Oxadiazole derivatives as a novel class of antimitotic agents: Synthesis, inhibition of tubulin polymerization, and activity in tumor cell lines

Article abstract of DOI:10.1016/j.bmcl.2005.11.094

Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 μM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC₅₀ = 7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.

Full text of DOI:10.1016/j.bmcl.2005.11.094

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1191–1196
Oxadiazole derivatives as a novel class of antimitotic
agents: Synthesis, inhibition of tubulin polymerization,
and activity in tumor cell lines
Xiaohu Ouyang,a,* Evgueni L. Piatnitski,a Vatee Pattaropong,a Xiaoling Chen,a
Hai-Ying He,a Alexander S. Kiselyov,a Avdhoot Velankar,a Joel Kawakami,a
Marc Labelle,a Leon Smith, II,a Julia Lohman,a Sui Ping Lee,a Asra Malikzay,b
James Fleming,b Jason Gerlak,b Ying Wang,b Robin L. Rosler,b Kai Zhou,b
Stan Mitelman,b Margarita Camara,c David Surguladze,c
Jacqueline F. Doodyb and M. Carolina Tumab
aDepartment of Chemistry, ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA
bDepartment of Protein Sciences, ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA
cDepartment of Experimental Therapeutics, ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA
Received 7 November 2005; revised 22 November 2005; accepted 23 November 2005
Available online 11 January 2006
Abstract—Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause
mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 lM. Lead
analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10,
EC50 = 7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also
investigated and are reported herein, along with structure–activity relationships for this novel series of antimitotic agents.
Ó 2005 Elsevier Ltd. All rights reserved.
Antimitotic drugs have been successfully used as chemo-
therapeutic agents in the treatment of cancer.1 Most
antimitotic drugs target microtubules—dynamic ele-
ments of the cell cytoskeleton responsible for the forma-
tion of the mitotic spindle, required for proper
chromosomal separation during cell division. Agents
that affect tubulin polymerization impair microtubule
dynamics and consequently arrest cells during mitosis.2
Evidence that microtubules are a validated cancer target
comes mainly from the successful use of natural prod-
ucts such as Taxanes and Vincas as chemotherapeutic
agents to clinically treat various tumors. However, the
complex synthesis, difficult formulation, lack of oral
availability and, more importantly, acquired and intrin-
sic resistance to TaxolÒ and Vinca alkaloids render these
drugs suboptimum for clinical treatment of cancer.3
Hence, there is considerable interest in the discovery
and development of novel small molecule inhibitors of
tubulin polymerization that can circumvent the difficul-
ties seen with natural products.4
Many synthetic small molecule tubulin inhibitors have
been reported and several are currently in clinical trials.5
Two small molecule clinical candidates, D-24851 and
ABT-751, deserve notice for their unique characteristics
(Fig. 1). Indole based D-24851 demonstrated impressive
efficacy in a variety of tumor models including multiple-
drug resistant (MDR) xenographs.6 This compound
does not bind to any of the characterized binding sites
on tubulin nor does it seem to cause neurotoxicity in
mice. ABT-751, a pyridine containing sulfonamide,
binds to the colchicine site on tubulin and shows anti-
vascular effects in addition to its predicted antimitotic
activity.7 Both these compounds are orally bioavailable,
an advantage over existing therapies.
Keywords: Tubulin polymerization inhibitor; 1,3,4-Oxadiazole; Anti-
mitotic agent; Multiple-drug resistance.
*
We have previously reported a triazole class of tubulin
inhibitors with potent antimitotic activity in tumor cells
Corresponding author. Tel.: +1 347 523 0018; e-mail:
shawn_ouyang@yahoo.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.11.094

1192
X. Ouyang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1191–1196
H
oxadiazole (Scheme 3). Therefore, oxadiazole deriva-
tives could be obtained in two easy steps without purifi-
cation by column chromatography.
