Discovery of 4-substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: Synthesis, biological evaluation, and structure-activity relationships

Article abstract of DOI:10.1021/jm801449a

A series of 4-substituted methoxybenzoyl-aryl-thiazoles (SMART) have been discovered and synthesized as a result of structural modifications of the lead compound 2-arylthiazolidine-4-carboxylic acid amides (ATCAA). The antiproliferative activity of the SMART agents against melanoma and prostate cancer cells was improved from μM to low nM range compared with the ATCAA series. The structure-activity relationship was discussed from modifications of "A", "B", and "C" rings and the linker. Preliminary mechanism of action studies indicated that these compounds exert their anticancer activity through inhibition of tubulin polymerization.

Full text of DOI:10.1021/jm801449a

J. Med. Chem. 2009, 52, 1701–1711
1701
Discovery of 4-Substituted Methoxybenzoyl-aryl-thiazole as Novel Anticancer Agents: Synthesis,
Biological Evaluation, and Structure-Activity Relationships
Yan Lu,† Chien-Ming Li,‡ Zhao Wang,† Charles R. Ross, II,§ Jianjun Chen,† James T. Dalton,‡ Wei Li,† and Duane D. Miller*,†
Department of Pharmaceutical Sciences, UniVersity of Tennessee, Health Science Center, Memphis, Tennessee 38163, DiVision of
Pharmaceutics, College of Pharmacy, The Ohio State UniVersity, Columbus, Ohio 43210, St. Jude Children’s Research Hospital,
Memphis, Tennessee 38103
ReceiVed NoVember 17, 2008
A series of 4-substituted methoxybenzoyl-aryl-thiazoles (SMART) have been discovered and synthesized
as a result of structural modifications of the lead compound 2-arylthiazolidine-4-carboxylic acid amides
(ATCAA). The antiproliferative activity of the SMART agents against melanoma and prostate cancer cells
was improved from µM to low nM range compared with the ATCAA series. The structure-activity
relationship was discussed from modifications of “A”, “B”, and “C” rings and the linker. Preliminary
mechanism of action studies indicated that these compounds exert their anticancer activity through inhibition
of tubulin polymerization.
Introduction
ATCAA-2 analogues, structure modifications were made on
thiazolidine ring and 4-carboxylic amide linker. Thus, substituted
methoxybenzoyl-aryl-thiazole (SMART) compounds were dis-
covered and showed highly improved growth inhibition on tested
cancer cells in vitro.
In 2008, about 565,650 Americans are expected to die of cancer,
more than 1500 people a day. Cancer is the second most common
cause of death in the U.S., exceeded only by heart disease. In the
U.S., cancer accounts for 1 of every 4 deaths. The 5-year relative
survival rate for all cancer patients diagnosed in 1996-2003 is
66%, up from 50% in 1975-1977.1 The improvement in survival
reflects progress in diagnosing at an earlier stage and improvements
in treatment. Discovering highly effective anticancer agents with
low toxicity is a goal of our research.
In this paper, we described a series of the SMART agents
with general structure as showed in Figure 1. The SMART
agents have a structure containing three conjugated aromatic
rings (“A”, “B”, and “C” rings, respectively) with a ketone
linkage between “B” and “C” rings. Thiazole was introduced
in “B” ring instead of thiazolidine ring in ATCAA. The linker
between “B” and “C” rings was modified from an amide to
carbonyl group. The “C” ring was characterized by the presence
of differently substituted phenyl groups, in particular, the 3,4,5-
trimethoxy substituted phenyl at “C” ring played an important
role of antiproliferative activity against melanoma and prostate
cancer. Synthesis, SAR studies, biological evaluation, and the
anticancer mechanism of the SMART analogues was undertaken
and reported in this paper.
Chemistry. The general synthesis of the ATCAA and
SMART analogues are shown in Schemes 1-3. To prepare
ATCAA compounds 2a-b, L-cysteine was allowed to react with
appropriate benzaldehydes in ethanol and water at ambient
temperature to give cyclized (2RS,4R)-2-aryl-thiazolidine-4-
carboxylic acids 1,12 which were converted to the corresponding
BOC-protected derivatives. Reaction of BOC-protected car-
boxylic acids with 3,4,5-trimethoxyaniline using EDCI/HOBt
gave corresponding amides, which were treated with TFA to
form the target compounds 2a-b.
To synthesize thiazoline and thiazole series compounds 4a-b
and 5, (4R or 4S)-2-phenyl-4,5-dihydro-thiazole-4-carboxylic
acid 3a and 3b were obtained by reacting L- or D-cysteine with
benzonitrile in methanol and pH 6.4 phosphate buffer solution
at ambient temperature for several days.13 Coupling reactions
of 3a-3b with 3,4,5-trimethoxyaniline under EDCI/HOBt
conditions gave 4R or 4S amide 4a-4b. Oxidation with BrCCl3/
DBU of 4a-4b gave the same dehydrogenation thiazole product
5.14
The SMART compounds were synthesized as illustrated in
Scheme 3. (4R)-2-(Substituted phenyl)-4,5-dihydro-thiazole-4-
carboxylic acids 3 were synthesized according the similar
preparation of 3a and 3b from L-cysteine with appropriate
We have recently discovered 2-aryl-thiazolidine-4-carboxylic
acid amides (ATCAAa, Figure 1) as potent cytotoxic agents
for both prostate cancer and melanoma.2-6 ATCAA was
designed from lysophosphatidic acid (LPA) structure with a lipid
chain in order to inhibit guanine-binding protein-coupled
receptor (GPCR) signaling, which was involved in proliferation
and survival of prostate cancer.7-10 The most potent compounds
in ATCAA-1 derivatives could inhibit prostate cancer cells
with an average IC50 in the range from 0.7 to 1.0 µM and
average IC50s against melanoma cells were 1.8-2.6 µM.2
(2RS,4R)-2-Phenyl-thiazolidine-4-carboxylic acid hexadecy-
lamide (ATCAA-1) was sent to the U.S. National Cancer
Institute 60 human tumor cell line anticancer drug screen
(NCI-60). Results from NCI-60 assay showed that compound
ATCAA-1 could inhibit growth of all nine types of cancer cells
with IC50 in the range from 0.124 µM (leukemia, CCRF-CEM)
to 3.81 µM (non-small cell lung cancer, NCI-H522). SAR
studies of ATCAA indicated that replacement of the lipid chain
with a bulky aromatic ring in the 4-amide position of ATCAA-2
attached to the thiazolidine ring still kept the antiproliferative
activity.11 This finding afforded us a new point to replace the
fatty amide chain with a number of aromatic groups, which
would maintain the cytotoxicity. With further investigation of
* To whom correspondence should be addressed. Phone: (901) 448-6026.
Fax: (901) 448-3446. E-mail: dmiller@utmem.edu.
†
University of Tennessee.
The Ohio State University.
St. Jude Children’s Research Hospital.
‡
§
a Abbreviations: ATCAA, 2-aryl-thiazolidine-4-carboxylic acid amides;
LPA, lysophosphatidic acid; GPCR, guanine-binding protein-coupled recep-
tor; SMART, 4-substituted methoxybenzoyl-aryl-thiazoles; SAR, structure-
activity relationships.
10.1021/jm801449a CCC: $40.75
2009 American Chemical Society
Published on Web 02/25/2009

1702 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Lu et al.
reduction of para-nitro compound 8p.23 3,4,5-Trihydroxyl
compound 11 was obtained using BBr3 as demethylation
reagent.24
Crystal Structure. The SMART compound 8f was recrystal-
lized from hexane and ethyl acetate, and single colorless crystals
suitable for X-ray diffraction were obtained. An ORTEP drawing
of 8f with the atom labeling scheme is shown in Figure 3. The
X-ray structure showed that 8f molecule contained a conjugated
system composed of three aromatic rings and a carbonyl group
linker between the “B” and “C” rings as expected (“A” ring )
phenyl; “B” ring ) thiazole; “C” ring ) 3,4,5-trimethoxyphe-
nyl). As a result, two C-C bonds adjacent to CdO and C-C-
bond between the “A” phenyl and “B” thiazole rings display
(C1-C7 ) 1.496(2) Å; C7-C8 ) 1.492(2) Å; C10-C11 )
1.471(2) Å) shorter bond lengths than normal C-C single bond
(1.54 Å) and longer than a normal CdC double bond (1.34 Å)
(see Table 1). Thus conjugation of the π system is possible for
“A”, “B”, and “C” rings and carbonyl group. The carbonyl group
is nearly coplanar with the adjacent “B” thiazole ring
(O-C7-C1-C6 16.2(2)°, O-C7-C8-C9 9.7(2)°).
