Synthesis and structure-activity relationships of 2-amino-1- aroylnaphthalene and 2-hydroxy-1-aroylnaphthalenes as potent antitubulin agents

Article abstract of DOI:10.1021/jm8008635

A series of aroylnaphthalene derivatives were prepared as bioisosteres of combrestatin A-4 and evaluated for anticancer activity. 2-Amino-1- aroylnaphthalene and 2-hydroxy-1-aroylnaphthalene, 9 and 8, respectively, showed strong antiproliferative activity

Full text of DOI:10.1021/jm8008635

J. Med. Chem. 2008, 51, 8163–8167
8163
Synthesis and Structure-Activity Relationships of 2-Amino-1-aroylnaphthalene and
2-Hydroxy-1-aroylnaphthalenes as Potent Antitubulin Agents§
Gadarla Randheer Reddy,†,¶ Ching-Chuan Kuo,‡,¶ Uan-Kang Tan,| Mohane Selvaraj Coumar,† Chi-Yen Chang,‡
Yi-Kun Chiang,† Mei-Jung Lai, Jiann-Yih Yeh,† Su-Ying Wu,† Jang-Yang Chang,‡,§ Jing-Ping Liou,*, and
Hsing-Pang Hsieh*,†
DiVision of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli
County 350, Taiwan, Republic of China, National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan,
ROC, Department of Chemical and Materials Engineering, Technology and Science Institute of Northern Taiwan, Taipei 112, Taiwan, ROC,
DiVision of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung UniVersity Hospital, Tainan 704, Taiwan, ROC,
and College of Pharmacy, Taipei Medical UniVersity, Taipei 110, Taiwan, ROC
ReceiVed July 13, 2008
A series of aroylnaphthalene derivatives were prepared as bioisosteres of combrestatin A-4 and evaluated
for anticancer activity. 2-Amino-1-aroylnaphthalene and 2-hydroxy-1-aroylnaphthalene, 9 and 8, respectively,
showed strong antiproliferative activity with IC50 values of 2.1-26.3 nM against a panel of human cancer
cell lines including multiple-drug resistant cell line. Compound 9 demonstrated better antiproliferative activity
and has a comparable tubulin binding efficacy as that of colchicine.
Introduction
Microtubules play a pivotal role in mitosis and cell division
and are recognized as an important target in cancer therapy.1
Recent literature reveals that some antitubulin agents targeting
colchicine-binding domain can act as vascular-disrupting
agents.2 For example, 2, 4, and 5 rapidly depolymerize micro-
tubules of tumor vasculature by changing the morphology of
the endothelial cellsm thereby blocking the blood supply to the
tumors (Figure 1).
The pharmacological and clinical profiles of 4 as an antivas-
cular/anticancer agent have drawn a lot of attention for medicinal
chemists to develop a variety of derivatives or analogues in an
effort to obtain better compounds.3 The analysis of the structures
Figure 1. Antitubulin agents targeting colchicine-binding domain of
tubulin.
of 3 analogues, for example, 2-aminobenzophenones,4 2-amino-
3-aroylthiophenes,5 2-aroyl-3-aminothiophenes,6 2-amino- and
2′-aminocombretastatins,7 2-amino-3-aroylbenzothiophene,8 and
2-aroyl-3-aminoindoles,9 shows that the ortho relationship
between the aroyl group (3,4,5-trimethoxybenzoyl) and amino
group plays an important role in activity. Our work on
3-aroylindoles10 (6) exploited the “endo enamine-ketone”
conjugated indole ring as a bioisosteric replacement for the olefin
functionality of the 3 structure. The methoxy substitution located
at sixth position of indole ring contributed to the maximal
activity by mimicking the methoxy group present at the para
position to the double bond moiety in 3 (Figure 2). On the basis
of the above observations, we synthesized amino or hydroxyl
substituted 1- and 2-aroylnaphthalene derivatives utilizing the
“exo enamine- and enol-ketone” conjugated naphthalene ring
to mimic the olefin functionality of 3. In addition, the methoxy
group was also introduced to optimize the activity. We herein
describe the synthesis and structure-activity relationships of
1-aroyl- and 2-aroylnaphthalene derivatives as potent antitubulin
agents in the continuation of our search for antitumor agents.
