Discovery of N-methyl-4-(4-methoxyanilino)quinazolines as potent apoptosis inducers. Structure-activity relationship of the quinazoline ring

Article abstract of DOI:10.1016/j.bmcl.2010.01.155

As a continuation of our efforts to discover and develop apoptosis inducing N-methyl-4-(4-methoxyanilino)quinazolines as novel anticancer agents, we explored substitution at the 5-, 6-, 7-positions of the quinazoline and replacement of the quinazoline by

Full text of DOI:10.1016/j.bmcl.2010.01.155

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2330–2334
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of N-methyl-4-(4-methoxyanilino)quinazolines as potent
apoptosis inducers. Structure–activity relationship of the quinazoline ring
Nilantha Sirisoma a, Azra Pervin a, Hong Zhang a, Songchun Jiang a, J. Adam Willardsen b, Mark B. Anderson b,
Gary Mather b, Christopher M. Pleiman b, Shailaja Kasibhatla a, Ben Tseng a, John Drewe a, Sui Xiong Cai a,
*
a EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA
b Myriad Pharmaceuticals Inc., 320 Wakara Way, Salt Lake City, UT 84108, 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 apoptosis inducing N-methyl-4-(4-methoxyani-
lino)quinazolines as novel anticancer agents, we explored substitution at the 5-, 6-, 7-positions of the
quinazoline and replacement of the quinazoline by other nitrogen-containing heterocycles. A small group
at the 5-position was found to be well tolerated. At the 6-position a small group like an amino was pre-
ferred. Substitution at the 7-position was tolerated much less than at the 6-position. Replacing the carbon
at the 8-position or both the 5- and 8-positions with nitrogen led to about 10-fold reductions in potency.
Replacement of the quinazoline ring with a quinoline, a benzo[d][1,2,3]triazine, or an isoquinoline ring
showed that the nitrogen at the 1-position is important for activity, while the carbon at the 2-position
can be replaced by a nitrogen and the nitrogen at the 3-position can be replaced by a carbon. Through
the SAR study, several 5- or 6-substituted analogs, such as 2a and 2c, were found to have potencies
approaching that of lead compound N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (1g,
EP128495, MPC-6827, AzixaÒ).
Received 22 December 2009
Revised 22 January 2010
Accepted 27 January 2010
Available online 4 February 2010
Keywords:
Apoptosis inducers
Anticancer agents
SAR
Ó 2010 Elsevier Ltd. All rights reserved.
Apoptosis is a well-controlled process for the elimination of
excessive cells.1 The mechanism of apoptosis involves a cascade
of initiator and effector caspases that are activated sequentially.2
Caspase-3 is one of the key effector caspases that cleaves multiple
protein substrates in cells, leading to cell death.3 It has been
determined that many clinically useful cytotoxic agents induce
apoptosis in cancer cells.4 Among them, the proapoptotic chemo-
therapeutic agents that target tubulin, including taxanes such as
Taxol and Taxotere and vinca alkaloids such as vincristine, vinblas-
tine and vinorelbine are among the most successful anticancer
therapies.5 Compounds that induce apoptosis in cancer cells by tar-
geting the clinically validated tubulin/microtubule system while
retaining activity in multi-drug-resistant tumors, exemplified by
the recent approval of the epothilone analog ixabepilone,6 should
provide new treatment options for cancers.7 In addition, since
there are few treatments for neurologic cancers due to the
blood–brain barrier (BBB) that prevents many traditional and new-
er anticancer drugs from entering the brain parenchyma,8 there is
an urgent need for effective anticancer drugs with good BBB
penetration.
