Synthesis and antiproliferative activities of ottelione a analogues

Article abstract of DOI:10.1021/ml300283f

Through the syntheses of its C-1 desvinyl, C-7 methylene, C-7 exocyclic ethylidene, and various C-3 phenylmethyl analogues, the structure-Activity relationship of antimitotic ottelione A (4) against tubulin and various cancer cells was established. The re

Full text of DOI:10.1021/ml300283f

Letter
pubs.acs.org/acsmedchemlett
Synthesis and Antiproliferative Activities of Ottelione A Analogues
Tsai-Yuan Chang,† Yun-Peng Tu,† Win-Yin Wei,‡ Hsiang Yu Chen,‡ Chih-Shang Chen,§
Ying-Shuan E. Lee,‡ Jiann-Jyh Huang,*,‡,§ and Chin-Kang Sha*,†
†Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, Republic of China
‡Development Center for Biotechnology, No. 101, Lane 169, Kangning Street, Xizhi City, Taipei County, Taiwan 221, Republic of
China
§Department of Applied Chemistry, National Chiayi University, No. 300, Syuefu Rd., Chiayi City, Taiwan 60004, Republic of China
S
* Supporting Information
ABSTRACT: Through the syntheses of its C-1 desvinyl, C-7
methylene, C-7 exocyclic ethylidene, and various C-3 phenylmethyl
analogues, the structure−activity relationship of antimitotic ottelione
A (4) against tubulin and various cancer cells was established. The
results indicated that compound 4 was a colchicine-competitive
inhibitor and that the C-1 vinyl group is unnecessary for its potency,
whereas the C-7 exocyclic double bond is essential, possibly because of
its irreversible interaction with tubulin. Further optimization of the
substituents on the phenylmethyl group at the C-3 position generated compound 10g with a 3′-fluoro-4′-methoxyphenylmethyl
substituent, which was 6−38-fold more active against MCF-7, NCI-H460, and COLO205 cancer cells relative to 4. Results from
in vitro tubulin polymerization assay confirmed the potency of compounds 4, 10g, and 11a.
KEYWORDS: ottelione A, antimitotic, microtubule, tubulin, anticancer
fter the success of antimitotic taxanes and vinca alkaloids
most potent natural products that possess in vitro antiprolifer-
ative activity. Its IC50 values lie in the pM−nM range against a
panel of 60 human cancer cell lines through acting as a
colchicine-competitive inhibitor.12,13 Because of its promising
antitumor activity and intriguing core structure with four
stereogenic centers, several synthetic groups have investigated
the total synthesis of 4,14−21 but no analogue has been reported
and assayed for anticancer activity, perhaps because of the many
steps in its preparation.
We already achieved an enantioselective total synthesis of 4
using our α-carbonyl radical cyclization method.21 The
bicyclo[4.3.0]nonane core structure was constructed via radical
cyclization. The C-3 3′-hydroxy-4′-methoxyphenylmethyl
group, C-1 vinyl group, and C-7 exocyclic double bond were
then sequentially introduced. We thus envisaged that our
scheme could be adaptable for the preparation of various
analogues of 4, which would be useful to establish its
structure−activity relationship.
1,2
Aas anticancer drugs,
antimitotic agents that target the
colchicine-binding site to inhibit tubulin polymerization have
attracted much attention. Many structurally diverse compounds
binding to the colchicine-binding site have been discovered
from natural or synthetic sources.3,4 Despite no compound of
this class having been approved for clinical use, the prototype
colchicine (1, Figure 1) has been used to treat gout for many
years.5 Combretastatin A-4 (2)6−9 and ABT-751 (3)10,11 in
Figure 1 are representative examples of colchicine-competitive
inhibitors currently in clinical trials to treat various cancers.
Ottelione A (4, Figure 1), isolated from the fresh water plant
Ottelia alismoides collected in the Nile Delta,12 is among the
As shown in Scheme 1, we first prepared compounds 10a−g
and 11a−c according to our scheme for the total synthesis of 4.