Biological Results and Discussion. ATCAA to SMART
molecules: Modifications of the “B” ring from a thiazolidine to
thiazole system and the linker from an amide to a ketone. In
the previous ATCAA compounds, we found the thiazolidine
ring, which contained a free NH at its 3-position, was important
for cytotoxicity. Once the “B” ring thiazolidine moiety was
replaced by a thiazoline ring, the antiproliferative activity
decreased sharply from 0.6 µM to over 50 µM on WM-164
cell line.2 The ATCAA-1 fatty amide derivatives that was most
effective against melanoma and prostate cancer cell lines were
examined and shown to have an IC50 0.4-2.2 µM (Table 2).
Replacement of the long fatty chain with a certain aromatic
bulky subsistent such as fluorene (ATCAA-2) showed inhibitory
activity on both cancer cell lines (IC50 ) 1.6-3.9 µM).11 The
fluorene group in 4-carboxylic amide position was also replaced
by 3,4,5-trimethoxyphenyl group (2a and 2b), but the potency
against both cancer cell lines was lost. The subsequent “B” ring
modification from saturated thiazolidine compound 2a to
unsaturated thiazole 5 did not show any cytotoxicity against
either cancer cell line tested. But thiazoline enantiomers 4a and
4b (R-isomer and S-isomer showed similar antiproliferative
activities) showed improved activity (IC50 ) 3.4-38.3 µM)
compared with 2a, 2b, and 5. When the amide CONH linkage
between the “B” ring and the “C” ring was replaced by a
carbonyl linker, the mixtures of thiazoline/thiazole ketone 8f
were obtained instead of desired thiazoline ketone, because the
autodehydrogenation between thiazoline and thiazole occurred
(the conversion was shown in Figure 2). Surprisingly, introduc-
tion of the carbonyl group linker and thiazole led to a significant
enhancement of growth inhibition of examined cancer cell lines
with a low nanomolar level (8f, IC50 ) 0.021-0.071 µM), which
is comparable to the natural anticancer agent colchicine. Thus
a series of the SMART compounds with “B” as a thiazole ring
were designed and synthesized based on the discovery of 8f
and their anticancer activity was evaluated against melanoma
and prostate cancer.
Figure 1. Structures of LPA, ATCAA, and SMART.
benzonitriles.13,15,16 Compounds 3 can be easily converted to
the corresponding Weinreb amides 6a-6p17 using EDCI/HOBt
as coupling reagents. Thiazole intermediate 7 can be obtained
from BrCCl3/DBU dehydrogenation of 6a-6p. Compound 6
or 7 was reacted with appropriate lithium reagents or Grignard
reagents in anhydrous THF to give the final SMART compounds
8a-8z.17 Compound 10 was obtained by the same method.
Thiazoline Weinreb amides 6a-6p reacted directly with ap-
propriate lithium reagents or Grignard reagents, and after
quenching with saturated NH4Cl solution, the mixtures of
thiazoline compounds and the corresponding thiazole com-
pounds were afforded. When thiazoline/thiazole mixtures were
placed in the solvent and exposed to air under ambient
atmosphere for some time (overnight to several days), the
thiazoline ring spontaneously dehydrogenated to thiazoles
8a-8z, which were clearly indicated by 1H NMR, mass spectra,
and elemental analysis. As an example, in solution with
deuterated chloroform, mixtures of thiazoline/thiazole com-
pounds can be slowly converted to almost pure thiazole
compound 8f after 9 days (see Figure 2). No report of
autodehydrogenations was found in the literature. Most reports
of thiazoline-thiazole dehydrogenations need an oxidant
(MnO218), oxidase in biosynthesis,19 or catalysts (Hg(OAc)2,
K3FeCN6).20 The thiazoline Weinreb amide was reported to
undergo dehydrogenation to form thiazole under base/solvent
(NaH/MeOH, TMSOK/THF, etc.) conditions.21 The base could
abstract the acidic 4-position proton of thiazoline ring, with
subsequent intramolecular attack of carbanion on the methoxy
amide and release of MeO-, followed by three-position proton
elimination. We did not observe these autodehydrogenation
phenomena between intermediate thiazoline amides 6a-6p and
thiazole amides 7. The triple aromatic ring system formed highly
stable conjugated SMART structures 8a-8z, which could be a
favorable reason for autodehydrogenation. X-ray crystallography
demonstrated the conjugated structure of compound 8f. Benzoic
acid 8r was prepared from the acidic hydrolysis of benzonitrile
8q in HCl/HOAc.22 Methyl ester 8s was obtained by the
esterification of 8r in methanol and acetyl chloride. para-Amino
compound 8w was synthesized by using iron and acetic acid
Modifications of the “C” Ring of the SMART Molecules.
We started our investigation of the “C” position of the SMART
by introducing different substituted phenyls or alkyl chain.
Variation of the phenyl substituents has a remarkable change
in effect on potency. The in vitro assay as shown in Table 3
gave us an interesting result, but only 3,4,5-trimethoxyphenyl
in the “C” ring (8f) showed excellent inhibition against all cancer
cells (IC50) 21-71 nM, average IC50 ) 41 nM). Compound

SMART as Anticancer Agents
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1703
Figure 2. Autodehydrogenation from thiazoline to thiazole compound 8f. At 0 day, NMR sample contained thiazoline and thiazole mixtures in
CDCl3; ratio is about 3: 2. At ninth day, thiazoline compound was almost converted to thiazole compound 8f.
8g, with a 3,5-dimethoxyphenyl group, showed 6-fold average
cytotoxicity lower than 8f against six different cell lines (IC50
) 170-424 nM, calcd average IC50 ) 261 nM). Modifications
of 8f by removal of one methoxy at meta-position (8e) or two
methoxy groups (8b, 8c, and 8d) from 8f led to a dramatic loss
in activity (IC50 > 20 µM). Although ortho-substituted
monomethoxy compound 8d exhibited weak activity against a
certain cell lines compared with meta-/para-MeO substituted
8c/8b and dimethoxyphenyl compound 8e, none of them showed
significant potency in inhibition compared with 8f. Similar trends
were also seen in 8h and 8j with 2-fluorophenyl and hexadecyl
in “C” ring modifications.
2-position of the thiazolidine ring strongly affected the anti-
cancer activity in ATCAA compoundsselectron-withdrawing
groups (EWG) on 2-phenyl gave higher activities than those
with electron-donating groups (EDG).6 We also introduced
different para-substituted EWG and EDG on the “A” phenyl
ring of the SMART molecules. From the IC50 value against these
cancer cell lines, electronic effects of “A” ring phenyl substit-
uents did not show clear influence on antiproliferative activity.
Introduction of a weak EWG (4-F in 8n, IC50s: 6-43 nM) or
weak EDG (4-CH3 in 8k, IC50s: 5-21 nM), both increased the
potency compared with 8f (see Table 4). The replacement of
the para-position with strong EWG such as NO2 (8p), CN (8q),
CF3 (8t), or introducing strong EDG (3,4-dimethoxy) to the “A”
phenyl ring (8o) exhibited comparable antiproliferative activity.
Modifications of the “A” Ring of the SMART Molecules.
In SAR studies of the ATCAA compounds, we found that the
electronic properties of substituents of the phenyl ring in the

1704 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Lu et al.
and synthesized water-soluble salts of the SMART by introduc-
ing a hydrophilic group such as NH2 (8w) and COOH (8r) into
the “A” ring and generated the HCl or sodium salt. Another
modification is replacing “A”/“C” rings in 8a with pyridine (8i,
8x, 8y) or pyrimidine rings, which could also be converted into
HCl salts. These modifications reduced the calculated LogP
values (LogP ) 2.74-3.90) compared with 8a and 8f (LogP )
4.46 and 4.08, see Table 5). Introducing p-amino to “A” phenyl
(8w) is the only case to increase the antiproliferative activity
(HCl salt, IC50s: 11-29 nM) compared with 8f against all cell
lines. Although replacing phenyl with pyrimidine (8y) kept
partial activity against both cancer cells, the potency range was
markedly reduced from nM to µM compared with 8f. Unfor-
tunately, introducing COOH to the para-phenyl “A” ring and
pyridine to the “A” or “C” rings (8i, 8r, 8x) all resulted in the
total loss of the anticancer activity. A total loss of potency was
seen in the methyl ester 8s of acid 8r against both cancer cell
lines. Demethylation of compound 8f afforded water soluble
3,4,5-trihydroxyphenyl at “C” ring compound 11, but this
demethylation results in complete loss of antiproliferative
activity against all tested cancer cells, which also points out
the importance of 3,4,5-trimethoxyphenyl at the “C” position.