We have been interested in the discovery and development of
apoptosis inducers as potential anticancer agents, and have devel-
oped a cell-based Anticancer Screening Apoptosis Platform (ASAP)
using our novel fluorescent caspase-3 substrates.9 We have re-
ported the discovery and structure–activity relationship (SAR)
studies of several novel series of apoptosis inducers as well as
the identification of their molecular targets.10 These include
gambogic acid (1a)11 and the transferrin receptor as its molecular
target,12 3-aryl-5-aryl-1,2,4-oxadiazoles (e.g., 1b)13 and tail inter-
acting protein (TIP47), an insulin growth factor II (IGF II) receptor
binding protein as its molecular target,14 4-aryl-4H-chromenes
(e.g., 1c) as potent apoptosis inducers15 and vascular disrupting
agents,16 as well as 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1H)-
quinolinones (e.g., 1d) that activate apoptosis in cancer cell lines
with deregulated Myc17 (Chart 1). More recently, we have reported
the discovery of N4-(4-methoxyphenyl)-N4-methyl-N2-((E)-3,7-
dimethylocta-2,6-dienyl)quinazoline-2,4-diamine (1e) as a potent
apoptosis inducer using our cell- and caspase-based HTS assay,
and SAR studies that led to the identification of 2-chloro-N-(4-
methoxyphenyl)-N-methylquinazolin-4-amine (1f)18 and N-(4-
methoxyphenyl)-N,2-dimethylquinazolin-4-amine (1g, EP128495,
MPC-6827, AzixaÒ)19 as potent apoptosis inducers with activity
in multi-drug-resistant cancer cell lines, high BBB penetration,
good pharmacokinetics and high efficacies in in vivo anticancer
xenograft models.20 Utilizing a tritium labeled photoaffinity ana-
* Corresponding author at present address: IMPACT Therapeutics, 10 Xinghuo
Road, Floor 9, High and New Technology Zone, Nanjing, Jiangsu 210061, China.
Tel.: +86 25 58619055.
E-mail address: s.cai@impacttherapeutics.com (S.X. Cai).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.155

N. Sirisoma et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2330–2334
2331
OMe
CO2H
MeO
Br
Cl
O
Cl
O
F
O
O
N
O
CN
S
N
O
N
Me2N
O
1c
NH2
OH
1b
1a
OMe
N
O
5
8
4
Br
NO2
6
7
3
2
N
N
R
N
H
O
1
1e, R = HN
1f, R = Cl
1d
1g, R = Me
Chart 1.
log, the primary molecular target of these N-methyl-4-anilinoqui-
nazolines has been identified as tubulin and compound 1g was
found to inhibit tubulin polymerization via binding at or near the
colchicine site.20 Compound 1g is currently under clinical develop-
ment as an novel anticancer agent.
Cl
OH
H2N
H2N
N
O
5c, R = 5-NO2
5d, R = 4-NO2
R
N
5e
NH2
We have reported the SAR study of N-methyl-4-anilinoquinaz-
olines that showed that a small alkyl group at the nitrogen of the
anilino group is essential for apoptosis inducing activity. A small
and electron-donating group like methoxy or ethoxy at the 4-posi-
tion of the anilino ring is important for activity and a small group
such as chloro, methyl, methoxy, fluoromethyl or hydroxymethyl
is preferred at the 2-position of the quinazoline. Substitution at
the 6- and 7-positions of the quinazoline results in reduced activ-
ity. These data showed that the SAR of 4-anilinoquinazolines as
apoptosis inducers is significantly different from the reported
SAR of 4-anilinoquinazolines as EGFR kinase inhibitors such as Ir-
essa and Tarceva.18,19 As a continuation of our efforts to optimize
the apoptosis inducing N-methyl-4-(4-methoxyanilino)quinazo-
lines as potential anticancer therapeutics, herein, we report further
modification of the quinazoline ring.