Results and Discussion
Chemistry. The general method for the synthesis of 1-aroyl-
naphthalenes 7-17 is shown in Scheme 1. The synthesis of
2-hydroxy-1-aroylnaphthalene (8) was carried out in six steps
starting with formylation of 2,6-dimethoxynaphthalene (22) with
N-methylformanilide and phosphoryl chloride to obtain 1-formyl-
2,6-dimethylnaphthalene 23.11 The demethylation of 23 with
1-propanethiol followed by benzylation gave 2412 in 48% yield
(three steps). Grignard reaction of 3,4,5-trimethoxyphenylmag-
nesium bromide with 24 followed by pyridinium dichromate
(PDC) oxidation and Pd/C-mediated debenzylation afforded the
desired 2-hydroxy-1-aroylnaphthalenes (8) (35% yield, three
steps). 1-Aroylnaphthalene (7) was obtained from 8 in 24% yield
by converting it into 2-triflate-1-aroylnaphthalene (26) with
phenyl trifluoromethanesulfonate13 and then reducing the triflate
with Pd/C in Et3N.14 The C2-alkyl substituted compounds
15-17 were synthesized in 41-51% yield from triflate 26 by
an iron-catalyzed coupling reaction with the corresponding
* To whom correspondence should be addressed. For J.-P.L.: (phone)
886-2-2736-1661, extension 6130; (fax) 866-2-27369558; (e-mail) jpl@
tmu.edu.tw. For H.-P.H.: (phone) 886-37-246166, extension 35708; (fax)
886-37-586-456; (e-mail) hphsieh@nhri.org.tw.
§
This paper is dedicated to Professor Chun-Chen Liao, Department of
Chemistry, National Tsing Hua University,Taiwan, on the occasion of his
retirement.
†
Division of Biotechnology and Pharmaceutical Research, National
Health Research Institutes.
¶
These authors contributed equally to this work.
National Institute of Cancer Research, National Health Research
‡
Institutes.
|
Technology and Science Institute of Northern Taiwan.
Taipei Medical University.
National Cheng Kung University Hospital.
§
10.1021/jm8008635 CCC: $40.75
2008 American Chemical Society
Published on Web 11/25/2008

8164 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24
Brief Articles
Scheme 2a
a Reagents and conditions: (a) HCO2Et, NaOCH3, Ph-H, room temp;
(b) DDQ, 1,4-dioxane, room temp, (c) BnBr, K2CO3, DMF, reflux; (d) 3,4,5-
trimethoxyphenylmagnesium bromide, THF, 0 °C f room temp; (e) PDC,
4 Å molecular sieves, CH2Cl2, room temp; (f) 10% Pd/C, EtOAc; (g) phenyl
trifluoromethanesulfonamide, Et3N, CH2Cl2, room temp; (h) Pd(OAc)2,
BINAP, Cs2CO3, Ph2CdNH, THF, 65-70 °C; (i) NaOAc, NH2OH·HCl,
CH3OH, room temp; (j) CH3I, K2CO3, acetone, reflux; (k) 10% Pd/C, Et3N,
CH3OH.
2-amino-1-aroylnaphthalene (9) (31% yield, two steps). The C2-
amino-1-aroylnaphthalene (9) was converted into C2-methyl-
amino 10 and C2-dimethylamino 11 derivatives in 18% and
30% yields, respectively, by reacting with iodomethane in the
presence of potassium carbonate and DMF.
Figure 2. Design of 1- and 2-aroylnaphthalenes as antimitotics.