Mechanism of Action Studies: The SMART Compounds
Inhibit Tubulin Polymerization. By observing cell cycle
progression in response to 8f, a significant increase in G2/M
phase arrest was detected (unpublished data). This is similar to
the induction by an mitotic inhibitor, such as colchicine.25 To
investigate whether the antiproliferative activities of these
compounds were related to interaction with tubulin, the SMART
compound 8f was evaluated for inhibition of polymerization of
purified tubulin in a cell-free system. The results are shown in
Figure 4. Compared with nontreated control, 8f (“A” ring )
phenyl, “C” ring ) 3,4,5-trimethoxyphenyl) inhibits tubulin
polymerization. The effect of 8f on tubulin assembly was
examined at concentrations from 0.625 µM to 20 µM. We
observed that compound 8f inhibited tubulin polymerization in
a dose-dependent manner (Figure 4), with an IC50 value of 4.23
µM.
Figure 3. ORTEP drawing of 8f with thermal ellipsoids depicted at
50% probability level.
Table 1. Selected Geometric Parameters of 8f (Å, deg)
C1sC7
C7sO
C7sC8
C8sC9
C8sN
C9sS
SsC10
C10sN
C10sC11
C2sC1sC6
C2sC1sC7
C6sC1sC7
OsC7sC8
1.496(2)
1.224(2)
1.492(2)
1.371(2)
1.380(2)
1.711(2)
1.747(2)
1.303(2)
1.471(2)
121.2(2)
122.3(2)
116.4(2)
118.0(2)
OsC7sC1
C8sC7sC1
C9sC8sN
C9sC8sC7
NsC8sC7
C8sC9sS
C9sSsC10
NsC10sC11
NsC10sS
C11sC10sS
C10sNsC8
C12sC11sC10
C16sC11sC10
120.1(2)
121.9(2)
115.1(2)
121.7(2)
123.0(2)
110.0(1)
89.6(1)
123.5(2)
113.9(1)
122.6(1)
111.4(2)
122.3(2)
118.5(2)
To compare the effects of ortho-, meta-, and para-substitu-
tions, a fluoro atom was introduced to different positions of the
“A” phenyl ring (8l, 8m, and 8n). The various o-, m-,
p-substituents did not exhibit equal activities. p-Fluoro substi-
tuted 8n has the best activity for examined prostate cancer cells
(6-13 nM), while o-fluoro substituted 8l showed the lowest
IC50s (27-30 nM) against melanoma cells. 8n has similar
average IC50s (33-43 nM) against melanoma compared with
8l. But o-fluoro-substituted 8l has lowest potency (IC50s: 52-114
nM) among the three substituted compounds on prostate cancer
cells. Meta-substituted compound 8m showed lowest activity
on melanoma cells (IC50s: 287-304 nM) but showed moderate
inhibition on prostate cancer cells (IC50s: 23-46 nM).
Turning to the effects of steric hindrance group on the “A”
phenyl ring substituents, we found that p-bromo (8u, IC50s:
18-44 nM) caused a decrease in antiproliferative activity
relative to p-fluoro position (8n, IC50s: 6-12 nM) only against
prostate cancer cells. Reduced activity against both cancer cell
lines occurred when p-methyl (8k, IC50s: 5-21 nM) was
replaced with a p-ethyl group (8v, IC50s: 17-70 nM).
To investigate if phenyl played an essential role at the “A”
ring in cytotoxicity, we also removed phenyl at 2-thiazole
position and compound 10 was obtained. This modification
caused a total loss of activity compared with 8f. The replacement
of the “A” ring by pyridine (compound 8x) had the same effect.
Moreover, substituting 2-pyrimidine in “A” ring (compound 8y)
also caused a significant loss of activity (IC50s: 11.8-41.0 µM).
However, introducing the thiophene replacement of phenyl (8z)
into the “A” position improved the potency calcd 1-3 fold on
all examined cell lines (IC50s: 9-38 nM) compared to 8f (IC50s:
21-71 nM).
Conclusions
We have discovered a new class of simple synthetic inhibitors
of tubulin polymerization, based on a 2-aryl-4-(3,4,5-tri-
methoxybenzoyl)-thiazole molecular skeleton, which was de-
rived from thiazolidine ring modification of ATCAA structures.
A series of the SMART compounds were synthesized. Chemical
modification of different substituted aryl in “A” and “C” rings
and structure-activity relationship of the SMART were inves-
tigated (Figure 5) based on biological evaluation against
melanoma and prostate cancer cells in vitro. Present SAR studies
revealed that 3,4,5-trimethoxyphenyl was the essential group
in the “C” ring to keep excellent antitumor potency. p-Fluoro,
p-NH2, and p-CH3 substituents in “A” ring will increase the
activity, with no clear difference in effect on activity between
EWG and EDG when “A” are substituted phenyl rings. The
carbonyl linkage between “B” ring and “C” ring played an
important role for the high potency. Further modification of “B”
and “C” rings, carbonyl linkage, tubulin binding site studies,
mechanism of action of the SMART compounds, and in vivo
animal testing are currently underway.
Experimental Section
Addition of Pharmaceutically Acceptable Salt Groups
to the SMART Molecules. Most of the SMART compounds
have good solubility in organic solvents such as CHCl3, CH2Cl2,
and DMSO. But they show poor water solubility. We designed
General. All reagents were purchased from Sigma-Aldrich
Chemical Co., Fisher Scientific (Pittsburgh, PA), AK Scientific
(Mountain View, CA), Oakwood Products (West Columbia, SC),

SMART as Anticancer Agents
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1705
Table 2. In Vitro Inhibitory Effects of Modified ATCAA Compounds against the Proliferation of Melanoma (A 375, B16-F1) and Prostate Cancer
Cells (DU145, PC-3, LNCaP, PPC-1)
a TZD ) thiazolidine, TZL ) thiazoline, TZ ) thiazole. b For ATCAA-1, “C” position contains a lipid chain.
Table 3. In Vitro Growth Inhibitory Effects of Compounds 8a-8j with Different “C” Rings against the Proliferation of Melanoma (A 375, B16-F1)
and Prostate Cancer Cells (DU145, PC-3, LNCaP, PPC-1)
a Compound 8j has a lipid chain at “C” ring position.
Table 4. In Vitro Growth Inhibitory Effects of the SMART Compounds with Different “A” Rings against the Proliferation of Melanoma (A 375,
B16-F1) and Prostate Cancer Cells (DU145, PC-3, LNCaP, PPC-1)
a Compound 10 has a proton at “A” ring position.
etc. and were used without further purification. Moisture-sensitive
reactions were carried under an argon atmosphere. Routine thin
layer chromatography (TLC) was performed on aluminum backed
Uniplates. (Analtech, Newark, DE). Melting points were measured
with Fisher-Johns melting point apparatus (uncorrected). NMR
spectra were obtained on a Bruker AX 300 (Billerica, MA)
spectrometer or Varian Inova-500 spectrometer. Chemical shifts
are reported as parts per million (ppm) relative to TMS in CDCl3.

1706 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Lu et al.
Table 5. In Vitro Growth Inhibitory Effects of Compounds Contained Hydrophilic Group Against the Proliferation of Melanoma (A 375, B16-F1) and
Prostate Cancer Cells (DU145, PC-3, LNCaP, PPC-1)
IC50 ( SEM (nM)
compd
8i
8i·HCl
8r
8s
8x
8x·HCl
8y
B16-F1
A375
DU145
PC-3
LNCaP
PPC-1
CLogPa
3.55
>100000
>100000
>100000
>100000
>100000
>100000
2300 ( 860
29 ( 10
>100000
>100000
>100000
>100000
>100000
>100000
4100 ( 740
11 ( 2
>20000
>20000
>20000
>20000
>20000
>20000
2813 ( 92
20 ( 2
>20000
>20000
>20000
>20000
>20000
>20000
2657 ( 40
12 ( 1
>20000
>20000
>20000
>20000
16630
>20000
2370 ( 85
13 ( 1
>20000
>20000
>20000
>20000
18000
>20000
1186 ( 22
15 ( 1
3.64
3.90
2.74
3.04
8w·HCl
11
8a
>100000
>100000
55 ( 5
>100000
>100000
28 ( 5
>20000
>20000
71 ( 4
>20000
>20000
21 ( 1
>20000
>20000
28 ( 4
>20000
>20000
43 ( 5
3.29
4.46
4.08
8f
a Calculated LogP data using Chemoffice 2005, Chemdraw Ultra 9.0 software. b LogP value were calculated based on free base.
General Procedure for the Preparation of (2RS,4R)-2-Aryl-
N-(3,4,5-trimethoxyphenyl)thiazolidine-4-carboxamide (2a-2b).
A mixture of appropriate BOC protected carboxylic acids (0.3-0.5
g), EDCI (1.2 equiv), and HOBT (1.05 equiv) in CH2Cl2 (20 mL)
was stirred at room temperature for 10 min. To this solution, 3,4,5-
trimethoxyaniline (1.05 equiv) and Et3N (1.2 equiv) were added
and stirring continued at room temperature for 6-8 h. The reaction
mixture was diluted with CH2Cl2 (30 mL) and sequentially washed
with water, satd NaHCO3, brine, and dried over MgSO4. The solvent
was removed under reduced pressure to yield a crude oil, which
were stirred with TFA (0.6-1 mL) in 20 mL CH2Cl2 at rt for 1-8
h to cleave the BOC group. The reaction mixture was concentrated,
washed with satd NaHCO3, and dried over MgSO4. The solvent
was removed to yield a crude solid, 2a-2b were purified by column
chromatography. Yield was reported as a two-steps yield.