b
c
OH
OH
Cl
a
A
B
A
d
O
N
N
R
R
R
B
NH2
N
B
N
5a, R = 6-OMe, B = C
5b, R = H, B = N
6a-6d
7a, R = 5-OMe, A, B = C
7b, R = H, A = C, B = N
7c, R = 6-NO2, A, B = C
7d, R = 7-NO2, A, B = C
7e, R = H, A, B = N
OMe
N
2a, R = 5-OMe, A, B = C
2b, R = 6-NO2, A, B = C
2f, R = 7-NO2, A, B = C
3a, R = H, A = C, B = N
3b, R = H, A, B = N
e
A
N
R
B
N
Compounds 2a–2b, 2f and 3a–3b were prepared as shown in
Scheme 1 using previously reported procedures.18,19 4-Chloro-5-
methoxy-2-methylquinazoline (7a) was prepared via reaction of
2-amino-6-methoxybenzoic acid (5a) and acetyl chloride in the
presence of 4-N,N-dimethylaminopyridine (DMAP) and triethyl-
amine followed by treatment with ammonium acetate to produce
2-methyl-5-methoxyquinazolin-4-ol (6a), followed by the reaction
of 6a with freshly distilled POCl3 in anhydrous toluene and
diisopropylethylamine (DIPEA). 4-Chloro-2-methylpyrido[2,3-d]-
pyrimidine (7b) was prepared similarly from reaction of 2-aminon-
icotinic acid (5b). 4-Chloro-6-nitro-2-methylquinazoline (7c) was
prepared via reaction of 2-amino-5-nitrobenzoic acid (5c) with
acetic anhydride followed by treatment of the intermediate with
ammonia in dioxane to produce 2-methyl-6-nitroquinazolin-4-ol
(6c), which was subsequently treated with POCl3. 4-Chloro-7-ni-
tro-2-methylquinazoline (7d) was prepared similarly to 7c starting
from 2-amino-4-nitrobenzoic acid (5d). 4-Chloro-2-methylpteri-
dine (7e) was prepared from condensation of 6-chloro-2-methyl-
pyrimidine-4,5-diamine (5e) with 1,4-dioxane-2,3-diol. Reaction
of 7a–7e with N-methyl-4-methoxyaniline (8) in anhydrous iso-
propanol (IPA) in the presence of concentrated HCl produced com-
pounds 2a–2b, 2f and 3a–3b (Scheme 1).
Scheme 1. Reagents: (a) (1) AcCl/Et3N/DMAP/DMF; (2) NH4Ac; (b) (1) (AcO)2O; (2)
NH3/dioxane; (c) 1,4-dioxane-2,3-diol/EtOH; (d) POCl3, DIPEA, toluene; (e) 4-MeO–
PhNHMe (8), IPA, HCl.
analog 2d. The 6-acetamide analog 2e was prepared from reaction
of 2c with acetyl chloride (Scheme 2). 7-Amino analog 2g was sim-
ilarly prepared from hydrogenation of 7-nitro analog 2f. The azido
analog 2h was prepared via reaction of 2g with sodium nitrite in
aqueous HCl followed by treatment with sodium azide. The corre-
sponding tritium labeled analog 2k was prepared similarly from
the dibromo analog 2i, which was prepared from reaction of
OMe
a
OMe
N
N
N
N
O2N
R2R1N
N
N
2c, R1 = R2 = H
2b
b
c
2d, R1 = R2 = Me
2e, R1 = H, R2 = Ac
6-Amino compound 2c was prepared from hydrogenation of the
6-nitro analog 2b. Reaction of 2c with formaldehyde in the pres-
ence of sodium cyanoborohydride produced the 6-dimethylamino
Scheme 2. Reagents: (a) H2, Pd/C, EtOH; (b) HCHO, NaBH3CN; (c) AcCl.

2332
N. Sirisoma et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2330–2334
4-chloro-7-nitro-2-methylquinazoline (7d) with 3,5-dibromo-N-
methyl-4-methoxyaniline. Treatment of 2i with tritium gas under
hydrogenation conditions produced the ditritium analog 2j. Diazo-
tization of 2j followed by treatment with sodium azide, using pro-
cedures similar to the preparation of the cold azido analog 2h
produced tritium analog 2k (Scheme 3). Compound 2k was synthe-
sized as a photoaffinity agent for target identification.
1-(4-Methoxyanilino)-N-methylisoquinoline (4a) was prepared
via reaction of a mixture of 1-chloroisoquinoline with N-methyl-4-
methoxyaniline (8) in a sealed tube heated to 140 °C overnight. 4-
(4-Methoxyanilino)-N-methylquinoline 4b was prepared similarly
from reaction of 4-chloroquinaline with N-methyl-4-methoxyani-
line (8) (Scheme 4). 4-Chlorobenzo[d][1,2,3]triazine (7f) was pre-
pared from benzo[d][1,2,3]triazin-4-ol via reaction with
phosphorus oxychloride in toluene and diisopropylethylamine.