Scheme 1a
The syntheses of 2-aroylnaphthalenes (18-21) are depicted
in the Scheme 2. Starting from commercially available 6-meth-
oxy-1-tetralone (27), the preparation of 19 was carried out in
six steps through ethyl formate mediated formylation, 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQa) mediated aro-
mation,17 protection with the benzyl group, Grignard reaction
of 3,4,5-trimethoxyphenylmagnesium bromide followed by
alcohol oxidation with pyridinium dichromate and then depro-
tection with Pd/C. Similar to the synthesis of 2-amino-1-
aroylnaphthalene (9), 1-amino-2-aroylnaphthalene (18) was
obtained from the key intermediate 31. The 1-hydroxy-6-
methoxy-2-(3′,4′,5′-trimethoxybenzoyl)naphthalene (19) was
treated with phenyl trifluoromethane sulfonamide in trimethy-
lamine to give 1-triflate 31. Palladium-catalyzed imination of
31 in the presence of benzophenoneimine and cesium carbonate
followed by cleavage of imine moiety with NaOAc/
NH2OH·HCl afforded 18 in 12% yield (three steps). Compound
20, with a methoxy group at the C1-position of the naphthalene
ring, was prepared in 82% yield by treatment of 19 with
iodomethane in acetone, utilizing K2CO3 as base. Compound
21, a dehydroxy analogue of 19, was prepared by treatment of
triflate 31 with Pd/C in triethylamine in 51% yield.
Biological Evaluation. A. In Vitro Cell Growth
Inhibitory Activity. The synthesized 1-aroylnaphthalenes 7-17,
2-aroylnaphthalenes 18-21, and reference compounds 1 and 6
were evaluated for their antiproliferative activities against five
human cancer cell lines, cervical carcinoma KB cells, colorectal
carcinoma HT29 cells, non-small-cell-lung carcinoma H460
cells, and stomach carcinoma MKN45 cells, as well as MDR-
positive cell line, KB-vin10 cells, which overexpress P-gp 170/
MDR (Table 1).
a Reagents and conditions: (a) N-methylformanilide, POCl3; (b) 1-pro-
panethiol, NaH, DMF, 50-60 °C; (c) BnBr, K2CO3, acetone, reflux; (d)
3,4,5-trimethoxyphenylmagnesium bromide, THF, 0 °C f room temp; (e)
PDC, CH2Cl2, 4 Å molecular sieves, room temp; (f) 10% Pd/C, EtOAc,
room temp; (g) phenyl trifluoromethanesulfonamide, triethylamine, CH2Cl2,
room temp; (h) Pd/C, Et3N, CH3OH, room temp; (i) Fe(acac)2, N-
methylpyrrolidine, methyl- or ethyl- or propylmagnesium iodide, THF; (j)
CH3I or C2H5I or C3H7I, K2CO3, acetone, reflux; (k) Pd(OAc)2, BINAP,
Ph2CdNH, Cs2CO3, THF, 65-70 °C; (l) NaOAc, NH2OH·HCl, CH3OH,
room temp; (m) CH3I, K2CO3, DMF, reflux.
alkylmagnesium halides in the presence of iron(II) acetylac-
etonate and N-methylpyrrolidine.15 A series of 2-alkoxy-1-
aroylnaphthalenes were prepared from 8 in 70-81% yield.
Compound 8 was treated with the corresponding alkyl halides
in the presence of potassium carbonate in acetone to afford
2-alkoxy-1-aroylnaphthalenes (12-14). The 2-amino-1-aroyl-
naphthalene (9) was synthesized by palladium-catalyzed ami-
nation of triflate.16 1-Trifluorosulfonyl-2-aroylnaphthalene (26)
was reacted with palladium acetate/benzophenoimine to give
imine, which on treatment with NaOAc/NH2OH·HCl afforded
a Abbreviations: BINAP, (()-2,2′-bis(diphenylphosphino)-1,1′-binaph-
thalene; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; POCl3, phos-
phorus(III) oxychloride; Cs2CO3, cesium carbonate; Pd(OAc)2, palladium(II)
acetate; DMF, N,N-dimethylformamide; THF, tetrahydrofuran; MDR,
multidrug-resistant.

