Discovery of 3-aryl-5-aryl-1,2,4-oxadiazoles as a new series of apoptosis inducers. 2. Identification of more aqueous soluble analogs as potential anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2009.05.052

As a continuation of our efforts to discover and develop the 3-aryl-5-aryl-1,2,4-oxadiazole series of apoptosis inducers as potential anticancer agents, we explored substitutions at the 2- and 3-positions of the 3-aryl group to improve the aqueous solubil

Full text of DOI:10.1016/j.bmcl.2009.05.052

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4410–4415
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 3-aryl-5-aryl-1,2,4-oxadiazoles as a new series of apoptosis
inducers. 2. Identification of more aqueous soluble analogs as potential
anticancer agents
William Kemnitzer, Jared Kuemmerle, Han-Zhong Zhang, Shailaja Kasibhatla, Ben Tseng,
*
John Drewe, Sui Xiong Cai
EpiCept Corporation, Inc. 6650 Nancy Ridge Drive, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
As a continuation of our efforts to discover and develop the 3-aryl-5-aryl-1,2,4-oxadiazole series of apop-
tosis inducers as potential anticancer agents, we explored substitutions at the 2- and 3-positions of the 3-
aryl group to improve the aqueous solubility properties and identify development candidates. A small
substitution such as methyl or hydroxymethyl at the 2-position was well tolerated. This modification,
in combination with a 3-substituted furan ring as the 5-aryl group, resulted in 4g and 4h, which have
improved solubility properties. Compound 4g was found to have good in vivo efficacy in animal studies
via intravenous administration.
Received 29 April 2009
Revised 13 May 2009
Accepted 14 May 2009
Available online 18 May 2009
Keywords:
Apoptosis inducers
Anticancer agents
HTS
Ó 2009 Elsevier Ltd. All rights reserved.
SAR
Currently, cancer is the second leading cause of death in the
United States and in developed countries.1 Tremendous progress
has been made in the war against cancer with the development
of many novel chemotherapy agents,2 including paclitaxel, doce-
taxel3 and ixabepilone,4 as well as small molecule targeted thera-
pies5 such as imatinib6 and sorafenib.7 However, due to toxicity
and drug-resistance problems with many currently available treat-
ments, it remains a great challenge to discover and develop more
effective drugs to conquer cancer.1
Since it is known that the anti-tumor efficacy of many chemo-
therapeutic agents are correlated with their ability to induce apop-
tosis,8 novel approaches to promote apoptosis in cancer cells via
targeting regulators of apoptosis9 could lead to the development
of new anticancer treatments.10 In addition, these new agents
may overcome tumor resistance to conventional anti-cancer
drugs.11 We therefore have developed a cell-based, high through-
put screening technology using our novel caspase-3 substrates,12
termed Apoptosis Screening and AntiCancer Platform (ASAP), for
the identification of apoptosis inducers as potential new anticancer
agents. Since the screening technology measures the activation of
downstream caspase-3 in the cells, our assay can discover apopto-
sis inducers that interact with either known or novel targets up-
stream of caspase-3.
Applying this HTS assay, we have reported the discovery and
structure–activity relationship (SAR) studies of several novel series
of apoptosis inducers interacting with known or novel molecular
targets (Chart 1).13 These include N-phenyl nicotinamides (1a),14
4-aryl-4H-chromenes (1b),15 gambogic acid (1c),16 4-anilino-2-
(2-pyridyl)pyrimidines (1d),17 N-methyl-N-phenylnaphthalen-1-
amines (1e),18 4-anilinoquinazolines (1f),19 N-phenyl-1H-pyrazol-
o[3,4-b]quinolin-4-amines (1g),20 1-benzoyl-3-cyanopyrrolo[1,2-
a]quinolines (1h),21 and N-aryl-9-oxo-9H-fluorene-1-carboxam-
ides (1i).22 We also have reported the discovery of 3-(4-chloro-
phenyl)-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole (1j) as
a
novel apoptosis inducer with tumor selective properties,23 and
the identification of TIP47, an insulin-like growth factor II (IGF II)
receptor binding protein, as its molecular target.24 SAR study of
3-aryl-5-aryl-1,2,4-oxadiazoles indicated that a 3-substituted thio-
phen-2-yl or a furan-2-yl in the 5-position of 1,2,4-oxadiazole is
essential for the apoptosis inducing activity. In the 3-position of
the 1,2,4-oxadiazole, a substituted phenyl or pyridyl is important
for activity.23 Due to the three aryl ring structure of 3-aryl-5-
aryl-1,2,4-oxadiazoles, these molecules are relatively planar,
resulting in low aqueous solubility and our initial in vivo studies
were done by ip administration.24 Herein we wish to report addi-
tional SAR studies to improve the aqueous solubility properties
of 3-aryl-5-aryl-1,2,4-oxadiazoles and identify potential clinical
development candidates.