For economy, these compounds were all synthesized in their
racemic forms. Compound 5, prepared via α-carbonyl radical
cyclization,21 served as the starting material. Hydroboration of
5 with 9-borabicyclo(3.3.1)nonane (9-BBN) at its exocyclic
double bond, followed by Suzuki−Miyaura coupling with
various aryl iodides and subsequent removal of the tert-
Received: September 14, 2012
Accepted: October 30, 2012
Published: October 30, 2012
Figure 1. Structures of colchicine (1), combretastatin A-4 (2), ABT-
751 (3), and ottelione A (4).
© 2012 American Chemical Society
1075
dx.doi.org/10.1021/ml300283f | ACS Med. Chem. Lett. 2012, 3, 1075−1080

ACS Medicinal Chemistry Letters
Letter
a
Scheme 1. Synthesis of Compounds 10a−g and 11a−c
a
Reagents and conditions: (a) 9-BBN, ArI, PdCl2(dppf), NaOH (3 M), THF. (b) HF (50%), CH3CN, 23−65% (from 5). (c) PCC, CH2Cl2, 61−
93%. (d) Ph3P+CH3Br−, tBuOK, benzene, 71−95%. (e) NaOH, MeOH. (f) PCC, CH2Cl2, 38−95% (from 8a−g). (g) LiN(SiMe3)2, PhSeBr, THF.
(h) H2O2, CH2Cl2, 45−74% (from 9a−g). (i) TFA, THF, H2O, 55−65% (from 10a−c).
butyldimethysilyl (TBDMS) protective group, gave compounds
6a−g in 23−65% yields. Oxidation of 6a−g with pyridinium
chlorochromate (PCC) in CH2Cl2 generated 7a−g in 61−93%
Scheme 2. Synthesis of C-7 Exocyclic Methylene Analogue
19
a
t
yields. Treatment of 7a−g with Ph3P+CH3Br− and BuOK
afforded compounds 8a−g possessing a C-7 exocyclic double
bond. Removal of the acetyl group from 8a−g with NaOH
followed by oxidation with PCC afforded compounds 9a−g in
38−95% yields. To introduce the double bond at the C-5 and
C-6 positions, we treated compounds 9a−g first with
LiN(SiMe3)2 and PhSeBr then mCPBA to give compounds
10a−g in 45−74% yields. Removal of the methoxymethyl
(MOM) protective group in 10a−c provided compounds 11a−
c in 55−65% yields (Scheme 1).
Compound 19, lacking a C-1 vinyl and C-7 exocyclic double
bond, was prepared from 2-cyclohexen-1-one (12) according to
our method similar to that for 11a−c (Scheme 2).22 Reaction
of 12 with 4-(trimethylsilyl)-3-butynylmagnesium chloride in
the presence of CuI and TMSCl followed by iodination with
NaI and mCPBA gave α-iodoketone 13 in 96% yield. Radical
cyclization of 13 followed by reduction with NaBH4 and
protection with Ac2O afforded 15 through the key intermediate
14. Compound 15 was converted to compound 16 by
hydroboration and Suzuki−Miyaura coupling in 30% yield.
Deprotection of 16 followed by oxidation gave ketone 17 in
74% yield. Compound 17 was converted to α,β-unsaturated
enone 18 in 33% yield via treatment with LiN(SiMe3)2 and
PhSeBr followed by oxidative elimination. Acidic hydrolysis of
the MOM protecting group in 18 provided 19 in 63% yield.
To prepare C-7 exocyclic ethylidene derivative 23, we treated
a
Reagents and conditions: (a) 4-(Trimethylsilyl)-3-butynylmagnesium
chloride, CuI, HMPA, TMSCl, Et3N. (b) NaI, mCPBA, THF, 96%
(two steps). (c) Bu6Sn2, benzene, then Bu3SnH, AIBN. (d) TFA,
CH2Cl2. (e) NaBH4, MeOH; (f) Ac2O, pyridine, CH2Cl2, 56% (from
13). (g) ArI, 9-BBN, PdCl2(dppf), NaOH, THF, 30%. (h) NaOH,
MeOH. (i) PCC, CH2Cl2, 74% (two steps). (j) LiN(SiMe3)2, PhSeBr,
THF. (k) H2O2, CH2Cl2, 33% (two steps). (l) TFA, THF, H2O, 63%.
obtained in Z and E mixtures and could not be separated by
simple column chromatography; we therefore employed NOE
experiments to determine the E/Z ratio of 23. Two doublet
peaks at 7.34 and 6.82 ppm, corresponding to the C-6
t
compound 7a with Ph3P+CH2CH3Br− and BuOK to give
compound 20 in 88% yield (Scheme 3). Removal of the acetyl
group in 20 followed by oxidation gave 21 in 81% yield.