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 8165
Table 1. IC50 Values (nM ( SDa) of Compounds 6-21 and 1
cell type (IC50 ( SD,a nM)
compd
KB
KB-vin10
H460
HT29
MKN45
6
7
8
9
4.6 ( 0.4
6.2 ( 1
7.1 ( 2
5.9 ( 1.5
3.2 ( 0.2
72.9 ( 22 58 ( 38
85.5 ( 29 69.4 ( 13.2 44.1 ( 22
8.2 ( 0.9
2.9 ( 1.1
11 ( 4
12.6 ( 9
3.6 ( 0.2
416 ( 18
>10000
84 ( 24
26.3 ( 7.1 21 ( 5.4
15.4 ( 10.7 2.1 ( 0.3
512 ( 30
>10000
144 ( 102 53 ( 15
3.3 ( 2.2
364 ( 12
>10000
70 ( 32
10 381 ( 6
11 >10000
12 65 ( 19
338 ( 26
>10000
13 1000 ( 50 912 ( 52
14 2600 ( 400 2431 ( 610 2716 ( 318 2851 ( 541 1762 ( 412
15 276 ( 14
16 600 ( 100 512 ( 10
17 1000 ( 102 1104 ( 57 987 ( 65
18 8800 ( 200 7910 ( 367 >10000
1210 ( 120 1134 ( 204 874 ( 76
263 ( 29
321 ( 56
764 ( 32
412 ( 38
667 ( 62
1320 ( 512 840 ( 50
9850 ( 760 7432 ( 850
254 ( 25
320 ( 71
19 >10000
20 >10000
21 510 ( 83
>10000
>10000
530 ( 28
116 ( 15
>10000
>10000
716 ( 21
18 ( 7
>10000
>10000
548 ( 30
10 ( 2
>10000
>10000
462 ( 12
13 ( 4
1
11 ( 2
Figure 4. Superimposition of 8 (blue) and 19 (green) over 3 (yellow)
in colchicine binding site of tubulin (PDB code 1SA0) using Gold 4.0.
Dark-gray dotted lines represent intramolecular hydrogen bond.
a SD: standard deviation. All experiments were independently performed
at least three times.
presence of a methoxy group at the C6 position of 1-aroyl-
naphthalenes would mimic the methoxy group present at the
position para to the olefin double bond of z-stilbene (3), resulting
in maximum cytotoxicity (Figure 3). However, N,N-dimethy-
lamino (11), C2-alkoxy (12-14), or alkyl substituted (15-17)
compounds do not have this conformation restricting intramo-
lecular hydrogen-bonding interaction to mimic the conformation
of 3, resulting in decreased activity for these compounds. Even
though compounds without intramolecular hydrogen-bonding
interaction, like 7, 12, and 15, have good antiproliferative
activity, an increase in steric bulk at this position leads to lower
antiproliferative activity as in the case of 13 and 14 vs 12 and
of 16 and 17 vs 15. Moreover, complete inactivity of 11
indicates that the N,N-dimethylamino substitution through steric
bulk prevents the molecule from taking up the conformation of
3. Thus, unsubstituted 7’s activity is maximized by the presence
of conformation restricting intramolecular hydrogen-bonding
interaction as in the case of 8 and 9.
Since 1-aroylnaphthalenes, such as 7-9 and 12, demonstrated
substantial activity, we attempted to evaluate the effect of
switching the functional groups at C1 and C2 positions of
1-aroylnaphthalenes with each other to prepare the 2-aroyl-
naphthalene derivatives 18-21. Results indicated exchanging
C1 aroyl group and C2 amino moiety of 1-aroylnaphthalenes
(9) with each other, as in 18, led to a dramatic loss of activity
against KB, KB-vin10, H460, HT29, and MKN45 lines. A
similar phenomenon was also observed in the cases of 19 and
20. Unexpectedly, 2-aroylnaphthalene 21, namely, 6-methoxy-
2-(3′,4′,5′-trimethoxybenzoyl)naphthalene, showed moderate
activity with a mean IC50 of 553 nM against five cell lines.