3-Aryl-5-aryl-1,2,4-oxadiazoles 4a–4b, 4e and 4g–4h were pre-
* Corresponding author. Tel.: +1 858 202 4006; fax: +1 858 202 4000.
E-mail addresses: scai@epicept.com, sxcai@sbcglobal.net (S.X. Cai).
pared in two steps according to reported procedures (Scheme 1).23
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.05.052

W. Kemnitzer et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4410–4415
OMe
O
4411
OMe
MeO
Br
OH
CF3
N
OMe
OMe
N
NO2
O
H
N
N
N
O
O
O
CN
O
N
N
H
O
N
O
1b
NH2
OEt
NMe2
OH
1a
1c
1d
1e
O
OMe
CN
O
N
Cl
N
HN
O
Cl
N
O
N
N
N
H
N
S
N
N
N
Me
O
N
N
N
N
1f
1g
1h
1i
1j
Chart 1.
H2N
R
Ar1
N
Ar2
Ar2
R
a
NC Ar2
b
Cl
Cl
a
O
N
N
HO
N
N
X
X
2a-2e
3a-3e
4a-4b, 4e, 4g-4h
O
N
O
N
Scheme 1. Reagents: (a) H2NOH/EtOH/THF; (b) Ar1COCl/dioxane/pyridine.
Br
4f, X = S, R = Cl
4i, X = O, R = Br
1l, X = S, R = Cl
4g, X = O, R = Br
Reaction of substituted arylnitriles 2a–2e with hydroxylamine in
ethanol and THF25 produced N-hydroxy-arylamidines 3a–3e,
which reacted with substituted aryl-2-carbonyl chloride in a one-
pot reaction to produce the 3-aryl-5-aryl-1,2,4-oxadiazoles.26
Dimethylamino analog 4c was prepared from methylation of the
amino compound 4b (Scheme 2). The dimethylaminoethylamino
analog 4d was synthesized from alkylation of 4b (Scheme 3). The
bromomethyl analogs 4f and 4i were prepared from bromination
of 1l and 4g, respectively. Reaction of 4i with sodium hydroxide
in water/dioxane produced the hydroxymethyl analog 4j (Scheme
4). The phosphate prodrug was synthesized using procedures sim-
ilar to what was reported for the preparation of combretastatin A-4
phosphate prodrug and other prodrugs.27,28 Reaction of the bromo-
methyl analog 4i with di-tert-butylphosphate in CH3CN with ce-
sium fluoride produced the phosphate ester 4k, which was
treated with HCl in dioxane to produce the acid 4l. The disodium
salt 4m was synthesized by reaction of the acid 4l with sodium
methoxide in methanol (Scheme 5).
Br
Cl
b
N
O
O
N
OH
4j
Scheme 4. Reagents: (a) NBS/AIBN/Br2/CCl4/h
m
; (b) NaOH/H2O/dioxane.
The apoptosis inducing activity of these 3-aryl-5-aryl-1,2,4-oxa-
diazoles was measured by our cell- and caspase-based HTS assay14
against three cell lines, T47D breast cancer cells, DLD-1 colon can-
cer cells, and H-1299 non-small cell lung cancer cells, and the re-
sults are summarized in Table 1. It was previously reported that
the 3,4-dichlorophenyl analog 1k maintained the activity of the
4-substituted analog 1j.23 We therefore explored introduction of
other groups at the 3-position. Encouragingly, the 3-methyl analog
4a was found to have activity similar to that of 1k, while introduc-
tion of an amino (4b) or dimethylamino (4c) group at the 3-posi-
tion only lowered slightly the activity. Introduction of
dimethylaminoethylamino group (4d) in an effort to increase
aqueous solubility resulted in an inactive compound up to
a
Cl
Cl
Cl
Cl
a
N
N
10
position.