Introduction of the double bond between C-5 and C-6
positions gave 22 in 63% yield. Compound 22 was
subsequently hydrolyzed in acidic conditions to remove the
MOM group to afford the desired exocyclic ethylidene
derivative 23 in 80% yield. Compounds 20−23 were all
1
hydrogen with an integral ratio 1/3.4, were recorded in the H
NMR spectrum of 23. Irradiation of the peak at 7.34 ppm
showed a positive NOE effect with 7.58% enhancement at the
signal of CH3 at 1.83 ppm, indicating that the peak
corresponded to (E)-23; irradiation of the peak at 6.82 ppm,
however, showed no positive NOE effect, revealing it to
1076
dx.doi.org/10.1021/ml300283f | ACS Med. Chem. Lett. 2012, 3, 1075−1080

ACS Medicinal Chemistry Letters
Letter
vinyl might be less important for the potency of 4. We
subsequently prepared all analogues without the vinyl
substituent. Compound 11a also displayed a spectrum of
activities against the cancer cells similar to that of 4, being more
active to inhibit HCT-116 and A375 cells but less potent
against COLO205.
Scheme 3. Synthesis of C-7 Exocyclic Ethylidene Analogue
23
a
Unlike the C-1 vinyl group, the C-7 exocyclic double bond
was crucial for the potency of 4; the evidence came from the
loss of the antimitotic (CBI %, 39.2%) and antiproliferative
activities (IC50 > 1.0 μM) of 19 that did not bear the moiety
(Table 1). As the C-7 exocyclic double bond is conjugated with
the C-4 carbonyl, it might be susceptible to nucleophilic 1,6-
addition23 with amino acid residues in the binding site, for
example, serine, threonine, and cysteine residues.24 As a result,
an irreversible inhibition of tubulin polymerization caused by
the C-7 exocyclic double bond was hinted. To provide further
evidence, we introduced a methyl substituent on the double
bond to generate analogue 23 that was more hindered for
nucleophilic addition. It showed decreased antiproliferative
activities (1.5−8.6-fold) relative to 11a, which indicated that
the 1,6-addition was possible. The nucleophile would be a thiol,
for T138067, a pentafluorobenzenesulfonamide that possesses
an N-aryl group similar to that of 2, is reported to covalently
modifies tubulin at a conserved cysteine residue in the
colchicine-binding site.25
After clarifying the roles of the C-1 and C-7 moieties, we
examined the effect of substituents on the phenyl group of 4 on
the antimitotic and antiproliferative activities. Compounds
10b−d, 11b, and 11c were subjected to the in vitro assays; the
results are summarized in Table 2. The unsubstituted 10d (R1
= R2 = R3 = H) was less potent against the cancer cells with
IC50 values of 237−678 nM, which were 2.2−221-fold less
potent than 11a, especially on the sensitive HCT-116 and A375
cells (85- and 221-fold less potent, respectively). Its CBI % was
also decreased to 43.2%. For 11b bearing a para-hydroxyl
group, the antiproliferative activities and CBI % were greater
than unsubstituted 10d. Blocking the para-hydroxyl in 11b with
a MOM group gave compound 10b with decreased antimitotic
and antiproliferative activities.
a
t
Reagents and conditions: (a) Ph3P+CH2CH3Br−, BuOK, benzene,
88%. (b) NaOH, MeOH. (c) PCC, CH2Cl2, 79% (two steps). (d)
LiN(SiMe3)2, PhSeBr, THF. (e) H2O2, CH2Cl2, 63% yield (two
steps). (f) HClO4, CH2Cl2, 80%.
correspond to (Z)-23. The E/Z ratio of 23 was hence
determined to be 1/3.4.