O
S
O
N
O
N
O
NH
N
N
H
OMe
N
Compounds of the general formula given in Table 1
were evaluated in two assays. Compounds that showed
inhibition of tubulin polymerization in vitro were evalu-
ated for inducing cell cycle arrest in A431 human cancer
cells (Table 1). To identify an alternative group to 3,5-
dimethoxyaniline, we initially kept R2 constant as either
2,3-dihydro-benzo[1,4]dioxin-6-yl or benzo[1,3]dioxol-5-
yl groups (preferred substitutions at R2 position ob-
tained from the triazole series8) and used various
alkylamines (R1CH2NH2) to determine the effect of R1
on activity (1–21, Table 1). This strategy proved to be
successful as compounds with a variety of groups at
R1 were active. Aryl groups were the most favorable
as R1 substituents: compounds displayed double digit
nanomolar activity in cellular assays when R1 was alk-
oxylphenyl (1–3), fluorophenyl (4–6), methanesulfon-
amidophenyl (7–8), pyridyl (9–14), pyrazinyl (15) or
furanyl (17) moiety. R1 alkyl groups generally demon-
strated a weaker activity than aromatic analogs. For
example, tetrahydrofuran analogs (19) and (20) had
EC50s >150 nM. Compounds with polar groups at R1
(i.e., 21) lost functional and cellular activities. Notewor-
thy, compounds with a 2,3-dihydro-benzo[1,4]dioxin-6-
yl group at R2 are often more potent than closely related
analogs with a benzo[1,3]dioxol-5-yl group. Benzodioxin
analogs (5), (7), (11), (13), (15), and (17) are at least
twice as potent as their corresponding benzodioxole
analogs (6), (8), (12), (14), (16), and (18), indicating that
a benzodioxin group is the preferred substitution at R2.
Cl
OH
D-24851
ABT-751
N
N
N
N
NH
NH
N
N
H
O
N
NH
O
N
NH
O
O
O
10
MeO
OMe
Triazole
Oxadiazole
Figure 1. Structures of D-24851, ABT-751, triazole, and oxadiazole.
and have shown that the presence of the electron-rich
3,5-dimethoxyphenyl moiety is necessary for cellular
potency (Fig. 1).8 In an effort to improve the physico-
chemical properties and pharmacokinetic profile of
these compounds, we designed a series of oxadiazoles
where the 3,5-dimethoxyaniline group is not required
for potent antimitotic activity in cells (i.e., 10 in
Fig. 1). The present report describes the synthesis and
evaluation of oxadiazoles as a novel class of tubulin
inhibitors that are potent and effective against tumor
cells including a cell line with MDR. Structure–activity
relationships (SARs) and pharmacokinetic studies of
this novel tubulin inhibitor class are reported herein.
In contrast, our attempts to find a replacement for the
benzodioxin or benzodioxole groups at the R2 position
were unsuccessful. While keeping R1 constant, various
substituted phenyl groups at R2 were evaluated. Only
a 4-methoxyphenyl analog (22) demonstrated apprecia-
ble activity, whereas 3-methoxyphenyl, 4-methylphenyl,
3-methyl, and 4-hydroxyphenyl analogs were inactive,
indicating potential hydrogen bond that involved the
oxygen atom at the para position. Compounds contain-
ing substitutions at the R2 phenyl ring, including elec-
tron-donating groups such as 3,4-dimethylamino,
amino, and electron-withdrawing groups such as cyano,
difluoro, and nitro, had diminished activity in tubulin
polymerization assays (see supporting information sec-
tion). Difluoro-benzodioxole analog (23) displayed
much weaker activity than the corresponding benzodi-
oxole analog (14).
Oxadiazole compounds in this report were synthesized
according to Method I described by Sunder (Scheme
1).9 Ester A was treated with hydrazine monohydrate
to yield hydrazide B, which was reacted further with
an isothiocyanate to form thiourea intermediate C.