Figure 4. Effect of 8f on tubulin assembly.
(2RS,4R)-2-Phenyl-N-(3,4,5-trimethoxyphenyl)thiazolidine-4-
carboxamide (2a). Yield: 69.5%; mp 158-159 °C. 1H NMR (300
MHz, CDCl3) δ 9.14 (s, 0.8 H), 8.61 (s, 0.2 H), 7.58-7.32 (m, 5
H), 6.90 (s, 1.6 H), 6.71 (s, 0.4H), 5.71 (dd, 0.2 H, J ) 9.0 Hz),
5.42 (dd, 0.8 H, J ) 11.7 Hz), 4.53 (dt, 0.8 H), 4.19 (m, 0.2 H),
3.87, 3.80 (s, s, 6 H), 3.82, 3.78 (s, s, 3 H), 3.80-3.78 (m, 0.4 H),
3.62-3.42 (m, 1.6 H), 2.96 (t, 0.2 H, J ) 9.0 Hz), 2.74 (dd, 0.8 H,
J ) 11.7 Hz). MS (ESI) m/z 375.1 [M + H]+ 397.1 [M + Na]+.
,
Anal. (C19H22N2O4S) C, H, N.
(2RS,4R)-N,2-bis(3,4,5-trimethoxyphenyl)thiazolidine-4-car-
1
boxamide (2b). Yield: 34.5%; mp 147-149 °C. H NMR (300
MHz, CDCl3) δ 9.10 (s, 0.7 H), 8.59 (s, 0.3 H), 6.90 (s, 1.4 H),
6.80 (s, 0.6 H), 6.74 (s, 1.4H), 6.71 (s, 0.6 H), 5.66 (br, 0.3 H),
5.35 (d, br, 0.7 H, J ) 7.5 Hz), 4.52 (br, 0.7 H), 4.21 (br, 0.3 H),
3.90, 3.87, 3.86, 3.84, 3.82, 3.81, 3.79, 3.78 (all s, 18 H), 3.66-3.61,
3.54-3.38 (m, 1.6 H), 2.98, 2.72 (br, 1 H). MS (ESI) m/z 465.1
[M + H]+ 487.1 [M + Na]+. Anal. (C22H28N2O7S) C, H, N.
Figure 5. SAR relationship of the SMART molecules.
,
2-(Substituted-phenyl)-4,5-dihydrothiazole-4-carboxylic acids
(3). Substituted benzonitrile (40 mmol) was combined with L- or
D-cysteine (45 mmol) in 100 mL of 1:1 MeOH/pH6.4 phosphate
buffer solution. The reaction was stirred at 40 °C for 3 days. The
precipitate was removed by filtration, and MeOH was removed
using rotary evaporation. The remaining solution was added 1 M
HCl to adjust pH ) 4 under 0 °C. The resulting precipitate was
extracted into CH2Cl2, dried, and concentrated to yield a white to
light-yellow solid 3, which were used directly to the next step
without purification.
(4R)-2-Phenyl-4,5-dihydrothiazole-4-carboxylic acid (3a).
Yield: 58.3%. 1H NMR (300 MHz, CDCl3) δ 9.31 (br, 1 H),
7.88-7.85 (m, 2 H), 7.55-7.41 (m, 3 H), 5.38 (t, 1 H, J ) 9.6
Hz), 3.75 (dt, 2 H, J ) 9.6 Hz, 2.7 Hz). MS (ESI) m/z 162.0 [M
- COOH]-.
(4S)-2-Phenyl-4,5-dihydrothiazole-4-carboxylic acid (3b).
Yield: 53.9%. 1H NMR (300 MHz, CDCl3) δ 7.89-7.85 (m, 2 H),
7.55-7.41 (m, 3 H), 5.38 (t, 1 H, J ) 9.3 Hz), 3.75 (dt, 2 H, J )
9.3 Hz, 2.7 Hz). MS (ESI) m/z 162.0 [M - COOH]-.
2-Phenyl-N-(3,4,5-trimethoxyphenyl)-4,5-dihydrothiazole-4-
carboxamide (4a-4b). The compounds were prepared following
the same EDCI/HOBt method as 2a-2b described.
Mass spectral data was collected on a Bruker ESQUIRE electro-
spray/ion trap instrument in positive and negative ion modes.
Elemental analyses were performed by Atlantic Microlab Inc.
(Norcross, GA).
General Procedure for the Preparation of (2RS,4R)-2-Aryl-
thiazolidine-4-carboxylic (1). A mixture of L-cysteine (3.16 g,
26.11 mmol) and appropriate aldehyde (26.15 mmol) in ethanol
(300 mL) and water (30 mL) was stirred at room temperature for
6-15 h, and the solid precipitated out was collected, washed with
diethyl ether, and dried to afford according (2RS,4R)-2-aryl-
thiazolidine-4-carboxylic acid 1 with yields of 70-99%. At 0 °C,
1 (5.95 mmol) was dissolved in 1 N NaOH (6 mL) and 1,4-dioxane
(15 mL), and then di-tert-butyldicarbonate (2.80 g, 12.80 mmol)
was added slowly and stirred at room temperature for 1 h. The
reaction mixture was concentrated in vacuum and washed with ethyl
acetate (20 mL). The aqueous phase was adjusted to pH ) 4 by
adding 1 N HCl or 5% KHSO4 and then extracted with ethyl acetate,
dried with magnesium sulfate, filtered, and concentrated in vacuum
to give corresponding BOC protected acids as white foam-solids,
which were used for the next step without further purification.

SMART as Anticancer Agents
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1707
Scheme 1a
a Reagents and conditions: (a) C2H5OH, H2O, rt; (b) Boc2O, 1 N NaOH, 1, 4-dioxane, H2O; (c) EDCI, HOBt, TEA, 3,4,5-trimethoxyaniline; (d) TFA,
CH2Cl2.
Scheme 2a
a Reagents and conditions: (a) MeOH/pH ) 6.4 phosphate buffer, rt; (b) EDCI, HOBt, TEA, 3,4,5-trimethoxyaniline; (c) CBrCl3, DBU.
(4R)-2-Phenyl-N-(3,4,5-trimethoxyphenyl)-4,5-dihydrothiaz-
ole-4-carboxamide (4a). Yield: 98.7%; mp 121-122 °C. 1H NMR
(300 MHz, CDCl3) δ 8.98 (s, 1 H), 8.02-7.94, 7.62-7.48 (m, 5
H), 6.93 (s, 2 H), 5.38 (t, 1 H, J ) 9.6 Hz), 3.92-3.85 (m, 2 H),
3.87 (s, 6 H), 3.82 (s, 3 H). MS (ESI) m/z 373.1 [M + H]+. Anal.
(C19H20N2O4S) C, H, N.
(4R)-2-Phenyl-N-(3,4,5-trimethoxyphenyl)-4,5-dihydrothiaz-
ole-4-carboxamide (4b). Yield: 70.7%; mp 122-123 °C. 1H NMR
(300 MHz, CDCl3) δ 8.62 (s, 1 H), 7.93-7.90 (m, 2 H), 7.55-7.45
(m, 3 H), 6.88 (s, 2 H), 5.31 (t, 1 H, J ) 9.6 Hz), 3.86 (s, 6 H),
3.79 (s, 3 H), 3.83-3.70 (m, 2 H). MS (ESI) m/z 395.1 [M + Na]+,
370.9 [M - 1]-. Anal. (C19H20N2O4S) C, H, N.
2-Phenyl-N-(3,4,5-trimethoxyphenyl)thiazole-4-carboxam-
ide (5). Yield: 89.7%; mp 157-158 °C. 1H NMR (300 MHz,
CDCl3) δ 9.30 (s, 1 H), 8.20 (s, 1 H), 8.04-8.01 (m, 2 H),
7.53-7.51 (m, 3 H), 7.08 (s, 2 H), 3.92 (s, 6 H), 3.86 (s, 3 H). MS
(ESI) m/z 393.1 [M + Na]+. Anal. (C19H18N2O4S) C, H, N.
2-(Substituted-phenyl)-4,5-dihydrothiazole-4-carboxylic acid
methoxymethylamides (6a-6p and 9). General procedure: A
mixture of appropriate 2-(substituted-phenyl)-4,5-dihydrothiazole-4-
carboxylic acid 3 (5mmol), EDCI (6 mmol), and HOBt (5 mmol) in
CH2Cl2 (50 mL) was stirred for 10 min. To this solution, NMM (5
mmol) and HNCH3OCH3 (5 mmol) were added, and stirring continued
at room temperature for 6-8 h. The reaction mixture was diluted with
CH2Cl2 (100 mL) and sequentially washed with water, satd NaHCO3,
brine, and dried over MgSO4. The solvent was removed under reduced
pressure to yield a crude product, which was purified by column
chromatography.