Similar to 1-aroylnaphthalene derivatives 8 and 9, 2-aroylnaph-
thalene compounds 18 and 19 possess conformation restricting
intramolecular interaction between the C2 carbonyl group and
C1 amino (or hydroxyl) group. However, the 1-amino- and
1-hydroxy-2-aroyl-6-methoxynaphthalenes, 18 and 19, respec-
tively, would adopt a conformation that is different from 3,
thereby causing inactivity in the 2-aroylnaphthalene series by
the presence of conformation restricting intramolecular interac-
tion (Figure 3). The moderate antiproliferative activity of 21
without substitution at the C1 position and intramolecular
hydrogen-bonding interaction might be due to its flexible
structure conformation. Presence of intramolecular hydrogen
bonding as discussed above is evidenced from the appearance
of an OH proton at a downfield position (∼δ 10.5) from the
Figure 3. 2D-Conformation of 3 and intramolecular bonded 8, 9, 18,
and 19.
We evaluated the effect of the substitution of 2-hydroxy or
2-amino group on the naphthalene ring in the 1-aroyl-6-
methoxynaphthalene series on the antiproliferative activity.
Compounds 8 and 9 with hydroxyl and amino groups, respec-
tively, demonstrated strong cytotoxicity with mean IC50 values
of 15.8 and 5.4 nM, respectively, against a panel of human
cancer cell lines. The antiproliferative activity of 2-amino-1-
aroylnaphthalene (9) was superior to 1 and comparable to
3-aroylindole 6. Compound 7, with no substitution at the C2
position, showed double-digit nanomolar IC50 values against five
cell lines. To understand the steric effect of alkyl substitution
on the amino function at the C2 position, methylamino and N,N-
dimethylamino substituted compounds 10 and 11 were synthe-
sized. Compound 10 exhibited a decreased cytotoxicity in
comparison with 9 with a mean IC50 of 402 nM, but an increase
in the bulkiness of the substitution, for example, 11, resulted in
a dramatic loss of activity, thus revealing the influence of the
steric effect of the substituent at the C2 position of the
naphthalene ring on cell growth inhibitory activity.
A similar phenomenon was also observed with the C2-alkoxy
substituents (12-14) and C2-alkyl substituents (15-17) 1-aroyl-
naphthalene derivatives. Compounds 12, 13, and 14 with a
methoxy, ethoxy, and propyloxy group at the C2 position of
naphthalene ring, respectively, showed cytotoxicity with mean
IC50 values of 83, 1026, and 2472 nM, respectively. The
alkylation at the C2 position in 1-aroyl-6-methoxynaphthalenes,
for instance, 15, 16, and 17 with methyl, ethyl, and propyl
moieties, respectively, resulted in moderate activity against all
five cell lines with IC50 values of 254-1320 nM.
A comparison of the structures of 7-9 indicated that an
intramolecular hydrogen-bonding interaction between the 3′,4′,5′-
trimethoxybenzoyl carbonyl group and hydroxyl/amino group
on the naphthalene ring (Figure 3) would lock the conformation
of 8 and 9 to mimic 3 better than unsubstituted compound 7,
leading to enhanced potency (8 and 9 vs 7). In addition, the

8166 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24
Brief Articles
Table 2. Growth Inhibition of Compounds 8 and 9 against Drug-Resistant Cell Lines
IC50
VP-16, µM
cell lines
KB
KB-VIN10
KB-TAX50
KB-7D
resistant type
vincristine, nM
paclitaxel, nM
8, nM
9, nM
Parental
0.4 ( 0.1
90.1 ( 7.4
17.6 ( 2.2
1.2 ( 0.4
3.3 ( 1.2
16500 ( 707
273 ( 15
7.9 ( 0.5
1.1 ( 0.2
23 ( 3
3.5 ( 0.3
54 ( 3.5
8.2 ( 0.9
11 ( 4
15 ( 2.5
16.9 ( 3.1
2.9 ( 1.1
3.3 ( 2.2
3.1 ( 1.6
3.5 ( 1.4
P-gp170/MDR v
P-gp170/MDR v
MRP v
Table 3. Inhibition of Tubulin Polymerization and Colchicine Binding
by Compounds 7-9, 12, 15, 18, 1, 6, and 3
of potent antitubulin agents acting through the colchicine binding
site of the microtubule. Compounds 8 and 9 demonstrated
antiproliferative activities with mean IC50 values of 15.8 and
5.4 nM, respectively, in a diverse set of human cancer cell lines,
including the MDR/MRP-positive drug resistant cell line. They
also exhibited substantial inhibition of tubulin polymerization
with IC50 values of 2.6 and 2.4 µM, respectively, which were
comparable to those of reference compounds 1 and 6. The SAR
information indicated that the introduction of the amino or
hydroxyl group at the C2-position of 6-methoxy-1-aroylnaph-
thalenes resulted in an increased activity compared with
unsubstituted compound (8 and 9 vs 7), thus revealing that the
C2-amino or C2-hydroxyl substitution in the 1-aroylnaphthalene
core plays an important role for maximal activity. Using a
bioisosterism approach via an exo enamine- and enol-ketone
conjugated naphthalene ring to mimic the olefin functionality
of 3, we effectively prepared potent antimitotic agents, 2-amino
and 2-hydroxy-1-aroylnaphthalenes (8 and 9), which would be
further evaluated as potential anticancer agents.