Finally, C was cyclized to produce oxadiazole D by
heating with DCC. Oxadiazole analogs similar to (10)
(Fig. 1) were synthesized by the displacement of chlorine
atom from 2-chloronicotinic acid ethyl ester by a variety
of amines under thermal conditions. As a result, the 2-
alkylaminonicotinic acid ethyl ester E was generated
and then converted via Method I to the oxadiazole ana-
logs listed in Table 1 (Scheme 2).
Compounds listed in Table 1 can also be prepared via a
very efficient protocol utilizing cyclization of commer-
cially available 2-fluoronicotinic acid with a thiosemi-
carbazide provided oxadiazole intermediate F, which is
substituted with an amine of choice to give a final
Biaryl ether analogs such as compound (24, X = O),
synthesized by a modified procedure at step (i) in
O
R2
NH
O
O
N
H
H
N
(iii)
(i)
(ii)
N
N
Ar
N
R2
Ar
OEt
Ar
NHNH2
O
H
Ar
S
A
C
B
D
Scheme 1. Method I. Reagents and conditions: (i) hydrazine monohydrate, isopropanol, 120 °C, 2–4 h, 60–90%; (ii) R2NCS, CHCl3, 30–60 °C,
2–6 h, 80–95% (iii) DCC, toluene, 110 °C, 8–16 h, 60–80%.

X. Ouyang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1191–1196
Table 1. Effects of various R1 and R2 groups on activity
1193
R2
N
N
N
R3
O
N
X
R1
Compound
R1
R2
R3
X
ITPa IC50
G2/M blockb
(lM)
EC50 (lM)
CA4c
Taxol
1
2.1 0.24
NA
0.0035 0.0008
0.009 0.0023
0.057 0.009
0.018 0.002
0.023 0.002
0.060 0.012
0.015 0.003
0.051 0.001
0.023 0.008
0.071 0.037
0.018 0.0024
0.020 0.003
0.013 0.002
0.031 0.001
0.016 0.001
0.049 0.011
0.031 0.001
0.21 0.019
0.045 0.007
0.13 0.027
0.16 0.003
0.33 0.052
>10
2,3-Dihydro-benzo[1,4]dioxin-6-yl
Benzo[1,3]dioxol-5-yl
4-Methoxyphenyl
4-Fluorophenyl
3,4-Difluorophenyl
3,4-Difluorophenyl
4-Methanesulfonamidophenyl
4-Methanesulfonamidophenyl
Pyridin-4-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
Benzo[1,3]dioxol-5-yl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
1.8 0.3
0.5 0.1
1.6 0.26
5.0 0.5
0.7 0.1
2.2 0.4
2.0 0.4
3.8 0.6
29.9 1.8
1.0 0.1
0.7 0.03
8.8 0.7
1.9 0.1
1.7 0.2
2.2 0.4
9.6 0.44
2.0 0.4
4.9 0.03
1.7 0.25
15.5 2.0
>30
2
3
4
5
6
7
2,3-Dihydro-benzo[1,4]dioxin-6-yl
Benzo[1,3]dioxol-5-yl
8
9
2,3-Dihydro-benzo[1,4]dioxin-6-yl
Benzo[1,3]dioxol-5-yl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Pyridin-4-yl
Pyridin-3-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
Benzo[1,3]dioxol-5-yl
Pyridin-3-yl
Pyridin-2-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
Benzo[1,3]dioxol-5-yl
Pyridin-2-yl
Pyrazin-2-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
Benzo[1,3]dioxol-5-yl
Pyrazin-2-yl
Furan-2-yl
Furan-2-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
Benzo[1,3]dioxol-5-yl
Tetrahydro-furan-2-yl
Tetrahydro-furan-2-yl
1-Methyl-pyrrolidin-2-ylamine
Pyridin-2-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
Benzo[1,3]dioxol-5-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
4-Methoxyphenyl
1.5 0.1
13.3 1.9
18.1 0.08
>30
0.020 0.004
0.78 0.19
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
2,2-Difluoro-benzo[1,3]dioxol-5-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
2,3-Dihydro-benzo[1,4]dioxin-6-yl
0.26 0.024
NT
NH
NA, not applicable; NT, not tested.
a Compound concentration required for 50% inhibition of maximum tubulin assembly.
b Compound concentration required for 50% of A431 cells to accumulate at the G2/M phase of the cell cycle.
c CA4 = Combretastatin A4.