After these compounds were prepared, assays of the
percentage of colchicine binding inhibition (CBI %) and
antiproliferation against human cancer cells including KB
(nasopharyngeal), MCF-7 (breast), NCI-H460 (lung), HCT-
116 (colon), A375 (melanoma), and COLO205 (colon) were
employed to evaluate their potencies. Compound 4 and its C-1
desvinyl derivative 11a, C-7 methylene derivative 19, and C-7
exocyclic ethylidene derivative 23 were assayed first (Table 1).
Enantiomerically pure 4, prepared according to our published
method,21 showed strong inhibition of the growth of the cancer
cells with IC50 values of 0.40−92.8 nM; the results are
consistent with the reported potency of 4 from natural12 and
synthetic sources.17 The cells most sensitive toward 4 were
HCT-116 and A375 cells, which were inhibited at subnano-
molar concentrations (IC50, 0.74 and 0.40 nM, respectively).
Compound 4 also showed great CBI % with a near-plateau
value of 98.3%, revealing its binding to the colchicine-binding
site that contributed to its remarkable antiproliferative activities.
The C-1 desvinyl analogue 11a was also active against the
cancer cells with IC50 values ranging from 1.07 to 243.9 nM
(Table 1). Although slightly less potent than 4, compound 11a
also exhibited a satisfactory CBI % (95.8%). As a result, the C-1
As the structure of 4 is similar to that of 2, we synthesized
compound 10e with a trimethoxyphenyl substituent, but a
complete loss of activity was observed (CBI % = 8.93% and
IC50 > 1.0 μM). The 3′-hydroxyl-4′-methoxyphenyl in 4
evidently did not occupy the same space as the trimethox-
ylphenyl group in 2 in the colchicine-binding site.
Table 1. CBI % and Antiproliferative Activities of Compounds 4, 11a, 19, and 23
b
antiproliferative IC50 (nM)
a
compd
CBI %
KB
1.59
4.94
>103
22.6
MCF-7
NCI-H460
HCT-116
A375
COLO205
4
98.3
95.8
39.2
96.1
1.17
3.73
>103
14.49
16.04
>103
0.74
3.01
>103
0.40
1.07
914
92.8
243.9
>103
739
11a
19
23
26.3
24.6
14.0
9.2
a
b
CBI %: percentage of colchicine-binding inhibition at a compound concentration of 10 μM, replicated. The IC50 values were averaged from two
independent dose−response curves; the variation was generally <15%.
1077
dx.doi.org/10.1021/ml300283f | ACS Med. Chem. Lett. 2012, 3, 1075−1080

ACS Medicinal Chemistry Letters
Letter
Table 2. Percentage of Colchicine-Binding Inhibition and Antiproliferative Activities of C-1 Desvinyl Compounds 10b−e, 11b,
and 11c
b
antiproliferative IC50 (nM)
a
compd
R1
R2
R3
CBI %
KB
MCF-7
NCI-H460
HCT-116
A375
COLO205
10d
11b
10b
10e
10c
11c
10f
H
H
H
43.2
71.6
69.3
8.93
68.9
37.3
61.7
97.1
591
68.8
208
>103
76.6
156
260
33.8
63.6
>103
77.2
147
678
77.6
226
257
38.5
129
>103
77.4
126
237
30.8
77.4
>103
40.0
98.4
222
547
218.1
219
>103
75.7
3003
428
H
OH
H
H
OMe
F
H
OCH2OCH3
OMe
OMe
H
>103
OCH2OCH3
OH
106
H
F
229
H
F
F
478
233
511
235
10g
H
OMe
F
2.77
0.130
2.62
1.11
1.68
2.45
a
b
CBI %: percentage of colchicine-binding inhibition at a compound concentration of 10 μM, replicated. The IC50 values were averaged from two
independent dose−response curves; the variation was generally <15%.