As an alternate approach for increasing solubility, we reasoned
lM, indicating that a large group is not tolerated at the 3-
S
S
NH2
NMe2
O
N
O
N
4b
4c
that a substitution at the 2-position would force the phenyl ring
out of the plane of the 1,2,4-oxadiazole ring and might improve
solubility properties. Based on ChemDraw3D models after energy
minimizations, the phenyl group was found to lie out of the plane
of the 1,2,4-oxadiazole ring by about 30° for compound 1j, but in-
creased to about 40° for the 2-methyl analog 1l and about 50° for
the 2-bromomethyl analog 4f (Fig. 1), suggesting that a substitu-
tion in the 2-position of the phenyl does make the molecule less
planar. The 2-methyl analog 1l was equipotent to 1j23 while the
2-amino (4e) and 2-bromomethyl (4f) analogs were found to be
3–4-fold less active.
Scheme 2. Reagents: (a) HCHO/NaBH4/THF/H2SO4.
Cl
Cl
a
N
4b
S
N
N
O
N
H
4d
Scheme 3. Reagents: (a) BrCH2CH2NMe2ÁHBr/NEt3/EtOH.

4412
W. Kemnitzer et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4410–4415
Br
Br
Cl
Cl
a
b
N
N
4i
O
O
O
O
N
O
O
N
Ot-Bu
R
R
P
P
O
O
Ot-Bu
4l, R = OH
c
4m, R = O-Na+
4k
Scheme 5. Reagents: (a) CsF/KOP(O)–(Ot-Bu)2/CH3CN; (b) 4.0 M HCl/dioxane; (c) NaOMe/MeOH.
Table 1
Activity of 3-aryl-5-aryl-1,2,4-oxadiazoles in the caspase activation assay
Ar1
N
Ar2
O
N
Compound #
Ar1
Ar2
EC50
DLD1
(l
M)a
T47D
H1299
>10
Cl
Cl
Cl
1jb
1.2 0.1
0.44 0.06
0.37 0.05
S
Cl
Cl
1kb
1lb
4a
1.4 0.2
0.91 0.09
1.7 0.1
2.4 1.1
>10
>10
>10
>10
S
S
S
S
Cl
Cl
Cl
Cl
0.38 0.06
0.59 0.01
0.58 0.10
Me
Cl
Me
Cl
4b
NH2
Cl
N
Cl
Cl
Cl
Cl
4c
4d
4e
4f
2.1 0.4
0.54 0.16
>10
S
S
S
S
Cl
>10
>10
>10
NH(CH2)2NMe2
Cl
3.1 0.3
1.1 0.1
>10
H2N
Cl
4.5 0.1
1.1 0.04
8.6 0.7
BrH2C

W. Kemnitzer et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4410–4415
4413
Table 1 (continued)
Compound #
Ar1
Ar2
EC50 (l
M)a
T47D
DLD1
H1299
>10
Br
Br
Br
Br
Br
Br
Cl
4g
4h
4i
1.1 0.1
0.71 0.11
1.2 0.1
NDc
O
Me
N
Cl
Cl
0.94 0.06
2.2 0.2
2.9 0.5
>10
>10
O
O
O
O
O
Me
2.3 1.5
BrH2C
Cl
4j
NDc
>10
HOH2C
Cl
4l
NDc
>10
O
OH
OH
P
O
Cl
4m
>10
NDc
>10
O
O-Na+
O-Na+
P
O
Vinblastine
Colchicine
Taxol
NAd
NA
NA
NA
NA
NA
0.032 0.006
0.014 0.003
0.037 0.003
0.16 0.04
0.18 0.04
0.054 0.007
0.082 0.016
0.05 0.01
0.098 0.015
a
Cells were treated with the test compounds for 48 h, data are the mean of three or more experiments and are reported as mean standard error of the mean (SEM).
b
c
Data from Ref. 23.
ND, not determined.
NA, not applied.
d
To further improve the solubility properties, we replaced the
the activity towards T47D cells. Similar to compound 1j, all the
3-aryl-5-aryl-1,2,4-oxadiazoles tested were either inactive, or
much less active against non-small cell lung cancer cell line
H1299, indicating that modifications at the 2 and 3-positions of
the phenyl group did not change the selectivity profile of these
compounds. In comparison, vinblastine, colchicine and taxol, three
known cytotoxic compounds, had similar EC50 values in the cas-
pase activation assay in all the three cell lines.