Scheme 1,10 were less active than their amine analogs
(13). The importance of the NH functionality between
the oxadiazole ring and the R2 group was demonstrated
by alkylation of (13) where the presence of a methyl
group at R3 abolished its activity (25).
N
N
O
NH
R2
O
O
OEt
(i)
Method I
OEt
N
NH
R1
N
NH
R1
N
Cl
E
Table 2 lists our SAR investigation on the two central
ring moieties connecting R1 and R2. First, we synthe-
sized pyridine, pyrimidine, and pyrazine analogs (26–
31), using previously reported procedures similar to that
described in Scheme 1 where the corresponding com-
mercially available ring chloro derivatives were used in-
stead of ethyl-2-chloro-nicotinate E. We demonstrated
that only small substituents such as methyl or fluoro
groups on pyridine ring Y were tolerated (26, 28), while
bulkier groups such as trifluoromethyl (37) lowered
compound activity, presumably, due to steric limitations
around the Y ring. The inactive regioisomeric pyridine
analog (29) and pyrimidine analog (30) showed that a
basic nitrogen para to the NH is not desirable, while
nitrogen atoms ortho and meta to NH are allowed, as
demonstrated by the potent pyrazine analog (31). When
Scheme 2. Reagents and conditions: (i) R1CH2NH2, isopropanol,
80–100 °C, 2–10 h, 40–90%.
N
N
N
N
F
NH
R2
O
F
NH
R2
O
(i)
(ii)
O
OH
N
NH
R1
N
N
F
Scheme 3. Reagents and conditions: (i) R2NHC(S)NHNH2, EDCI,
DCM, 25 °C, 12 h, 64–78%; (ii) R1CH2NH2, isopropanol, sealed tube,
100 °C, 8–24 h, 89–94%.

1194
X. Ouyang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1191–1196
Table 2. Effect of central rings Y and Z on activitya
O
O
OMe
NH
(i)
Method I
Z
NH
OMe
NH2
32
Y
N
O
NH
N
G
O
Scheme 4. Reagents and conditions: (i) pyridine-2-carboxaldehyde,
AcOH, toluene, 100 °C, 12 h, then NaBH(OAc)3, 12 h, 85%. Method I,
see Scheme
dioxine).
(R2NCS = 6-isothiocyanato-2,3-dihydro-benzo[1,4]-
Compound
Y
Z
ITP (lM) G2/M block
(lM)
1
N
O
N
26
2.4 0.47 0.099 0.012
inactive (synthetic schemes are not shown, see support-
ing information section).
H3C
N
N
O
N
N
N
N
N
N
N
27
28
29
30
31
32
33
34
35
36
>30
NT
Making use of synthetic accessibility and keeping the Y
ring as a phenyl group, we were able to explore some
modifications of the oxadiazole Z ring with other five-
membered heterocycles. 1,3-Oxazole analog (34) was
the most successful replacement, while imidazole (36)
and thiazole (35) derivatives were inactive. Oxazole ana-
log (34) was prepared according to Scheme 5. Commer-
cially available 2-bromo-1-(2-nitro-phenyl)-ethanone
was first converted to an azido intermediate H, which
was reacted with an isothiocyanate in the presence of
PPh3 to give rise to the 1,3-oxazole intermediate I.11
The nitro group of I was reduced to amino compound
J, which was further reductively alkylated by an alde-
hyde to provide analog (34). The thiazole analog (35)
was prepared as described in Scheme 6. 2-Bromo-1-(2-
nitro-phenyl)-ethanone was reacted with thiourea to
form the nitro-thiazole intermediate K that was convert-
ed to final form (35) as shown in Scheme 5 for interme-
diate I. The imidazole compound (36) was analogous to
the thiazole analog (35), except for a protection step
needed for the transformation (Scheme 7).