9.3 Hz), 3.30 (s, 3 H), 2.93 (s, 3 H). MS (ESI) m/z 265.0 [M +
H]+, 287.0 [M + Na]+.
(R)-2-(2-Fluorophenyl)-N-methoxy-N-methyl-4,5-dihydrothia-
zole-4-carboxamide (6c). Yield: 39.6%. 1H NMR (300 MHz,
CDCl3) δ 7.91 (dt, 1 H, J ) 7.5 Hz, 1.8 Hz), 7.43 (m, 1 H),
7.19-7.09 (m, 2 H), 5.63 (t, 1 H), 3.88 (s, 3 H), 3.83 (br, 1 H),
3.48 (dd, 1 H, J ) 11.1 Hz, 9.6 Hz), 3.30 (s, 3 H). MS (ESI) m/z
291.0 [M + Na]+.
(R)-2-(3-Fluorophenyl)-N-methoxy-N-methyl-4,5-dihydrothia-
zole-4-carboxamide (6d). Yield: 84.3%. 1H NMR (300 MHz,
CDCl3) δ 7.60-7.56 (m, 2 H), 7.38 (dt, 1 H, J ) 8.1 Hz, 6.0 Hz),
7.16 (dt, 1 H, J ) 8.1 Hz, 2.4 Hz), 5.67 (t, 1 H), 3.90 (s, 3 H),
3.86-3.83 (br, 1 H), 3.52 (dd, 1 H, J ) 10.8 Hz, 9.3 Hz), 3.30 (s,
3 H). MS (ESI) m/z 291.0 [M + Na]+.
(R)-2-(4-Fluorophenyl)-N-methoxy-N-methyl-4,5-dihydrothia-
zole-4-carboxamide (6e). Yield: 66.0%. 1H NMR (300 MHz,
CDCl3) δ 7.90 (d, 2 H), 7.13 (d, 2 H), 5.63 (t, 1 H), 3.88 (s, 3 H),
3.83 (br, 1 H), 3.46 (dd, 1 H), 3.31 (s, 3 H). MS (ESI) m/z 269.0
[M + H]+.
(R)-2-(3,4-Dimethoxyphenyl)-N-methoxy-N-methyl-4,5-dihy-
drothiazole-4-carboxamide (6f). Yield: 36.7%. 1H NMR (300
MHz, CDCl3) δ 8.11 (d, 1 H), 7.93 (s, 1 H), 7.19-7.09 (d, 1H),
5.41 (t, 1 H), 3.97 (s, 6H), 3.89 (s, 3 H), 3.73 (br, 1 H), 3.39 (dd,
1 H), 3.31 (s, 3 H). MS (ESI) m/z 333.1 [M + Na]+.
(R)-N-Methoxy-N-methyl-2-(4-nitrophenyl)-4,5-dihydrothia-
zole-4-carboxamide (6g). Yield: 53.7%. 1H NMR (300 MHz,
CDCl3) δ 8.25(d, 2 H, J ) 9.0 Hz), 8.01 (d, 2 H, J ) 9.0 Hz), 5.73
(t, 1 H), 3.90 (s, 3 H), 3.87 (br, 1 H), 3.59 (dd, 1 H, J ) 11.1 Hz,
9.3 Hz), 3.31 (s, 3 H). MS (ESI) m/z 318.1 [M + Na]+.
(R)-2-(4-Cyanophenyl)-N-methoxy-N-methyl-4,5-dihydrothia-
zole-4-carboxamide (6h). Yield: 26.7%. 1H NMR (300 MHz,
CDCl3) δ 7.94(d, 2 H, J ) 8.1 Hz), 7.69 (d, 2 H, J ) 8.1 Hz), 5.71
(t, 1 H, J ) 9.3 Hz), 3.89 (s, 3 H), 3.87 (br, 1 H), 3.56 (dd, 1 H,
J ) 10.8 Hz, 9.3 Hz), 3.30 (s, 3 H). MS (ESI) m/z 298.0 [M +
Na]+.
(R)-N-Methoxy-N-methyl-2-phenyl-4,5-dihydrothiazole-4-car-
boxamide (6a). Yield: 92.0%. 1H NMR (300 MHz, CDCl3) δ
7.85-7.83 (m, 2 H), 7.48-7.36 (m, 3 H), 5.66 (t, 1 H, J ) 9.0
Hz), 3.90 (s, 3 H), 3.88-3.80 (br, 1 H), 3.55-3.47 (dd, 1 H, J )
10.8 Hz, 9.0 Hz), 3.30 (s, 3 H). MS (ESI) m/z 251.0 [M + H]+,
273.0 [M + Na]+.
(R)-N-Methoxy-N-methyl-2-p-tolyl-4,5-dihydrothiazole-4-car-
boxamide (6b). Yield: 55.8%. 1H NMR (300 MHz, CDCl3) δ 7.79
(d, 2 H, J ) 7.8 Hz), 7.22 (d, 2 H, J ) 7.8 Hz), 5.68 (t, 1 H, J )
8.7 Hz), 3.91 (s, 3 H), 3.80 (t, 1 H, J ) 9.3 Hz), 3.55 (t, 1 H, J )
(R)-N-Methoxy-N-methyl-2-(4-trifluoromethylphenyl)-4,5-di-
1
hydrothiazole-4-carboxamide (6i). Yield: 62.0%. H NMR (300
MHz, CDCl3) δ 7.95 (d, 2 H, J ) 8.1 Hz), 7.65 (d, 2 H, J ) 8.1

1708 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Lu et al.
Scheme 3a
a Reagents and conditions: (a) MeOH/pH ) 6.4 phosphate buffer, rt; (b) EDCI, HOBt, NMM, HNCH3OCH3; (c) CBrCl3, DBU; (d) ArBr/BuLi or ArMgBr,
THF; (e) HCl/HOAc; (f) MeOH/CH3COCl; (g) Fe/HOAc; (h) BBr3, CH2Cl2.
Hz), 5.70 (t, 1 H, J ) 9.6 Hz), 3.89 (s, 3 H), 3.85 (br, 1 H), 3.55
(dd, 1 H, J ) 10.8 Hz, 9.6 Hz), 3.30 (s, 3 H). MS (ESI) m/z 341.0
[M + Na]+.
(R)-2-(4-Bromophenyl)-N-methoxy-N-methyl-4,5-dihydrothia-
zole-4-carboxamide (6j). Yield: 20.0%. 1H NMR (300 MHz,
CDCl3) δ 7.71, 7.53 (d, d, 4 H, J ) 8.4 Hz), 5.63 (t, 1 H, J )
9.6 Hz), 3.88 (s, 3 H), 3.84 (t, 1 H, J ) 9.6 Hz), 3.52 (dd, 1 H,
J ) 10.8 Hz, 9.6 Hz), 3.30 (s, 3 H). MS (ESI) m/z 351.0 [M +
Na]+.
(s, 3 H), 3.81 (m, 1 H), 3.48 (dd, 1 H, J ) 10.8 Hz, 9.3 Hz), 3.29 (s,
3 H), 2.67 (q, 2 H), 1.24 (t, 3 H). MS (ESI) m/z 301.0 [M + Na]+.
(R)-N-Methoxy-N-methyl-2-(pyridin-4-yl)-4,5-dihydrothiaz-
ole-4-carboxamide (6l). Yield: 66.6%. 1H NMR (300 MHz, CDCl3)
δ 8.70 (d, 2 H, J ) 9.0 Hz), 7.67 (d, 2 H, J ) 9.0 Hz), 5.71 (t, 1
H, J ) 9.6 Hz), 3.90 (s, 3 H), 3.73 (t, 1 H), 3.55 (dd, 1 H, J ) 10.8
Hz, 9.6 Hz), 3.30 (s, 3 H). MS (ESI) m/z 252.1 [M + H]+, 274.0
[M + Na]+.
(R)-N-Methoxy-N-methyl-2-(pyrimidin-2-yl)-4,5-dihydrothia-
zole-4-carboxamide (6m). Yield: 32.5%. 1H NMR (300 MHz,
CDCl3) δ 8.88 (d, 2 H, J ) 4.8 Hz), 7.38 (t, 1 H, J ) 4.8 Hz), 5.83
(R)-N-Methoxy-N-methyl-2-(4-ethyl)-4,5-dihydrothiazole-4-
carboxamide (6k). Yield: 77.7%. H NMR (300 MHz, CDCl3) δ
7.75(d, 2 H, J ) 8.4 Hz), 7.21 (d, 2 H, J ) 8.4 Hz), 5.64 (t, 1 H), 3.89
1

SMART as Anticancer Agents
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1709
(t, 1 H, J ) 9.0 Hz), 3.87 (s, 3 H), 3.56 (dd, 2 H, J ) 9.0 Hz), 3.30
(s, 3 H). MS (ESI) m/z 275.0 [M + Na]+.