Selected compounds as well as control compounds were tested
by the traditional inhibition of cell proliferation (GI50) assay to con-
firm that the active compounds can inhibit tumor cell growth, as
well as to confirm the tumor selectivity as observed from the cas-
pase assay. The growth inhibition assays in T47D and H1299 cells
were run in a 96-well microtiter plate as described previously14
and the data are summarized in Table 2. Compound 4g had activity
similar to 1j as an inhibitor of T47D cancer cell growth, and was
thiophene ring in 1l with a less hydrophobic furan ring. Compound
4g has a C log P value of 4.56 compared to 4.98 for 1l and was
found to have activity similar to that of 1l. The 2-pyridyl analog
4h retained the activity of 4g while decreasing the C log P value
to 3.40. Several compounds were tested in a variety of solvents
and mixtures of solvents to determine the maximal solubility.
Compound 4g was found to be soluble in a solution (DMSO/etha-
nol/Cremophor EL/D5W = 11.5:2.25:11.25:75) at 4.8 mg/mL, while
compound 4h was soluble in a solution (ethanol/Cremophor EL/
D5W = 6.0:11.3:82.7) at 3.8 mg/mL. Both solutions are suitable
for intravenous (iv) administration in animal studies. The bromo-
methyl analog 4i and hydroxymethyl analog 4j were about 2–3-
fold less active than 4g. Compound 4j (C log P = 3.02) also had good
solubility in a solution (ethanol/Cremophor EL/D5W = 4.0:10.0:
86.0) at 4.0 mg/mL. The disodium salt phosphate prodrug 4m
was found to have good aqueous solubility (10 mg/mL in D5W),
similar to what has been reported for the combretastatin A-4 phos-
phate prodrug.27 However, the phosphate prodrugs 4l and 4m
were found to be inactive in the caspase activation assay up to
not active in H1299 cells up to 10 lM. This is comparable to what
was observed in the caspase activation assay, confirming that com-
pound 4g is selective against certain tumor types. Compounds 4h
and 4j also had good activity against T47D cells and were inactive
in H1299 cells. In comparison colchicine and taxol had similar GI50
values in both cell lines tested.
10 lM, suggesting that the conversion of 4l and 4m to the active
drug 4j might be slow under the assay conditions.
The activities of these 3-aryl-5-aryl-1,2,4-oxadiazoles against
the human colorectal cancer cell line DLD-1 roughly paralleled
Compound 4g was selected for in vivo tumor efficacy testing.
The MX-1 human breast cancer xenograft in vivo experiment

4414
W. Kemnitzer et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4410–4415
2000
1500
1000
500
0
Vehicle
Taxol 7 mg/kg
Compound4g 20 mg/kg
Combination
0
2
4
6
8
10 12 14 16 18 20
Day After Initial Dose
Figure 2. Compound 4g inhibited the growth of established (ꢀ100 mm3) MX-1
tumor xenografts in Crl:Nu/Nu-nuBR mice. Compound 4g and paclitaxel were dosed
intravenous at 20 and 7 mg/kg, respectively, days 1–5 and 8–12.
P value as
calculated by Student’s t-test is <0.01 for the combination.
for iv administration in animal studies as potential anticancer
agents. In addition, the phosphate prodrug 4m also had good aque-
ous solubility.
References and notes
1. Varmus, H. Science 2006, 312, 1162.
2. Harrison, M. R.; Holen, K. D.; Liu, G. Clin. Adv. Hematol. Oncol. 2009, 7, 54.
3. Kingston, D. G.; Newman, D. J. Curr. Opin. Drug Discovery Dev. 2007, 10, 130.
4. Hunt, J. T. Mol. Cancer Ther. 2009, 8, 275.
5. Baselga, J. Science 2006, 312, 1175.
6. Cross, S. A.; Lyseng-Williamson, K. A. Drugs 2007, 67, 2645.
7. Wood, L. S.; Manchen, B. Clin. J. Oncol. Nurs. 2007, 11, 649.
8. Vial, J. P.; Belloc, F.; Dumain, P.; Besnard, S.; Lacombe, F.; Boisseau, M. R.;
Reiffers, J.; Bernard, P. Leukocyte Res. 1997, 21, 163.
9. Fesik, S. W. Nat. Rev. Cancer 2005, 5, 876.
Figure 1. ChemDraw3D models of compounds 1j, 1l and 4f after MM2 energy
minimizations.