F3C
F
N
N
O
3.4 0.41 0.082 0.010
N
N
O
N
>30
>30
NT
NT
N
O
N
N
N
N
N
O
2.0 0.2 0.075 0.013
1.2 0.2 0.014 0.002
4.4 0.3 0.022 0.001
1.4 0.15 0.035 0.003
N
O
S
N
O
Once SAR trends were established, we proceeded with
further evaluation of our most active compounds. In
the NCI/ADR breast cancer MDR positive cell line that
is resistant to TaxolÒ, selected compounds were assayed
for their antimitotic activity. Most of the compounds
tested were shown to be highly active in arresting
MDR cells with EC50s as low as 7.8 nM. TaxolÒ was
completely inactive in this assay (Table 3). The binding
site of our compounds on tubulin was also determined.
When these compounds are tested in a colchicine com-
petition binding assay,12 representative analogs compet-
ed for the colchicine binding site on tubulin with an
IC50 = 0.01–0.4 lM (Table 3).
N
O
S
N
>30
>30
NT
NT
N
N
H
a See Table 1 for footnotes for the assay description.
Pharmacokinetic properties of several analogs were
evaluated (Table 4). When dosed ip, selected compounds
showed good in vivo exposure with AUC values ranging
from 6 to 100 lM h. Compounds (10), (13), and (33)
achieved significant AUC values (30–100 lM h). Such
an exposure suggests that even at moderate doses, effica-
cious compound concentrations are likely to be achieved
in vivo. It is noteworthy that compounds of the oxadiaz-
ole series reported here have longer half-lives than previ-
ously reported triazoles8 (data not shown). In addition,
some oxadiazoles (i.e., 13) demonstrated oral exposure
(AUC = 8.8 lM h). The desirable pharmacokinetic
pyridine ring Y was replaced by a phenyl ring, corre-
sponding compounds had similar or enhanced potency,
as exemplified by compound (32). Compound (32) was
synthesized using conditions listed in Scheme 4: 2-ami-
no-benzoic acid methyl ester was alkylated to give ester
intermediate G, which was then converted to its final
form (32) following Method I. Using a similar method-
ology, analog (33) with a thiophene Y ring was synthe-
sized and demonstrated good cellular potency. Other
compounds with alternative Y rings such as imidazole,
pyrazole, and isothiazole analogs were less potent or

X. Ouyang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1191–1196
1195
O
O
O
O
N
N
O
O
NH
(iv)
NH
(iii)
Br
N3
(i)
(ii)
O
O
34
NO2
NO2
NO2
NH2
H
I
J
Scheme 5. Reagents and conditions: (i) NaN3, acetone, H2O, 50 °C, 0.5 h, 88%; (ii) PPh3, 6-isothiocyanato-2,3-dihydro-benzo[1,4]dioxine, dioxane,
95 °C, 0.4 h, 15%; (iii) H2, Pd/C, MeOH, 50 °C, 4 h, 87%; (iv) pyridine-2-carboxaldehyde, NaBH(OAc)3, AcOH, toluene, 70 °C, 22 h, 66%.
O
O
O
O
S
S
O
O
NH
NH
(ii)
(iii)
(i)
S
N
N
35
H2N
N
NO2
NH2
H
K
Scheme 6. Reagents and conditions: (i) 2-Bromo-1-(2-nitro-phenyl)-ethanone, TEA, THF, À78–25 °C, 12 h, 81%; (ii) H2, Pd/C, EtOH, 60 °C, 4 h,
83%; (iii) pyridine-2-carboxaldehyde, NaBH(OAc)3, AcOH, DCE, 25 °C, 16 h, 49%.
