Discovery of N-substituted 3-arylisoquinolone derivatives as antitumor agents originating from O-substituted 3-arylisoquinolines via [2,3] or [3,3] rearrangement

Article abstract of DOI:10.1016/j.ejmech.2014.03.008

The present study discovers multiple N-substituted 3-arylisoquinolone derivatives as antitumor agents originating from O-substituted 3-arylisoquinolines via [2,3] or [3,3] rearrangement. The current [2,3] rearrangement of epoxy or acetal O-substituents converting to diol or alcohol N-substituents can be promoted by silica gel or by diluted hydrochloric acid, which is distinct from previously reported [2,3] rearrangements. Some of the derivatives displayed comparable or even stronger cytotoxicity than sorafenib and vemurafenib on HCT116 colon carcinoma and A375 melanoma cell lines. Therefore, the rearrangement via intramolecular carbon-oxygen bond cleavage and carbon-nitrogen bond formation should be a useful approach for developing novel anticancer drugs derived from isoquinolones.

Full text of DOI:10.1016/j.ejmech.2014.03.008

European Journal of Medicinal Chemistry 77 (2014) 204e210
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Discovery of N-substituted 3-arylisoquinolone derivatives as
antitumor agents originating from O-substituted 3-arylisoquinolines
via [2,3] or [3,3] rearrangement
,
,
Bo Li a 1, Gaihong Wang a 1, Zhijian Xu a, Yong Zhang a, Xiangui Huang b, Bubing Zeng b,
Kaixian Chen a, Jiye Shi c , Heyao Wang , Weiliang Zhu
,
a
,
a,
*
*
*
a Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
b School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
c Informatics Department, UCB Pharma, 216 Bath Road, Slough SL1 4EN, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The present study discovers multiple N-substituted 3-arylisoquinolone derivatives as antitumor agents
originating from O-substituted 3-arylisoquinolines via [2,3] or [3,3] rearrangement. The current [2,3]
rearrangement of epoxy or acetal O-substituents converting to diol or alcohol N-substituents can be
promoted by silica gel or by diluted hydrochloric acid, which is distinct from previously reported [2,3]
rearrangements. Some of the derivatives displayed comparable or even stronger cytotoxicity than sor-
afenib and vemurafenib on HCT116 colon carcinoma and A375 melanoma cell lines. Therefore, the
rearrangement via intramolecular carbon-oxygen bond cleavage and carbon-nitrogen bond formation
should be a useful approach for developing novel anticancer drugs derived from isoquinolones.
Ó 2014 Elsevier Masson SAS. All rights reserved.
Received 18 January 2014
Received in revised form
3 March 2014
Accepted 5 March 2014
Available online 6 March 2014
Keywords:
[2,3] rearrangement
[3,3] rearrangement
3-Arylisoquinolone
Antitumor
1. Introduction
substituents of 3-arylisoquinolone at the position of nitrogen in
search for potent antitumor agents.
3-Arylisoquinolone (Fig. 1) was initially discovered as an inter-
mediate for synthesizing benzo[c]phenanthridine alkaloids by W. J.
Cho et al. in 1996 [1], which exhibited potent antitumor activity.
Attributed to the simple structure and stable chemical properties,
the serendipitous discovery and continued studies have developed
3-arylisoquinolone into a series of lead compounds as anticancer
agents. Derivatives with various substituents at multiple
positions of the arylisoquinolone core, such as 1-substituted 3-
arylisoquinolinamine 1a, 2-substituted 3-arylisoquinolone 1b and
3,4-diphenyl quinolone 1c [1e5] (Fig. 2) exhibit potent antitumor
activities. Structurally, 1bec bear the same lactam group as several
well-known anticancer agents, such as topotecan (2a) and indote-
can (2b) (Fig. 2), the former an approved drug and the latter in
clinical trials [6,7]. Impressively, the substituent at the nitrogen of
2b looks much like the lactam side chains of 3-arylisoquinolones
1bec. We were intrigued to design and synthesize additional
In our previous work [8], we found that 3a and 3b could undergo
Overman rearrangement (as a [3,3]-sigmatropic rearrangement)
in refluxing toluene and a catalytic loading of PdCl2 to afford
3-arylisoquinolone 4a and 4b, respectively, with potent anti-
melanoma activity (IC50 ¼ 0.5 and 0.2
mM, respectively) (Scheme 1).
Therefore, we continue our efforts of synthesizing additional de-
rivatives with different groups at the nitrogen position.
Herein, we report several isoquinolones synthesized via [2,3] or
[3,3] rearrangement with potent antitumor activity. Especially,
substituted isoquinolones with hydroxyl or dihydroxyl group have
been successfully obtained through an unusual [2,3] rearrange-
ment. Bioassay evaluation indicates that these derivatives could be
a novel type of antitumor agents.
2. Results and discussion
2.1. Chemistry
* Corresponding authors.
5aeb were synthesized according to the previously reported
method [8]. They were then performed with alkyl halide in
the presence of sodium hydride, leading to O-substituted
E-mail addresses: boli@simm.ac.cn (B. Li), Jiye.Shi@ucb.com (J. Shi), hywang@
mail.shcnc.ac.cn (H. Wang), wlzhu@mail.shcnc.ac.cn (W. Zhu).
1
These authors (B. Li and G.H. Wang) contributed equally to this work.
http://dx.doi.org/10.1016/j.ejmech.2014.03.008
0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved.