10. (a) van Delft, M. F.; Wei, A. H.; Mason, K. D.; Vandenberg, C. J.; Chen, L.;
Czabotar, P. E.; Willis, S. N.; Scott, C. L.; Day, C. L.; Cory, S.; Adams, J. M.;
Roberts, A. W.; Huang, D. C. Cancer Cell 2006, 10, 389; (b) Zobel, K.; Wang, L.;
Varfolomeev, E.; Franklin, M. C.; Elliott, L. O.; Wallweber, H. J.; Okawa, D. C.;
Flygare, J. A.; Vucic, D.; Fairbrother, W. J.; Deshayes, K. ACS Chem. Biol. 2006, 1,
525; (c) Shangary, S.; Qin, D.; McEachern, D.; Liu, M.; Miller, R. S.; Qiu, S.;
Nikolovska-Coleska, Z.; Ding, K.; Wang, G.; Chen, J.; Bernard, D.; Zhang, J.; Lu,
Y.; Gu, Q.; Shah, B. R.; Pienta, K. J.; Ling, X.; Kang, S.; Guo, M.; Sun, Y.; Yang, D.;
Wang, S. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 3933.
Table 2
Cell growth inhibition of 3-aryl-5-aryl-1,2,4-oxadiazoles
Compound #
GI50 (l
M)a
T47D
H1299
11. Tolomeo, M.; Simoni, D. Curr. Med. Chem. Anticancer Agents 2002, 2, 387.
12. (a) Cai, S. X.; Zhang, H. Z.; Guastella, J.; Drewe, J.; Yang, W.; Weber, E. Bioorg.
Med. Chem. Lett. 2001, 11, 39; (b) Zhang, H. Z.; Kasibhatla, S.; Guastella, J.;
Drewe, J.; Tseng, B.; Cai, S. X. Bioconjugate Chem. 2003, 14, 458.
13. Cai, S. X.; Drewe, J.; Kasibhatla, S. Curr. Med. Chem. 2006, 13, 2627.
14. Cai, S. X.; Nguyen, B.; Jia, S.; Guastella, J.; Reddy, S.; Tseng, B.; Drewe, J.;
Kasibhatla, S. J. Med. Chem. 2003, 46, 2474.
1jb
4g
4h
4j
Colchicine
Taxol
0.19 0.03
0.13 0.04
0.66 0.23
0.50 0.01
0.14 0.03
0.026 0.003
>10
>10
>10
>10
0.063 0.016
0.023 0.003
15. (a) Kemnitzer, W.; Kasibhatla, S.; Jiang, S.; Zhang, H.; Wang, Y.; Zhao, J.; Jia, S.;
Herich, J.; Labreque, D.; Storer, R.; Meerovitch, K.; Bouffard, D.; Rej, R.; Denis,
R.; Blais, C.; Lamothe, S.; Attardo, G.; Gourdeau, H.; Tseng, B.; Drewe, J.; Cai, S.
X. J. Med. Chem. 2004, 47, 6299; (b) Gourdeau, H.; Leblond, L.; Hamelin, B.;
Desputeau, C.; Dong, K.; Kianicka, I.; Custeau, D.; Bourdeau, C.; Geerts, L.; Cai, S.
X.; Drewe, J.; Labrecque, D.; Kasibhatla, S.; Tseng, B. Mol. Cancer Ther. 2004, 3,
1375; (c) Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Zhao, J.; Crogan-
Grundy, C.; Xu, L.; Lamothe, S.; Gourdeau, H.; Denis, R.; Tseng, B.; Kasibhatla, S.;
Cai, S. X. J. Med. Chem. 2007, 50, 2858; (d) Kemnitzer, W.; Drewe, J.; Jiang, S.;
Zhang, H.; Crogan-Grundy, C.; Labreque, D.; Bubenick, M.; Attardo, G.; Denis,
R.; Lamothe, S.; Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S. X. J. Med. Chem.
2008, 51, 417.
16. (a) Zhang, H. Z.; Kasibhatla, S.; Wang, Y.; Herich, J.; Guastella, J.; Tseng, B.;
Drewe, J.; Cai, S. X. Bioorg. Med. Chem. 2004, 12, 309; (b) Kasibhatla, S.; Jessen,
K.; Maliartchouk, S.; Wang, J.; English, N.; Drewe, J.; Qui, L.; Archer, S.; Ponce,
A.; Sirisoma, N.; Jiang, S.; Zhang, H.-Z.; Gehlsen, K.; Cai, S. X.; Green, D. R.;
Tseng, B. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 12095.
17. (a) Sirisoma, N.; Kasibhatla, S.; Nguyen, B.; Pervin, A.; Wang, Y.; Claassen, G.;
Tseng, B.; Drewe, J.; Cai, S. X. Bioorg. Med. Chem. 2006, 14, 7761; (b) Sirisoma,
N.; Pervin, A.; Nguyen, B.; Kasibhatla, S.; Tseng, B.; Drewe, J.; Cai, S. X. Bioorg.