Reaction of 7f with N-methyl-4-methoxyaniline (8) in isopropanol
produced 4-(4-methoxyanilino)-N-methylbenzo[d][1,2,3]triazine
4c (Scheme 5).
The apoptosis inducing activity of N-methyl-4-(4-methoxyanili-
no)quinazolines and related compounds was measured in our cell-
and caspase-based HTS assay21 in two cell lines, human breast can-
cer cells T47D and human non-small cell lung cancer cells H1299,
the results are summarized in Table 1. Starting from compound 1g,
we explored the effects of various substituents at the 5,6,7-posi-
tions of the quinazoline ring. The 5-methoxy analog 2a was found
to be slightly less active than 1g, suggesting that substitution at the
5-position by a small group might be tolerated. The 6-nitro analog
2b was 200-fold less active than 1g, while the 6-amino analog 2c
was fourfold less active than 1g indicating that a small hydrophilic
group but not a strong electron withdrawing group is tolerated at
the 6-position. The 6-dimethylamino (2d) and 6-acetamide (2e)
analogs were more than 200-fold less active than 1g, suggesting
that the pocket around the 6-position may have size limitations.
OMe
N
B
Cl
B
a
A
A
4a, A = N, B = C
4b, A = C, B = N
Scheme 4. Reagents and conditions: (a) 4-MeO–PhNHMe (8), 140 °C, overnight.
OMe
OH
Cl
N
N
a
b
N
N
N
N
N
N
N
N
4c
7f
Scheme 5. Reagents: (a) POCl3, DIPEA, toluene; (b) 4-MeO–PhNHMe (8), IPA.
version of 2h, was prepared and used in the target identification
study to confirm that the molecular target of the apoptosis induc-
ing N-methyl-4-(4-methoxyanilino)quinazolines is tubulin.20
We then explored introduction of nitrogen into the benzo moi-
ety of the quinazoline ring. The 8-aza analog 3a was found to be
about sevenfold less active than 1g and the 5,8-aza analog 3b
was about 14-fold less active than 1g. Aza analogs still maintained
relatively good potency, but the quinazoline ring structure is pre-
ferred over other nitrogen-containing heterocycles.
We also explored the replacement of the pyrimidine moiety of
the quinazoline ring by other nitrogen-containing rings. The iso-
quinoline analog 4a was 100-fold less active than the correspond-
ing quinazoline analog 1h,18 indicating that the nitrogen at the 1-
position of the quinazoline structure is important for the apoptosis
inducing activity. The quinoline analog 4b was about threefold less
active than 1h, suggesting that the nitrogen at the 3-position is less
important for activity. The benzo[d][1,2,3]triazine analog 4c was
about twofold less active than 1h, indicating that the 2-position
carbon of quinazoline can be replaced by a nitrogen.
The 7-nitro analog 2f was not active at up to 10 lM, which is
>5000-fold less active than 1g, and the 7-amino analog 2g was
about 200-fold less active than the 6-amino analog 2c, indicating
substitution at the 7-position is less tolerated than the 6-position.
These data are in agreement with our previously reported SAR
around 1e which showed that substitution at the 6-position is
more tolerated than 7-position.18 The 7-azido analog 2h was about
50-fold less active than 1g but still had reasonable activity with an
EC50 value of 110 nM against T47D cells. Compound 2k, a tritium
The potencies of all reported compounds towards the human
non-small cell lung cancer cell line H1299 were roughly parallel
to their activity towards T47D cells. In general, H1299 cells were
slightly less sensitive (about 2–4-fold less sensitive as measured
by the EC50 value) to the compounds than T47D cells in this assay.
We have found that compound 1g and related compounds are
tubulin inhibitors that bind at or close to the colchicine site of b-
tubulin.20 Compounds 2a and 4b, which were highly active in the
caspase activation assay, were tested in the tubulin polymerization
assay.22 Both compounds were found to inhibit tubulin polymeri-
zation with IC50 values of about 0.4 lM, which is similar to that
of compound 1g. Compound 2g, which was less active in the cas-
pase activation assay, was also less active in the tubulin assay with
IC50 value of 2 lM. Therefore these modifications to the quinazo-
R1
OMe
Br
N
N
R1
OMe
Br
a
N
+
7d
N
H
O2N
2f, R1 = H
2i, R1 = Br
R1
R1
OMe
R1
OMe
R1
line structure do not change the mechanism of action of these
compounds.