Figure 2. Effect of compounds 1, 4, 10g, and 11a (each 10 μM) on tubulin polymerization. The assays were conducted with a fluorescence-based
assay kit (Cytoskeleton Inc.) using purified porcine neuronal tubulin. All compounds effectively inhibited the polymerization of tubulin; 10g and 4
showed activities comparable to that of 1.
Introduction of a m-fluoro group to 10b gave compound 10c
with the retention of CBI % (69.3% for 10b and 68.9% for 10c;
see Table 2), but 10c showed increased antiproliferative activity
against cancer cells relative to 10b, except MCF-7. Removal of
the MOM group in 10c afforded compound 11c with a ∼2-fold
decrease of CBI % (37.3%) as well as its antiproliferative
activities. Compound 10f with 3′,4′-difluoro substituents in the
phenyl ring was less active than 11c, in both CBI % and
antiproliferative activities. We eventually obtained compound
11g with a 3′-fluoro-4′-methoxylphenyl substituent that
showed a CBI % value, 97.1%, comparable with that of 4 and
11a. It was most potent among the compounds in this work
against various cancer cells, with IC50 values of 0.130−2.77 nM.
Even on the least sensitive COLO205 cells, its activity was also
remarkable, possessing an IC50 value of 2.45 nM, which was 38
times as active as 4.
2. The 3′-hydroxyl-4′-methoxylphenyl substituent in 2 and 4
would occupy the same space in the colchicine-binding site.
To confirm the drug target of the compounds in Tables 1
and 2, potent compounds 4, 10g, and 11a were tested using in
vitro tubulin polymerization assay at concentration of 10 μM
with 1 as the positive control. As presented in Figure 2, all
compounds significantly inhibited the polymerization of
tubulin; 4 and 10g showed potency similar to that of 1. In
combination with their CBI % values as shown in Tables 1 and
2, the results confirmed that the antiproliferative activity of the
compounds arose from inhibiting tubulin polymerization
through binding to the colchicine-binding site.
We summarize our work on the structure−activity relation-
ship of 4 against various cancer cells in Figure 3. As 11a showed
activity comparable with that of 4, the C-1 vinyl is unnecessary
for the activity, but the C-7 exocyclic double bond is essential
for the potency. The exocyclic double bond in conjugation with
the C-4 carbonyl might make it susceptible to nucleophilic
addition, thus irreversibly binding with tubulin. Among the
hydrogen, hydroxyl, methoxy, and MOM groups at the para
position of the phenyl group in 4, only the methoxy group
The change of the hydroxyl group in 2 to a fluoro atom was
found to retain its antiproliferative activity against K562 cells.26
In our work, the switch from OH to F in 11a also provided 10g
with retained or improved potency. As a result, compound 4
might bind in tubulin in a position similar to that of compound
1078
dx.doi.org/10.1021/ml300283f | ACS Med. Chem. Lett. 2012, 3, 1075−1080

ACS Medicinal Chemistry Letters
Letter
(6) Stevenson, J. P.; Rosen, M.; Sun, W. J.; Gallagher, M.; Haller, D.
G.; Vaughn, D.; Giantonio, B.; Zimmer, R.; Petros, W. P.; Stratford,
M.; Chaplin, D.; Young, S. L.; Schnall, M.; O'Dwyer, P. J. Phase I trial
of the antivascular agent combretastatin A4 phosphate on a 5-day
schedule to patients with cancer: magnetic resonance imaging evidence
for altered tumor blood flow. J. Clin. Oncol. 2003, 21, 4428−4438.
(7) Beerepoot, L. V.; Radema, S. A.; Witteveen, E. O.; Thomas, T.;
Wheeler, C.; Kempin, S.; Voest, E. E. Phase I clinical evaluation of
weekly administration of the novel vascular-targeting agent, ZD6126,
in patients with solid tumors. J. Clin. Oncol. 2006, 24, 1491−1498.
(8) Delmonte, A.; Sessa, C. AVE8062: A new combretastatin
derivative vascular disrupting agent. Expert Opin. Invest. Drugs 2009,
18, 1541−1548.
Figure 3. Structure−activity relationship of 4 against various cancer
cells.