Med. Chem. Lett. 2009, 19, 2305.
18. Jiang, S.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S. X. Bioorg. Med. Chem.
Lett. 2008, 18, 5725.
19. (a) Kasibhatla, S.; Baichwal, V.; Cai, S. X.; Roth, B.; Skvortsova, I.; Skvortsov, S.;
Lukas, P.; English, N. M.; Sirisoma, N.; Drewe, J.; Pervin, A.; Tseng, B.; Carlson, R.
O.; Pleiman, C. M. Cancer Res. 2007, 67, 5865; (b) Sirisoma, N.; Kasibhatla, S.;
a
Cells were treated with the test compounds for 48 h, data are the mean of three
or more experiments and are reported as mean standard error of the mean (SEM).
b
Data from Ref. 23.
was performed as described previously.24 Compound 4g, dosed iv
at 20 mg/kg once per day for 5 days for two weeks in combination
with paclitaxel, was found to be active in the MX-1 human breast
cancer xenograft model in mice, resulting in 80% tumor growth
inhibition ( Fig. 2), and is well tolerated with maximum body
weight decrease of <10%.
In conclusion, we have explored the synthesis of compounds
with substitutions at the 2- or 3-positions of the phenyl group of
3-aryl-5-aryl-1,2,4-oxadiazoles with the aim of improving aqueous
solubility properties. It was found that a small substitution at the
2-position is well tolerated. This substitution also forces rotation
of the phenyl ring out of the plane of the oxadiazole, making the
molecule less planar. Together with replacing the thiophene ring
by a furan ring, this study led to several potent compounds, such
as 4g and 4h, with improved solubility that can be formulated

W. Kemnitzer et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4410–4415
4415
Pervin, A.; Zhang, H.; Jiang, S.; Willardsen, J. A.; Anderson, M.; Baichwal, V.;
Mather, G. G.; Jessing, K.; Hussain, R.; Hoang, K.; Pleiman, C. M.; Tseng, B.;
Drewe, J.; Cai, S. X. J. Med. Chem. 2008, 51, 4771; (c) Sirisoma, N.; Pervin, A.;
Zhang, H.; Jiang, S.; Willardsen, A. J.; Anderson, M.; Mather, G. G.; Pleiman, C.
M.; Kasibhatla, S.; Tseng, B.; Drewe, J.; Cai, S. X. J. Med. Chem. 2009, 52, 2341.
20. Zhang, H.-Z.; Claassen, G.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S. X.
Bioorg. Med. Chem. 2008, 16, 222.
23. Zhang, H.-Z.; Kasibhatla, S.; Kuemmerle, J.; Kemnitzer, W.; Oliis-Mason, K.; Qui,
L.; Crogran-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S. X. J. Med. Chem. 2005, 48,
5215.
24. Jessen, K.; English, N.; Wang, J.; Qui, L.; Brand, R.; Maliartchouk, S.; Drewe, J.;
Kuemmerle, J.; Zhang, H.-Z.; Gehlsen, K.; Tseng, B.; Cai, S. X.; Kasibhatla, S. Mol.
Cancer Ther. 2005, 4, 761.
25. Bernasek, E. J. Org. Chem. 1957, 22, 1263.
21. Kemnitzer, W.; Kuemmerle, J.; Jiang, S.; Zhang, H.; Sirisoma, N.; Kasibhatla, S.;
Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S. X. Bioorg. Med. Chem. Lett. 2008,
18, 6259.
22. Kemnitzer, W.; Sirisoma, N.; Nguyen, B.; Jiang, S.; Kasibhatla, S.; Crogan-
Grundy, C.; Tseng, B.; Drewe, J.; Cai, S. X. Bioorg. Med. Chem. Lett. 2009, 19,
3045.
26. (a) Chiou, S.; Shine, H. J. J. Heterocycl. Chem. 1989, 26, 125; (b) Haugwitz, R. D.;
Martinez, A. J.; Venslavsky, J.; Angel, R. G.; Maurer, B. V.; Jacobs, G. A.;
Narayanan, V. L.; Cruthers, L. R.; Szanto, J. J. Med. Chem. 1985, 28, 1234.
27. Pettit, G. R.; Temple, C., Jr.; Narayanan, V. L.; Varma, R.; Simpson, M. J.; Boyd, M.
R.; Rener, G. A.; Bansal, N. Anticancer Drug Des. 1995, 10, 299.
28. Pettit, G. R.; Lippert, J. W., 3rd Anticancer Drug Des. 2000, 15, 203.