N
N
N
N
N
c
b
We have reported that compound 1g has high BBB penetra-
tion.19 The brain/plasma AUC (area under the concentration–time
curves) ratios of several compounds related with 1g were mea-
sured after a single intravenous (iv) dose of 2.5 mg/kg in mice
and determined via LC–MS/MS using plasma from blood samples
and homogenized whole brain samples as reported previously.19
As summarized in Table 2, all compounds have brain/plasma AUC
ratio of >1, indicating significant BBB penetration. These data are in
N
H2N
N3
2g, R1 = H
2h, R1 = H
2j, R1 = T
2k, R1 = T
Scheme 3. Reagents: (a) IPA, HCl; (b) H2, Pd/C, EtOH; or T2, Pd/C, EtOH; (c) NaNO2,
HCl, then NaN3.

N. Sirisoma et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2330–2334
2333
Table 1
Table 2
Caspase activation activity of N-methyl-4-(4-methoxyanilino)quinazolines and
The brain/plasma ratio of AUC of 4-arylaminoquinazolines
related compounds
Entry
Brain/plasma
ratio of AUC
MW
# of
HBA
# of
HBD
# of
N+O
Clog Pa
EC50 (nM)
T47Db
OMe
1g
2c
3a
3b
1h
4b
16.0
3.6
1.8
2.1
3.1
9.2
279
294
280
281
265
264
4
5
5
6
4
3
0
2
0
0
0
0
4
5
5
6
4
3
4.18
3.86
3.14
2.37
3.68
4.47
2
8
15
29
6
R1
N
N
R2
R3
N
21
a
Calculated using ChemDraw.
Data from Table 1.
R1
R2
R3
EC50
(
lM)
a
Entry
b
T47D
H1299
1g
2a
2b
2c
2d
2e
2f
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
NH2
N3
0.002 0.0001
0.004 0.001
0.40 0.04
0.008 0.001
0.45 0.07
0.96 0.16
>10
0.007 0.001
0.008 0.002
0.13 0.03
0.014 0.001
1.4 0.1
1.4 0.1
>10
0.57 0.03
0.13 0.02
7-positions, and replacement of the quinazoline ring by other
nitrogen-containing heterocycles. It was found that a small group
such as methoxy at the 5-position led to a potent compound. At
the 6-position, a small group like amino was preferred, while
slightly larger groups such as dimethylamino or a strong electron
withdrawing group like nitro resulted in significant reduction of
apoptotic activity. Substitution at the 7-position was much less
preferred than at the 6-position. Replacement of the carbon at
the 8-position or both 5- and 8-positions by nitrogen led to 7–
14-fold reduction in potency. Replacement of the quinazoline ring
by an isoquinoline ring resulted in 100-fold reductions in activity
while its replacement by a quinoline or benzo[d][1,2,3]triazine ring
was well tolerated with 2–3-fold reduction in potency. Several 5-
and 6-substituted analogs, such as 2a and 2c, were found to have
potencies approaching that of lead compound 1g. Additional stud-
ies of these 4-anilinoquinazolines, including in vivo study of com-
pound 1g in brain tumor model, will be reported in future
publications.
NO2
NH2
NMe2
NHAc
H
2g
2h
H
H
0.78 0.04
0.11 0.02
OMe
N
A
B
N
N
a
Entry
A
B
EC50
(l
M)