B. Li et al. / European Journal of Medicinal Chemistry 77 (2014) 204e210
205
arylisoquinolines 3cef (Yield 57e83%). The infrared characteristic
peaks of C]N at 1560e1570 cmꢀ1 proved that NaH-induced
alkylation takes place specifically on the oxygen atom. Interest-
ingly, 3c and 3d converted to N-substituted arylisoquinolones 4c
(Yield 98%) and 4d (Yield 95%), respectively, after being eluted
through silica gel. 3e and 3f were relatively stable. However, they
underwent rearrangements to give N-substituted arylisoquino-
lones 4e (Yield 93%) and 4f (Yield 90%), respectively, when treated
with hydrochloric acid in acetone solution. The proposed mecha-
nisms of the rearrangements from 3 (ced, eef) to 4 (ced, eef) are
described in Scheme 2. The conversion of epoxy or acetal O-sub-
stituents to diol or alcohol N-substituents is promoted by silica gel
or by diluted hydrochloric acid, respectively. This is a novel rear-
rangement observed on lactams and different from the well-known
[2,3] rearrangements, i.e. Wittig rearrangement [9e11] and Stevens
rearrangement [12,13].
Fig. 1. Structure of 3-arylisoquinolone.
O-substituted arylisoquinolines 3gej were synthesized using
the same method as 3cef. Notably, treatment of 3g with diluted
hydrochloric acid in acetone did not give the proposed N-
substituted arylisoquinolone but instead restored the initial mate-
rial 5b (Scheme 3).
4d and 4f were converted to 4g (Yield 84%) and 4h (Yield 97%),
respectively, through addition of iodomethane in the presence of
sodium hydride. 4f was oxidized by Dess-Martin periodinane
(DMP) to give aldehyde 4i (Yield 35%). The previously obtained
Overman rearrangement product 4b was reduced by hydrogena-
tion using catalytic palladium 10% on carbon in acetoacetate to give
4j (Yield 95%) (Scheme 4).
Fig. 2. Structures of 1aec and 2aeb.
2.2. Biological evaluation
IC50 cytotoxicity values (mM) of 3cej, 4cej and 5aeb on A375
melanoma and HCT116 human colon cancer cells were evaluated by
the 3-(4,5-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bro-
mide (MTT) assay. Sorafenib (a multi-kinase inhibitor for treating
cancer) [14] and vemurafenib (the first drug approved for BRAF-
mutant melanoma) [15] were used as positive control. The results
are presented in Table 1.
Scheme 1. Previous discovery about Overman rearrangement.
The bioassay data show that O-substituted arylisoquinolone 3ce
f and the corresponding rearrangement products, N-substituted
Scheme 2. Synthesis of 3cef, 4cef and the proposed mechanisms of the rearrangements.