compd
tubulin,a IC50 ( SD (µM)
colchicine binding,b % ( SD
6
7
8
9
12
15
18
1
2.8 ( 0.2
4.3 ( 0.1
2.6 ( 0.3
2.4 ( 0.3
2.7 ( 0.1
2.9 ( 0.4
>10
85 ( 3
68 ( 4
75 ( 2
85 ( 3
52 ( 2
67 ( 1
3.2 ( 0.3
1.3 ( 0.2
3
93 ( 2
a Inhibition of tubulin polymerization.18 b Inhibition of [3H]colchicine
binding.18-20 Tubulin was at 1 µM. [3H]Colchicine and inhibitor were both
at 5 µM.
1
usual in the H NMR spectra of 8 and 19. To further validate
our hypothesis for conformation restricting intramolecular
hydrogen-bonding playing an important role in enhancing the
potency, molecular modeling studies of 8 and 19 were carried
out. Compounds 8 and 19 were docked into the colchicine
binding site of tubulin (PDB code 1SA0) using Gold, version
3.1, in default docking mode. The results showed that 8
overlapped well with 3; however, 19 did not overlap well over
3 (Figure 4), further providing evidence for the potent activity
of 8 and inactivity of 19.
Experimental Section
2-Hydroxy-6-methoxy-1-(3′,4′,5′-trimethoxybenzoyl)naphtha-
lene (8). Compound 25 (2.2 g, 4.8 mmol) was dissolved in ethyl
acetate (10 mL). Then 10% Pd/C (0.1 g) was added to the reaction
solution, and then the reaction mixture under Parr hydrogenator
was shaken for 4 h at room temperature. The mixture was filtered
through a Celite pad and the organic layer evaporated under reduced
pressure. The remaining residue was purified by silica gel chro-
matography (ethyl acetate/n-hexane ) 1:4) to afford the desired 8,
In an effort to further understand the efficacy of 2-amino-
and 2-hydroxy-1-aroylnaphthalenes against drug-resistant cell
lines, 8 and 9 were evaluated for antiproliferative activity in
various resistant lines as shown in the Table 2. Despite the high
level of expression drug-resistant efflux protein (MDR/P-gp or
MRP) in KB-Vin 10, KB-TAX50, and KB-7D cells, 8 and 9
showed similar cytotoxic efficacy between parental cells and
these resistant lines. 8 and 9 were also evaluated for antipro-
liferative activity in normal cells, human fibroblast Detroit 551
cells. Data found that their IC50 values toward cultured fibroblast
Detroit 551 were >1000 nM. This result indicated that 8 and 9
possessed great selectivity between normal and cancer cells.
B. Inhibition of Tubulin Polymerization and Colchicine
Binding Activity. To investigate whether the activities of these
aroylnaphthalenes were related to interactions with micro-
tubule system, the selected compounds 7-9, 12, 15, 18 and
reference compounds 1, 3, and 6 were evaluated for their
antitubulin activities and colchicine binding activities (Table
3). The results indicated that the compounds’ antiproliferative
activity correlated with the inhibition of tubulin polymerization.
Compounds 8, 9, 12, and 15 were efficacious in inhibiting
microtubulin assembly, with IC50 values of 2.6, 2.4, 2.7, and
2.9 µM, respectively. These values were comparable to reference
compounds 1 and 6. In the [3H]colchicine-binding assay, results
indicated that 1-aroylnaphthalenes were bound to the colchicine-
binding site.