(9) Patterson, D. M.; Zweifel, M.; Middleton, M. R.; Price, P. M.;
Folkes, L. K.; Stratford, M. R. L.; Ross, P.; Halford, S.; Peters, J.;
Balkissoon, J.; Chaplin, D. J.; Padhani, A. R.; Rustin, G. J. S. Phase I
clinical and pharmacokinetic evaluation of the vascular-disrupting
agent OXi4503 in patients with advanced solid tumors. Clin. Cancer
Res. 2012, 18, 1415−1425.
(10) Mauer, A. M.; Cohen, E. E.; Ma, P. C.; Kozloff, M. F.;
Schwartzberg, L.; Coates, A. I.; Qian, J.; Hagey, A. E.; Gordon, G. B. A
phase II study of ABT-751 in patients with advanced non-small cell
lung cancer. J. Thorac. Oncol. 2008, 3, 631−636.
(11) Fox, E.; Maris, J. M.; Widemann, B. C.; Goodspeed, W.;
Goodwin, A.; Kromplewski, M.; Fouts, M. E.; Medina, D.; Cohn, S. L.;
Krivoshik, A.; Hagey, A. E.; Adamson, P. C.; Balis, F. M. A phase I
study of ABT-751, an orally bioavailable tubulin inhibitor, adminis-
tered daily for 21 days every 28 days in pediatric patients with solid
tumors. Clin. Cancer Res. 2008, 14, 1111−1115.
(12) Ayyad, S.-E. N.; Judd, A. S.; Shier, W. T.; Hoye, T. R. Otteliones
A and B: Potently cytotoxic 4-methylene-2-cyclohexenones from
Ottelia alismoides. J. Org. Chem. 1998, 63, 8102−8106.
(13) Combeau, C.; Provost, J.; Lancelin, F.; Tournoux, Y.;
Prod’homme, F.; Herman, F.; Lavelle, F.; Leboul, J.; Vuilhorgne, M.
RPR112378 and RPR115781: two representatives of a new family of
microtubule assembly inhibitors. Mol. Pharmacol. 2000, 57, 553−563.
(14) Mehta, G.; Islam, K. Total synthesis of ( )-otteliones A and B.
Angew. Chem., Int. Ed. 2002, 41, 2396−2398.
(15) Mehta, G.; Islam, K. Enantioselective total syntheses of (+)- and
(−)-ottelione A and (+)- and (−)-ottelione B. Absolute configuration
of the novel, biologically active natural products. Tetrahedron Lett.
2003, 44, 6733−6736.
(16) Araki, H.; Inoue, M.; Katoh, T. Total synthesis and absolute
configuration of otteliones A and B, novel and potent antitumor agents
from a freshwater plant. Org. Lett. 2003, 5, 3903−3906.
(17) Araki, H.; Inoue, M.; Suzuki, T.; Yamori, T.; Kohno, M.;
Watanabe, K.; Abe, H.; Katoh, T. Enantioselective total synthesis of
(+)-ottelione A, (−)-ottelione B, (+)-3-epi-ottelione A and prelimi-
nary evaluation of their antitumor activity. Chem.Eur. J. 2007, 13,
9866−9881.
(18) Clive, D. L. J.; Liu, D. Synthesis of the otteliones A and B: Use
of a cyclopropyl group as both a steric shield and a vinyl equivalent.
Angew. Chem., Int. Ed. 2007, 46, 3738−3740.
(19) Clive, D. L. J.; Liu, D. Synthesis of the potent anticancer agents
ottelione A and ottelione B in both racemic and natural optically pure
forms. J. Org. Chem. 2008, 73, 3078−3087.
(20) Lee, M. Y.; Kim, K. H.; Jiang, S.; Jung, Y. H.; Sim, J. H.; Hwang,
G.-S.; Ryu, D. H. Enantioselective formal synthesis of antitumor agent
(+)-ottelione A. Tetrahedron Lett. 2008, 49, 1965−1967.
provided potent compounds. For the meta position, a fluoro or
a hydroxyl group enhanced the potency, whereas trimethoxy
substituents on the phenyl group deactivated compound 10e.