T47D
H1299
3a
3b
CH
N
N
N
0.015 0.001
0.029 0.001
0.021 0.002
0.036 0.004
References and notes
OMe
1. Henson, P. M.; Bratton, D. L.; Fadok, V. A. Curr. Biol. 2001, 11, R795.
2. Green, D. R.; Reed, J. C. Science 1998, 281, 1309.
3. Stennicke, H. R.; Ryan, C. A.; Salvesen, G. S. Trends Biochem. Sci. 2002, 27, 94.
4. Rich, T.; Allen, R. L.; Wyllie, A. H. Nature 2000, 407, 777.
5. Kingston, D. G.; Newman, D. J. Curr. Opin. Drug Discov. Devel. 2007, 10, 130.
6. Hunt, J. T. Mol. Cancer Ther. 2009, 8, 275.
7. Li, Q.; Sham, H.; Rosenburg, S. Annu. Rev. Med. Chem. 1999, 34, 139.
8. Deeken, J. F.; Loscher, W. Clin. Cancer Res. 2007, 13, 1663.
N
D
A
B
a
Entry
A
B
D
EC50
(
l
M)
9. Cai, S. X.; Zhang, H.-Z.; Guastella, J.; Drewe, J.; Yang, W.; Weber, E. Bioorg. Med.
Chem. Lett. 2001, 11, 39.
T47D
H1299
10. Cai, S. X.; Drewe, J.; Kasibhatla, S. Curr. Med. Chem. 2006, 13, 2627.
11. Zhang, H.-Z.; Kasibhatla, S.; Wang, Y.; Herich, J.; Guastella, J.; Tseng, B.; Drewe,
J.; Cai, S. X. Bioorg. Med. Chem. 2004, 12, 309.
12. 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.
13. 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.
1hb
4a
4b
4c
N
N
CH
N
CH
CH
CH
N
N
CH
N
0.006 0.001
0.60 0.02
0.021 0.01
0.017 0.001
0.019 0.004
0.96 0.04
0.026 0.007
0.045 0.022
N
a
Data are the mean of three or more experiments and are reported as
mean standard error of the mean (SEM).
b
Data from Ref. 18.
14. 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.
agreement with the suggested rules that compounds having
hydrogen bond donor (HBD) of <3, Clog P of 2–5 and molecular
weight (MW) of <500 are preferred for potential BBB penetration,23
and that if the number of nitrogen plus oxygen (N+O) is five or less
in a molecule, then it has a high chance of entering the brain.24 For
comparison, the BBB penetration of compound 2c, with an amino
group added (one nitrogen and two hydrogen bond donors) to
1g, as measured by the brain/plasma AUC ratio was reduced from
16.0 to 3.6. Compounds 3a, with one additional nitrogen, resulted
in a brain/plasma AUC ratio reduction from 16.0 to 1.8. These data
are in agreement with our previous observations that increases in
the number of (N+O), or increases in the number of hydrogen bond
donors (HBD) reduce BBB penetration.19
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) 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; (c) 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) Kasibhatla, S.; Gourdeau, H.; Meerovitch, K.; Drewe, J.; Reddy, S.; Qiu, L.;
Zhang, H.; Bergeron, F.; Bouffard, D.; Yang, Q.; Herich, J.; Lamothe, S.; Cai, S. X.;
Tseng, B. Mol. Cancer Ther. 2004, 3, 1365; (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.
17. Claassen, G.; Brin, E.; Crogan-Grundy, C.; Vaillancourt, M. T.; Zhang, H.-Z.; Cai,
S. X.; Drewe, J.; Tseng, B.; Kasibhatla, S. Cancer Lett. 2009, 274, 243.
18. Sirisoma, N.; Kasibhatla, S.; 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.
In conclusion, we have explored further the SAR of the apopto-
sis inducing N-methyl-4-(4-methoxyanilino)quinazolines as po-
tential anticancer agents via modifications at the 5-, 6- and

2334
N. Sirisoma et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2330–2334
19. 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. 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.
21. Cai, S. X.; Nguyen, B.; Jia, S.; Herich, J.; Guastella, J.; Reddy, S.; Tseng, B.; Drewe,
J.; Kasibhatla, S. J. Med. Chem. 2003, 46, 2474.
22. Barron, D. M.; Chatterjee, S. K.; Ravindra, R.; Roof, R.; Baloglu, E.; Kingston, D. G.
I.; Bane, S. Anal. Biochem. 2003, 315, 49.
23. Hitchcock, S. A.; Pennington, L. D. J. Med. Chem. 2006, 49, 7559.
24. Norinder, U.; Haeberlein, M. Adv. Drug Delivery Rev. 2002, 54, 291.