3 H), 7.08-7.01 (m, 2 H), 3.78 (s, 3 H). MS (ESI) m/z 318.1 [M
+ Na]+. Anal. (C17H13NO2S) C, H, N.
(R)-N-Methoxy-N-methyl-2-(thiophen-2-yl)-4,5-dihydrothia-
zole-4-carboxamide (6p). Yield: 58.5%. 1H NMR (300 MHz,
CDCl3) δ 7.57 (br, 1 H), 7.49 (d, 1 H, J ) 4.8 Hz), 7.09 (dd, 1 H,
J ) 3.6 Hz, 4.8 Hz), 5.64 (t, 1 H, J ) 9.0 Hz), 3.90 (s, 3 H), 3.85
(br, 1 H), 3.57 (dd, 1 H, J ) 9.9, 9.0 Hz), 3.29 (s, 3 H). MS (ESI)
m/z 279.0 [M + Na]+.
(3,4-Dimethoxyphenyl)(2-phenylthiazol-4-yl)-methanone (8e).
Yield: 15.3%; mp 89-91 °C. 1H NMR (500 MHz, CDCl3) δ 8.24
(s, 1 H), 8.22 (dd, 1 H, J ) 8.5 Hz, 2.0 Hz), 8.04-8.02 (m, 2 H),
7.99 (d, 1 H, J ) 2.0 Hz), 7.49-7.47 (m, 3 H), 6.98 (d, 1 H, J )
8.5 Hz), 3.99 (s, 6 H). MS (ESI) m/z 348.0 [M + Na]+. Anal.
(C18H15NO3S) C, H, N.
N-Methoxy-N-methylthiazole-4-carboxamide (9). Yield: 58.7%.
1H NMR (300 MHz, CDCl3) δ 8.82 (d, 1 H, J ) 2.1 Hz), 8.10 (d,
1 H, J ) 2.1 Hz), 3.79 (s, 3 H), 3.45 (s, 3 H). MS (ESI) m/z 194.9
[M + Na]+.
(2-Phenyl-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)-metha-
none (8f). Yield: 27.3%; mp 133-135 °C. H NMR (300 MHz,
CDCl3) δ 8.29 (s, 1 H), 8.03 (q, 2 H), 7.80 (s, 2 H), 7.49-7.47 (m,
3 H), 3.96 (s, 6 H), 3.97 (s, 3 H). MS (ESI) m/z 378.1 [M + Na]+.
Anal. (C19H17NO4S) C, H, N.
1
2-(Substituted-phenyl)-thiazole-4-carboxylic Acid Methoxym-
ethylamide (7). General procedure: A solution of 6a-6p (1 equiv)
in CH2Cl2 was cooled to 0 °C, and distilled DBU (2 equiv) was
added. Bromotrichloromethane (1.7 equiv) was then introduced
dropwise via syringe over 10 min. The reaction mixtures were
allowed to warm to room temperature and stirred overnight. Upon
washing with satd aqueous NH4Cl (2 × 50 mL), the aqueous phase
was extracted with EtOAc (3 × 50 mL). The combined organic
layers were dried on MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography as needed
providing compounds 7.
(3,5-Dimethoxyphenyl)(2-phenylthiazol-4-yl)-methanone (8g).
Yield: 41.5%; mp 84-85 °C. 1H NMR (300 MHz, CDCl3) δ 8.23
(s, 1 H), 8.04-8.01 (m, 2 H), 7.99 (d, 2 H, J ) 2.4 Hz), 7.49-7.43
(m, 3 H), 6.72 (t, 1 H, J ) 2.4 Hz), 3.87 (s, 6 H). MS (ESI) m/z
348.3 [M + Na]+. Anal. (C18H15NO3S) C, H, N.
(2-Fluorophenyl)(2-phenylthiazol-4-yl)-methanone (8h). Yield:
1
66.4%; mp 77-79 °C. H NMR (300 MHz, CDCl3) δ 8.48-8.41
(m, 2 H), 8.28 (s, 2 H), 8.04-7.98 (m, 2 H), 7.50-7.46 (m, 3 H),
7.26-7.16 (m, 2 H). MS (ESI) m/z 306.0 [M + Na]+, 283.9 [M -
H]-. Anal. (C16H10FNOS) C, H, N.
2-Phenyl-thiazole-4-carboxylic Acid Methoxymethylamide.
Yield: 73.6%. 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1 H),
7.99-7.96 (m, 2 H), 7.47-7.44 (m, 3 H), 3.88 (s, 3 H), 3.49 (s, 3
H). MS (ESI) m/z 271.0 [M + Na]+.
(2-Phenylthiazol-4-yl)-(pyridin-2-yl)-methanone (8i). Yield:
1
20.7%; mp 95-97 °C. H NMR (300 MHz, CDCl3) δ 9.01 (s, 1
H), 8.77 (d, 1 H, J ) 4.8 Hz), 8.28 (d, 1 H, J ) 7.8 Hz), 8.08-8.05
(m, 2 H), 7.92 (dt, 1 H, J ) 7.8 Hz, 1.2 Hz), 7.52 (ddd, 1 H, J )
7.8 Hz, 4.8 Hz, 1.2 Hz), 7.48-7.46 (m, 3 H). (8i·HCl): Yield:
[2-(Substituted-phenyl)-thiazol-4-yl]-(3,4,5-trimethoxy-phen-
yl)-methanone (8a-8z and 10). Method 1: To a solution of n-BuLi
(1.6M, 0.713 mL) in 8 mL of THF was added a solution of 3,4,5-
trimethoxybromobenzene (1.09 mmol) in 3 mL of THF under -78
°C. The mixture was stirred for 2 h, and a solution of amides 6 or
7 (1.14 mmol) in 3 mL of THF was charged. The mixture was
allowed to warm to room temperature and stirred for overnight.
The reaction mixture was quenched with satd NH4Cl, extracted with
ethyl ether, dried with MgSO4, and exposed in air atmosphere for
overnight. The solvent was removed under reduced pressure to yield
a crude product, which was purified by column chromatography to
obtain pure compound 8a-8z. Method 2: To a solution of
corresponding Grignard reagents (0.5M, 3 mL) in 2 mL THF was
charged a solution of amides 6 or 7 (1 mmol) in 3 mL of THF at
0 °C. The mixtures were stirred for 30 min to 2 h until amides
disappeared on TLC plates. The reaction mixture was quenched
with satd NH4Cl, extracted with ethyl ether, dried with MgSO4,
and set in air atmosphere overnight to yield 6 as starting material.
The solvent was removed under reduced pressure to yield a crude
product, which was purified by column chromatography to obtain
pure compound 8a-8z. Accordingly, hydrochloride salt was
prepared as following: At 0 °C, to a solution of 10 mL of HCl in
ethyl ether (2 M) solution was added 8i, 8x, or 8w (100 mg) in 5
mL of CH2Cl2 (5 mL) and stirred overnight. The hydrochloride
precipitate was filtered and washed with ethyl ether. Dying under
high vacuum yielded the corresponding salts.
1
70.6%; mp 105-107 °C. H NMR (300 MHz, DMSO-d6) δ 9.03
(s, 1 H), 8.79 (d, 1 H, J ) 4.8 Hz), 8.10 (br, 1 H), 8.08 (br, 1 H),
8.03-8.00 (m, 2 H), 7.73-7.69 (m, 1 H), 7.56-7.54 (m, 3 H).
MS (ESI) m/z 267.0 [M + H]+. Anal. (C15H10N2OS, C15H10-
N2OS·HCl) C, H, N.
1-(2-Phenylthiazol-4-yl)-heptadecan-1-one (8j). Yield: 66.4%;
mp 63-64 °C. 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1 H),
8.02-7.99 (m, 2 H), 7.49-7.47 (m, 3 H), 3.16 (t, 2 H, J ) 7.5
Hz), 1.82-1.72 (m, 2 H), 1.26 (s, 26 H), 0.88 (t, 3 H, J ) 6.9 Hz).
MS (ESI) m/z 414.4 [M + H]+. Anal. (C26H39NOS) C, H, N.
(2-p-Tolylthiazol-4-yl)-(3,4,5-trimethoxyphenyl)-methanone (8k).
1
Yield: 53.2%; mp 116-119 °C. H NMR (300 MHz, CDCl3) δ
8.25 (s, 1 H), 7.91 (d, 2 H, J ) 8.1 Hz), 7.80 (s, 2 H), 7.28 (d, 2
H, J) 8.1 Hz), 3.96 (s, 3 H), 3.95 (s, 6 H). MS (ESI) m/z 392.1
[M + Na]+. Anal. (C20H19NO4S) C, H, N.