In conclusion, we have established the structure−activity
relationship of 4 focusing on the C-1 vinyl, C-7 exocyclic
double bond, and the substituents on the phenyl ring to inhibit
colchicine binding and the growth of cancer cells. Compound
10g, a less complicated analogue of 4, show potency
comparable with, or superior to, that of 4. Extensive syntheses
and biological evaluation are now in progress in our laboratory.
Using the information provided in this work, we are seeking
more potent and druggable molecules for further development.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures for compounds 6a−g, 7a−g, 8a−g,
9a−g, 10a−g, 11a−c, and 13−23 and procedures for bioassays.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +88652717959. Fax: +88652717901. E-mail: lukehuang@
mail.ncyu.edu.tw (J.-J.H.). Tel: +88635722427. Fax:
+88635725870. E-mail: cksha@mx.nthu.edu.tw (C.-K.S.).
■
Funding
National Science Council of the Republic of China (Taiwan)
provided financial support.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
9-BBN, 9-borabicyclo(3.3.1)nonane; CBI %, percentage of
colchicine-binding inhibition; MOM, methoxymethyl; PCC,
pyridinium chlorochromate; TBDMS, tert-butyldimethysilyl;
TFA, trifluoroacetic acid
REFERENCES
■
(1) Jordan, M. A.; Wilson, L. Microtubules as a target for anticancer
drugs. Nat. Rev. Cancer 2004, 4, 253−265.
(21) Chen, C.-H.; Chen, Y.-K.; Sha, C.-K. Enantioselective total
synthesis of otteliones A and B. Org. Lett. 2010, 12, 1377−1379.
(22) Sha, C.-K.; Jean, T.-S.; Wang, D.-C. Intramolecular radical
cyclization of silylacetylenic or olefinic α-iodo ketones: application to
the total synthesis of ( )-modhephene. Tetrahedron Lett. 1990, 31,
3745−3748.
(23) Csaky, A. G.; de la Herran, G.; Murcia, M. C. Conjugate
́ ́
̈
addition reactions of carbon nucleophiles to electron-deficient dienes.
Chem. Soc. Rev. 2010, 39, 4080−4102.
(2) Kingston, D. G. I. Tubulin-interactive natural products as
anticancer agents. J. Nat. Prod. 2009, 72, 507−515.
(3) Bhattacharyya, B.; Panda, D.; Gupta, S.; Banerjee, M. Anti-mitotic
activity of colchicine and the structural basis for its interaction with
tubulin. Med. Res. Rev. 2008, 28, 155−183.
(4) Chen, J.; Liu, T.; Dong, X.; Hu, Y. Recent development and SAR
analysis of colchicine binding site inhibitors. Mini-Rev. Med. Chem.
2009, 9, 1174−1190.
(5) Nuki, G. Gout. Medicine 2006, 34, 417−423.
1079
dx.doi.org/10.1021/ml300283f | ACS Med. Chem. Lett. 2012, 3, 1075−1080

ACS Medicinal Chemistry Letters
Letter
̈
(24) Powers, J. C.; Asgian, J. L.; Ekici, O. D.; James, K. E. Irreversible
inhibitors of serine, cysteine, and threonine proteases. Chem. Rev.
2002, 102, 4639−4750.
(25) Shan, B.; Medina, J. C.; Santha, E.; Frankmoelle, W. P.; Chou,
T.-C.; Learned, R. M.; Narbut, M. R.; Stott, D.; Wu, P.; Jaen, J. C.;
Rosen, T.; Timmermans, P. B. M. W. M.; Beckmann, H. Selective,
covalent modification of β-tubulin residue Cys-239 by T138067, an
antitumor agent with in vivo efficacy against multidrug-resistant
tumors. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 5686−5691.
(26) Lawrence, N. J.; Hepworth, L. A.; Rennison, D.; McGown, A.
T.; Hadfield, J. A. Synthesis and anticancer activity of fluorinated
analogues of combretastatin A-4. J. Fluorine Chem. 2003, 123, 101−
108.
1080
dx.doi.org/10.1021/ml300283f | ACS Med. Chem. Lett. 2012, 3, 1075−1080