1
yield 78%. H (300 MHz, CDCl3) δ 3.72 (s, 6H), 3.88 (s, 3H),
3.93 (s, 3H), 6.90 (s, 2H), 6.88 (dd, J ) 2.7, 9.6 Hz,1H), 7.08 (d,
J ) 3.0 Hz,1H), 7.21 (d, J ) 9.0 Hz, 1H), 7.28 (d, J ) 9.3 Hz,1H),
7.82 (d, J ) 9.0 Hz, 1H), 10.58 (s, 1H). 13C NMR (75 MHz, CDCl3)
δ 55.5, 56.4, 61.3, 107.2, 107.3, 114.9, 118.7, 119.7, 127.3, 127.9,
129.7, 135.1, 135.2, 142.3, 153.2, 156.0, 159.3, 199.2. HRMS (EI)
for C21H20O6 (M+): calcd, 368.1260; found, 368.1247. Anal.
(C21H20O6) C, H.
2-Amino-6-methoxy-1-(3′,4′,5′-trimethoxybenzoyl)naphtha-
lene (9). A stirred solution of 26 (0.5 g, 1.09 mmol), palladium(II)
acetate (5 mg, 0.022 mmol), (()-2,2′-bis(diphenylphosphino)-1,1′-
binaphthalene (20 mg, 0.032 mmol), benzophenoneimine (0.23 g,
1.31 mmol), and cesium carbonate (0.49 g, 1.50 mmol) in THF
(20 mL) was heated under 65-70 °C with stirring for 16 h. The
reaction mixture was diluted with CH2Cl2 (10 mL), washed with
brine, dried over MgSO4, and evaporated to give a crude residue,
which was dissolved in methanol (15 mL). Sodium acetate (0.26
g, 3.27 mmol) and hydroxyamine hydrochloride (0.15 g, 2.18 mmol)
were added to the reaction mixture with stirring at room temperature
for 16 h. The reaction solution was neutralized with 0.1 M and
extracted with CH2Cl2 (10 mL × 3). The combined organic extracts
were dried and evaporated to give a residue that was purified by
silica gel column chromatography (ethyl acetate/n-hexane ) 1:4)
1
to afford the desired 9, yield 31%. H (300 MHz, CDCl3) δ 3.73
(s, 6H), 3.86 (s, 3H), 3.91 (s, 3H), 4.58 (s, 2H), 6.88 (dd, J ) 2.7,
9.0 Hz, 1H), 6.94 (d, J ) 8.7 Hz, 1H), 7.02 (s, 2H), 7.03 (d, J )
2.7 Hz, 1H), 7.21 (d, J ) 9.0 Hz, 1H), 7.64 (d, J ) 8.7 Hz, 1H).
13C NMR (75 MHz, CDCl3) δ 55.4, 56.4, 61.2, 107.0, 107.4, 115.8,
118.9, 119.6, 124.7, 126.7, 128.1, 128.5, 131.4, 134.4, 143.3, 153.3,
155.3, 198.1. HRMS (EI) for C21H21NO5 (M+): calcd., 367.1420;
found, 367.1429. Anal. (C21H21NO5 ·0.5H2O) C, H, N.
Conclusion
Synthesis and structure-activity relationships studies for
1-aroylnaphthalenes and 2-aroylnaphthalenes as anticancer
agents were carried out. The 2-amino- and 2-hydroxy-6-
methoxy-1-aroylnaphthalenes were identified as a novel class

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 8167
of Potent Antitubulin agents. J. Med. Chem. 2006, 49, 3906
3915.
Acknowledgment. We thank Dr. Neeraj Mahindroo of St.
Jude Children’s Research Hospital for his valuable suggestions
concerning the manuscript. This research was supported by the
National Science Council of the Republic of China (Grants NSC-
95-2113-M-400-001-MY3, NSC 96-2752-B-400-001-PAE, and
NSC 97-2323-B-038-001) and by National Health Research
Institutes, Taiwan (Grant CA-097-PP-02).
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