[2-(2-Fluorophenyl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-
1
methanone (8l). Yield: 39.6%; mp 90-102 °C. H NMR (500
MHz, CDCl3) δ 8.40 (s, 1 H), 8.33 (dt, 1 H, J ) 1.5 Hz, 8.0 Hz),
7.78 (s, 2 H), 7.49-7.44 (m, 1 H), 7.30-7.23 (m, 2 H), 3.97 (s, 3
H), 3.95 (s, 6 H). MS (ESI) m/z 396.1 [M + Na]+. Anal.
(C19H16FNO4S) C, H, N.
[2-(3-Fluorophenyl)-thiazol-4-yl](3,4,5-trimethoxyphenyl)-
1
methanone (8m). Yield: 14.1%; mp 122-124 °C. H NMR (300
MHz, CDCl3) δ 8.31 (s, 1 H), 7.79 (s, 2 H), 7.76-7.74 (m, 2 H),
7.45 (dt, 1 H, J ) 6.0 Hz, 8.4 Hz), 7.18 (dt, 1 H, J ) 1.8 Hz, 8.4
Hz), 3.97 (s, 3 H), 3.96 (s, 6 H). MS (ESI) m/z 396.1 [M + Na]+.
Anal. (C19H16FNO4S) C, H, N.
Phenyl (2-Phenylthiazol-4-yl)-methanone (8a). Yield: 76.3%;
1
mp 65-66 °C. H NMR (300 MHz, CDCl3) δ 8.32-8.29 (m, 2
H), 8.24 (s, 1 H), 8.04-8.00 (m, 2 H), 7.64-7.52 (m, 3 H),
7.50-7.46 (m, 3 H). MS (ESI) m/z 288.0 [M + Na]+. Anal.
(C16H11NOS) C, H, N.
[2-(4-Fluorophenyl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-
1
methanone (8n). Yield: 40.2%; mp 153-155 °C. H NMR (300
MHz, CDCl3) δ 8.27 (s, 1 H), 8.04-8.00 (dd, 2 H, J ) 8.4 Hz, 5.7
Hz), 7.75 (s, 2 H), 7.21-7.15 (t, 3 H, J ) 8.4 Hz), 3.97 (s, 3 H),
3.95 (s, 6 H). MS (ESI) m/z 396.1 [M + Na]+. Anal. (C19H16FNO4S)
C, H, N.
(4-Methoxyphenyl)(2-phenylthiazol-4-yl)-methanone (8b).
Yield: 74.8%; mp 105-106 °C. H NMR (300 MHz, CDCl3) δ
8.41 (d, 2 H), 8.22 (s, 1 H), 8.02 (dd, 2 H), 7.47 (m, 3 H), 7.01 (d,
2 H), 3.80 (s, 3 H). MS (ESI) m/z 318.1 [M + Na]+. Anal.
(C17H13NO2S) C, H, N.
1
[2-(3,4-Dimethoxyphenyl)-thiazol-4-yl]-(3,4,5-trimethoxyphe-
1
nyl)-methanone (8o). Yield: 46.6%; mp 145-147 °C. H NMR
(3-Methoxyphenyl)(2-phenylthiazol-4-yl)-methanone (8c).
Yield: 58.8%; mp 43-44 °C. 1H NMR (300 MHz, CDCl3) δ 8.23
(s, 1 H), 8.05-8.01 (m, 2 H), 7.93 (d, 1 H), 7.84 (m, 1 H),
7.49-7.40 (m, 4 H), 7.16-7.15 (m, 1 H), 3.89 (s, 3 H). MS (ESI)
m/z 318.1 [M + Na]+. Anal. (C17H13NO2S) C, H, N.
(300 MHz, CDCl3) δ 8.20 (s, 1 H), 7.76 (s, 2 H), 7.58-7.54 (m,
2 H), 6.94 (d, 2 H, J ) 8.1 Hz), 3.96 (s, 6 H), 3.95 (s, s, 9H). MS
(ESI) m/z 438.1 [M + Na]+. Anal. (C21H21NO6S · 1/4H2O) C,
H, N.
(2-Methoxyphenyl)(2-phenylthiazol-4-yl)-methanone (8d).
[2-(4-Nitrophenyl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-meth-
anone (8p). Yield: 46.4%; mp 199-200 °C. 1H NMR (300 MHz,
CDCl3) δ 8.38 (d, 2 H, J ) 8.7 Hz), 8.34 (s, 1 H), 8.20 (d, 2 H, J
1
Yield: 57.4%; colorless oil. H NMR (300 MHz, CDCl3) δ 8.03
(s, 1 H), 7.98-7.95 (m, 2 H), 7.57-7.47 (m, 2 H), 7.47-7.42 (m,

1710 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Lu et al.
) 8.7 Hz), 7.73 (s, 2 H), 3.98 (s, 3 H), 3.95 (s, 6 H). MS (ESI) m/z
423.1 [M + Na]+. Anal. (C19H16N2O6S) C, H, N.
extracted with ethyl acetate, and dried with MgSO4. The solvent
was removed under reduced pressure to yield a crude product, which
was purified by column chromatography to obtain pure compound
4-[4-(3,4,5-Trimethoxybenzoyl)-thiazol-2-yl]-benzonitrile (8q).
1
1
as red crystalline solid. Yield: 50.9%; mp 175-176 °C. H NMR
Yield: 45.9%; mp 181-182 °C. H NMR (300 MHz, CDCl3) δ
(300 MHz, DMSO-d6) δ 8.44 (d, 1 H), 8.07-8.04 (m, 2 H),
7.57-7.55 (m, 3 H), 7.33 (s, 2 H). MS (ESI) m/z 336.1 [M + Na]+.
Anal. (C16H11NO4S) C, H, N.
8.37 (s, 1 H), 8.13 (d, 2 H, J ) 8.4 Hz), 7.78 (d, 2 H, J ) 8.4 Hz),
7.72 (s, 2 H), 3.97 (s, 3 H), 3.94 (s, 6 H). MS (ESI) m/z 403.1 [M
+ Na]+. Anal. (C20H16N2O4S) C, H, N.
X-ray Crystallography Structure Determination. X-ray crys-
tallographic data for 8f were collected from a single crystal mounted
with paratone oil on a nylon cryoloop. Data were collected at 100
K on a Bruker Proteum CCD area detector, controlled by Proteum2
software,26 using a rotating-anode generator and Osmic mirrors to
generate Cu radiation (λ ) 1.54178 Å). The data were reduced
using SAINT,27 with an absorption correction applied using
SADABS28 based on redundant reflections; this correction included
a spherical component. The structure was solved using direct
methods (SHELXSx4), which revealed all of the heavy atoms.
Structure refinement with SHELXL29 was carried out using full-
matrix methods based on F2 and proceeded smoothly. Hydrogen
atoms were added to the structural model assuming ideal C-H
distances and isotropic ADPs constrained to be similar to that of
the bonded carbon atom. In the final model, anisotropic ADPs were
refined for all heavy atoms and isotropic ADPs for chemically
similar hydrogens (e.g., methyl H) were constrained to be identical.
The final refinement parameters are: wR2 ) 0.084 for 228
parameters and 3066 independent observations, R1 ) 0.031, S
(goodness-of-fit) ) 1.057. The final structure has been submitted
to the Cambridge Crystallographic Data Center for deposition.
4-[4-(3,4,5-Trimethoxybenzoyl)-thiazol-2-yl]-benzoic acid (8r).
Yield: 61.9%; mp > 220 °C (dec). 1H NMR (300 MHz, CDCl3) δ
8.65 (s, 1 H), 8.00 (d, d, 4 H), 7.65 (s, 2 H), 3.88 (s, 6 H), 3.80 (s,
3 H). MS (ESI) m/z 397.9 [M - H]-, 353.9 [M - COOH]-. Anal.
(C20H17NO6S) C, H, N.
Methyl-4-[4-(3,4,5-trimethoxybenzoyl)-thiazol-2-yl]-ben-
1
zoate (8s). Yield: 72.5%; mp 172-174 °C. H NMR (300 MHz,
CDCl3) δ 8.35 (s, 1 H), 8.12 (dd, 4 H, J ) 8.4 Hz), 7.78 (s, 2 H),
3.97 (s, 3 H), 3.96 (s, 3H), 3.95 (s, 6 H). MS (ESI) m/z 436.1 [M
+ Na]+. Anal. (C21H19NO6S) C, H, N.