O
O
Boc
N
O
O
N
O
O
NH
N
(iv)
(i)
NH
(ii)
N
N
36
H
H2N
N
Boc
NH2
H
NO2
Scheme 7. Reagents and conditions: (i) 2-Bromo-1-(2-nitro-phenyl)-ethanone, DBU, CH3CN, 50 °C, 18 h, 25%; (ii) (Boc)2O, DMAP, 25 °C, 24 h,
93%; (iii) H2, Pd/C, EtOH, 40 °C, 4 h, 97%; (iv) pyridine-2-carboxaldehyde, NaBH(OAc)3, AcOH, toluene, 60 °C, 6 h, 83%; (v) TFA, DCM, 25 °C,
1 h, 93%.
Table 4. Pharmacokinetic properties for selected compounds in micea
Table 3. In vitro data for selected compounds and standards
Compound
Cmax (lM)
T1/2 (h)
AUC (0–4 h) (lM*h)
Compound
EC50 (lM)
IC50 (lM) colchicine
MDR cellsa
bindingb
Triazole
Triazoleb
7.3
BLDc
15.1
6.5
0.62
NA
2.6
13.6
NA
52.6
6.7
Taxol
Combretastatin A4
>10
NA
10
11
13
13b
14
19
32
33
34
0.0015 0.0003
0.0078 0.0019
0.019 0.003
0.027 0.003
0.256 0.0002
0.128 0.028
0.037 0.009
0.046 0.0012
0.103 0.017
0.03 0.02
0.03 0.005
0.03 0.001
0.19 0.04
0.03 0.0058
0.39 0.06
0.39 0.06
0.075 0.004
0.01 0.001
0.8
2.7
10
11
13
14
19
32
33
34
12.5
3.8
31.2
8.8
2.2
4.1
4.9
21.5
26.3
17.2
102
16.4
6.4
0.78
1.5
59.2
4.6
0.75
2.43
14.4
a IP dosing at 60 mg/kg in DMSO/cremophore.
b PO dosing at 60 mg/kg in ethanol/Tween 80/PEG400.
c BLD, below the level of detection.
a Compound concentration required for 50% of the NCI/ADR cells
(MDR) to accumulate at the G2/M phase of the cell cycle.
b Colchicine competition binding assay, with tubulin at 40 nM and
[3H]colchicine at 65 nM.
profile for this series strongly supports further evalua-
tion of oxadiazoles in mouse tumor models. Efficacy
studies in mouse xenograft models are currently in pro-
gress and will be reported in due course.
for this class of compounds in terms of inhibition of
tubulin polymerization in vitro and mitotic arrest of tu-
mor cells. Selected compounds displayed nanomolar
potency against tumor cells including those displaying
a MDR phenotype. Compounds from this series demon-
strated substantial plasma levels in mice via both oral
and intraperitoneal administration. In vivo evaluation
of the oxadiazole series as antimitotic agents is in
progress.
In conclusion, a series of oxadiazole derivatives has been
discovered as a novel class of tubulin polymerization
inhibitors that bind to the colchicine site on tubulin.13
Structure–activity relationships have been established

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X. Ouyang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1191–1196
6. Bacher, G.; Nickel, B.; Emig, P.; Vanhoefer, U.; Seeber,
Acknowledgments
S.; Shandra, A.; Klenner, T.; Beckers, T. Cancer Res 2001,
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We thank James Tonra, Wai Wong, Daniel Hicklin,
Paul Kussie, and Peter Bohlen for their guidance and
support, and Daniel Milligan, Raphael Rios, Paul
Calder, Hui-Hsien Chiang, and Sheetal Patel for techni-
cal assistance.
7. (a) Yoshimatsu, K.; Yamaguchi, A.; Yoshino, H.; Kitoh,
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Supplementary material
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2005.11.094.
10. Primary alcohol and NaH were used instead of primary
amine.
References and notes
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