206
B. Li et al. / European Journal of Medicinal Chemistry 77 (2014) 204e210
cytotoxicity of 4i against both A375 and HCT116 cell lines (IC50
values of 4i: 4.38 and >10
mM on A375 and HCT116 cells,
respectively).
In addition, the previously obtained Overman rearrangement
product 4b [8] was reduced to afford 4j. Interestingly, we found that
the antitumor activity of 4j improved approximately two fold (IC50
values: 0.20 and 0.11
mM for 4b and 4j on A375 cell; 0.86 and
0.48 M for 4b and 4j on HCT116 cells).
m
In summary, the observation that 4e and 5a are inactive while 4f
and 5b are moderate active against A375 or HCT116 might be
attributed to the different substitution of dimethoxy or methyl-
enedioxy on 3-aryl. The cytotoxicity of 4gej are more potent than 5b,
illustrating the importance of N-substituent of 3-arylisoquinolone.
Therefore, we postulated that the methylenedioxy of 3-aryl or the
hydrophobic substituent at the N-position of 3-arylisoquinolone
might facilitate the antitumor activity.
Scheme 3. Synthesis of 3gej.
arylisoquinolone 4cee, exhibit no cytotoxicity against either A375
or HCT116 tumor cell. The rearrangement product 4f exhibits
moderate cytotoxicity (IC50 values of 4f: 3.17 and 8.55 mM on A375
cell and HCT116 cell, respectively). Diol compounds 4ced with
hydrogen donors at N-position have poor solubility, which might be
one of the factors leading to their poor bioactivity. Alcohol 4e
having no activity versus alcohol 4f having moderate activity might
be attributed to the different substitution of dimethoxy or meth-
ylenedioxy on 3-aryl. The structureeactivity relationships are also
consistent with our previous discoveries [8].
In order to further confirm our postulation, we synthesized
lipophilic O-alkyl-substituted arylisoquinoline derivatives 3gej and
conducted bioactivity evaluation. The results show that these
compounds exhibit no cytotoxicity, demonstrating again that the
substituent site of 3-arylisoquinolone has significant effect on the
antitumor activity. The N-substituent facilitated more antitumor
activity compared with the O-substituent.
3. Conclusions
In order to improve the antitumor activity of [2,3] rearrange-
ment products 4d and 4f, hydroxyl methylation was conducted to
reduce the number of hydrogen bond donors for increasing
permeability. The methylation products 4g and 4h were obtained
and evaluated for antitumor activity. The results show that 4g and
4h exhibit higher potent cytotoxicity than 4d and 4f, respectively.
Especially for 4g, its anti-melanoma activity is improved greatly
The present study demonstrated multiple [2,3] or [3,3] rear-
rangement derivatives of isoquinolones with potent antitumor
activity. The current [2,3] rearrangement of epoxy or acetal O-
substituents converting to diol or alcohol N-substituents was pro-
moted by silica gel or by diluted hydrochloric acid. The derivative
4h exhibited more potent activity than sorafenib against A375
melanoma cells and its IC50 value is close to the approved anti-
melanoma drug vemurafenib. Moreover, 4h showed comparable
cytotoxicity to sorafenib on HCT116 colon cells. In addition, the [3,3]
rearrangement (Overman rearrangement) derivative 4j showed
more potent antitumor activity than both vemurafenib and sor-
afenib on A375 and HCT116 cell lines. Therefore, the rearrangement
via intramolecular carbon-oxygen bond cleavage and carbon-
nitrogen bond formation might provide a novel approach to
developing novel anticancer drugs derived from isoquinolones.
from no cytotoxicity to moderate activity (IC50 value of 4g: 2.77 mM
on A375 cells). There are also significant improvements in cyto-
toxicity of 4h compared with 4f against both A375 melanoma and
HCT116 human colon cancer cells (IC50 values of 4h: 0.43 and
5.34 mM on A375 and HCT116 cells, respectively). Furthermore, to
investigate the bio-effect of a hydrogen bonding acceptor at the N-
position, we oxidized the hydroxyl of 4f to the aldehyde of 4i and
evaluated its antitumor activity. We found
a decrease in
4. Experimental section
4.1. Chemistry
All starting materials were obtained from commercial suppliers
and used without further purification. Anhydrous THF was distilled
from sodium-benzophenone ketyl, other solvents were routinely
distilled prior to use. The 1H and 13C spectra were taken on Bruker
Avance-500 or 400, Varian-MERCURY Plus-400 or 300 NMR spec-
trometer operating at 400 MHz or 300 MHz for 1H, 125 MHz or
100 MHz for 13C NMR, using TMS as the internal standard and
MeOD4, CDCl3 or DMSO-d6 as the solvent. Chemical shifts were
reported in
d values (ppm) relative to that of the internal TMS. The
abbreviations s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quadruplet,
m ¼ multiplet, and b ¼ broad were used throughout. 13C NMR
spectra were recorded with complete proton decoupling. The ESI-
MS or EI-MS was recorded on Finnigan LCQ/DECA or Thermo-DFS,
respectively. The HRMS were obtained from Micromass Ultra Q-
TOF (ESI) or Thermo-DFS (EI) spectrometer. The IR spectra were
measured with PerkineElmer spectrum on FT-IR spectrophotom-
eter. Silica gel F254 was used in analytical thin-layer chromatog-
raphy (TLC) and silica gel was used in column chromatography,
Scheme 4. Synthesis of 4gej.

