AVE-8062. Tetrahedron Lett. 2007, 48, 7007–
7010.
(19) Ravelli, R. B.; Gigant, B.; Curmi, P. A.; Jourdain, I.; Lachkar, S.;
Sobel, A.; Knossow, M. Insight into tubulin regulation from a
complex with colchicine and a stathmin-like domain. Nature 2004,
198–202.
(20) Ohsumi, K.; Nakagawa, R.; Fukuda, Y.; Hatanaka, T.; Morinaga,
Y.; Nihei, Y.; Ohishi, K.; Suga, Y.; Akiyama, Y.; Tsuji, T.
(22) Zhang, L.-H.; Wu, L.; Raymon, H. K.; Chen, R. S.; Corral, L.;
Shirlei, M. A.; Narla, R. K.; Gamez, J.; Muller, G. W.; Stirling,
D. I.; Bartlett, J. B.; Schafer, P. H.; Payvandi, F. The synthetic
compound CC-5079 is a potent inhibitor of tubulin polymerization
and tumor necrosis factor-R production with antitumor activity.
Cancer Res. 2006, 66, 951–959.