(2-(4-(Trifluoromethyl)-phenyl)-thiazol-4-yl)(3,4,5-trimethox-
yphenyl)-methanone (8t). Yield: 45.5%; mp 144-145 °C. 1H
NMR (300 MHz, CDCl3) δ 8.35 (s, 1 H), 8.14, 7.65 (d, d, 4 H, J
) 8.1 Hz), 7.76 (s, 2 H), 3.97 (s, 3 H), 3.95 (s, 6 H). MS (ESI) m/z
446.1 [M + Na]+. Anal. (C20H16F3NO4S) C, H, N.
[2-(4-Bromophenyl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-
1
methanone (8u). Yield: 51.8%; mp 149-150 °C. H NMR (300
MHz, CDCl3) δ 8.28 (s, 1 H), 7.89, 7.62 (d, d, 4 H, J ) 8.1 Hz),
7.75 (s, 2 H), 3.97 (s, 3 H), 3.94 (s, 6 H). MS (ESI) m/z 456.0,
458.0 [M + Na]+. Anal. (C19H16BrNO4S) C, H, N.
[2-(4-Ethyl-phenyl)-thiazol-4-yl]-(3,4,5-trimethoxy-phenyl)-
methanone (8v). Yield: 40.0%; mp 86-87 °C. 1H NMR (300 MHz,
CDCl3) δ 8.25 (s, 1 H), 7.93, 7.31 (d, d, 4 H, J ) 8.4 Hz), 7.81 (s,
2 H), 3.97 (s, 3 H), 3.95 (s, 6 H). MS (ESI) m/z 406.1 [M + Na]+.
Anal. (C21H21NO4S) C, H, N.
Biology.
Cell Culture and Cytotoxicity Assay of Melanoma. We
examined the antiproliferative activity of the ATCAA and SMART
analogues in one human melanoma cell line (A375) and one mouse
melanoma cell line (B16-F1). We used activity on fibroblast cells
as a control to determine the selectivity of these compounds against
melanoma. A375 cells and B16-F1 cells were purchased from
ATCC (American Type Culture Collection, Manassas, VA). Human
dermal fibroblast cells were purchased from Cascade Biologics, Inc.,
Portland, OR. All cell lines were cultured in DMEM (Cellgro
Mediatech, Inc., Herndon, VA), supplemented with 5% FBS
(Cellgro Mediatech), 1% antibiotic/antimycotic mixture (Sigma-
Aldrich, Inc., St. Louis, MO), and bovine insulin (5 µg/mL; Sigma-
Aldrich). Cultures were maintained at 37 °C in a humidified
atmosphere containing 5% CO2. Standard sulforhodamine B assay
was used. Cells were exposed to a wide range of concentrations
for 48 h in round-bottomed 96-well plates. Cells were fixed with
10% trichloroacetic acid and washed five times with water. After
cells were air-dried overnight and stained with SRB solution, total
proteins were measured at 560 nm with a plate reader. IC50 (i.e.,
concentration which inhibited cell growth by 50% of no treatment
controls) values were obtained by nonlinear regression analysis with
GraphPad Prism (GraphPad Software, San Diego,CA).
Cell Culture and Cytotoxicity Assay of Prostate Cancer. We
examined the antiproliferative activity of the ATCAA and
SMART analogues in four human prostate cancer cell lines
(LNCaP, DU 145, PC-3, and PPC-1). LNCaP, PC-3, and DU
145 cells were purchased from ATCC (American Type Culture
Collection, Manassas,VA). Dr. Mitchell Steiner at University
of Tennessee Health Science Center kindly provided PPC-1cells.
All prostate cancer cell lines were cultured in RPMI 1640
(Cellgro Mediatech, Inc., Herndon, VA), supplemented with 10%
FBS (Cellgro Mediatech). Cultures were maintained at 37 °C in
a humidified atmosphere containing 5% CO2. Then 1000-5000
cells were plated into each well of 96-well plates depending on
growth rate and exposed to different concentrations of a test
compound for 96 h in 3-5 replicates. Cell numbers at the end
of the drug treatment were measured by the SRB assay. Briefly,
the cells were fixed with 10% of trichloroacetic acid and stained
with 0.4% SRB, and the absorbances at 540 nm were measured
using a plate reader (DYNEX Technologies, Chantilly, VA).
Percentages of cell survival versus drug concentrations were
plotted and the IC50 (concentration that inhibited cell growth by
[2-(4-Amino-phenyl)-thiazol-4-yl]-(3,4,5-trimethoxy-phenyl)-
1
methanone (8w). Yield: 61.8%; mp 177-179 °C. H NMR (300
MHz, CDCl3) δ 8.14 (s, 1 H), 7.82, 7.65 (d, d, 4 H, J ) 8.4 Hz),
7.78 (s, 2 H), 3.96 (s, 3 H), 3.94 (s, 6 H). (8w ·HCl): Yield: 50.1%;
mp 166-169 °C. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1 H),
7.84, 6.94 (d, d, 4 H, J ) 8.4 Hz), 7.62 (s, 2 H), 3.86 (s, 3 H), 3.79
(s, 6 H). MS (ESI) m/z 393.1 [M + Na]+. Anal. (C19H18N2O4S,
C19H18N2O4S·HCl) C, H, N.
[2-(Pyridin-4-yl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-meth-
anone (8x). Yield: 29.3%; mp 178-180 °C. 1H NMR (300 MHz,
CDCl3) δ 8.77 (dd, 2 H, J ) 6.0 Hz, 1.5 Hz), 8.40 (s, 1 H), 7.87
(dd, 2 H, J ) 6.0 Hz, 1.8 Hz), 7.75 (s, 2 H), 3.98 (s, 3 H), 3.95 (s,
1
6 H). (8x·HCl): Yield: 92.7%; mp 182-184 °C. H NMR (300
MHz, CDCl3) δ 8.85 (br, 2 H), 8.52 (s, 1 H), 8.22 (br, 2 H), 7.66
(s, 2 H), 3.98 (s, 3 H), 3.94 (s, 6 H). MS (ESI) m/z 379.1 [M +
Na]+. Anal. (C18H16N2O4S, C18H16N2O4S·HCl) C, H, N.
[2-(Pyrimidin-2-yl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-
1
methanone (8y). Yield: 51.9%; mp 190-191 °C. H NMR (300
MHz, CDCl3) δ 8.88 (d, 2 H, J ) 4.8 Hz), 8.44 (s, 1 H), 7.73 (s,
2 H), 7.37 (t, 1 H, J ) 4.8 Hz), 3.95 (s, 3 H), 3.94 (s, 6 H). MS
(ESI) m/z 380.1 [M + Na]+. Anal. (C17H15N3O4S) C, H, N.
[2-(Thiophen-2-yl)-thiazol-4-yl]-(3,4,5-trimethoxyphenyl)-meth-
1
anone (8z). Yield: 30.5%; mp 111-113 °C. H NMR (300 MHz,
CDCl3) δ 8.25 (s, 1 H), 7.90 (s, 2 H), 7.58 (dd, 1 H, J ) 3.6, 0.9
Hz), 7.46 (dd, 1 H, J ) 5.4, 0.9 Hz), 7.12 (dd, 1 H, J ) 5.4, 3.6
Hz), 3.98 (s, 6 H), 3.97 (s, 3 H). MS (ESI) m/z 384.1 [M + Na]+.
Anal. (C17H15NO4S2) C, H, N.
Thiazol-4-yl-(3,4,5-trimethoxy-phenyl)-methanone (10). Yield:
1
49.4%; mp 106-108 °C. H NMR (300 MHz, CDCl3) δ 8.92 (d,
1 H, J ) 2.1 Hz), 8.34 (d, 1 H, J ) 2.1 Hz), 7.61 (s, 2 H), 3.94 (s,
3 H), 3.93 (s, 6 H). MS (ESI) m/z 302.0 [M + Na]+. Anal.
(C13H13NO4S) C, H, N.
(2-Phenyl-thiazol-4-yl)-(3,4,5-trihydroxy-phenyl)-metha-
none (11). To a solution of 8f (123 mg, 0.35 mmol) in 5 mL anhyd
CH2Cl2 was added BBr3 (1 M solution in CH2Cl2, 1.75 mL, 5 mmol)
under -78 °C. The mixture was stirred for 2 h and a solution of
amide 7 (1.14 mmol) in 3 mL of THF was charged. The mixture
was allowed to warm to room temperature slowly and stirred
overnight. The reaction mixture was quenched with satd NH4Cl,

SMART as Anticancer Agents
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Acknowledgment. This research is supported by funds
from Department of Pharmaceutical Sciences, College of
Pharmacy, University of Tennessee Health Science Center,
the Van Vleet Endowed Professorship, and Division of
Pharmaceutics, The Ohio State University. Zhao Wang is
supported by the Alma & Hal Reagan Fellowship. Partial
support from USPHS CA-125623 is also acknowledged.
Support from the Cancer Center Support (CORE) grant CA
21765 and that of American Lebanese Syrian Associated
Charities (ALSAC) is gratefully acknowledged by C. R. Ross.
Supporting Information Available: Additional spectral data for
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