B. Li et al. / European Journal of Medicinal Chemistry 77 (2014) 204e210
207
Table 1
The IC50 values (m
M)a of cytotoxicity for 3cej, 4cej and 5aeb.
Compd.
R1, R2
R3
R4
A375
HCT116
3c
OCH3
e
>10
>10
3d
3e
OCH2O
OCH3
e
e
>10
>10
>10
>10
3f
OCH2O
OCH2O
e
e
>10
>10
>10
>10
3g
3h
3i
OCH3
OCH3
e
e
>10
>10
>10
>10
3j
OCH3
OCH3
e
>10
>10
>10
>10
4c
e
e
e
e
e
e
e
4d
4e
4f
OCH2O
OCH3
>10
>10
>10
>10
OCH2O
OCH2O
OCH2O
OCH2O
3.17 ꢁ 0.47
2.77 ꢁ 0.30
0.43 ꢁ 0.05
4.38 ꢁ 0.42
8.55 ꢁ 1.20
>10
4g
4h
4i
5.34 ꢁ 1.40
>10
4j
OCH2O
OCH3
e
e
0.11 ꢁ 0.02
>10
0.48 ꢁ 0.16
5a
H
>10
(continued on next page)

208
B. Li et al. / European Journal of Medicinal Chemistry 77 (2014) 204e210
Table 1 (continued )
Compd.
R1, R2
R3
R4
A375
HCT116
5b
OCH2O
e
H
7.99 ꢁ 1.36
7.56 ꢁ 1.83
0.18 ꢁ 0.005
>10
Sorafenib
Vemurafenib
5.65 ꢁ 1.97
>30
a
Data are presented as mean ꢁ SD, all experiments were performed in triplicate.
respectively, and the visualization was accomplished with UV light
(254 nm).
4.1.5. 3-(Benzo[d] [1,3]dioxol-5-yl)-1-(2,2-dimethoxyethoxy)-7,8-
dimethoxyisoquinoline (3f)
2-Bromo-1,1-dimethoxyethane (101.4 mg, 0.6 mmol) and 5b
(97.5 mg, 0.3 mmol) were used to give a white solid 3f (70.0 mg,
4.1.1. General procedure for the preparation of 1-alkyloxy substituent
arylisoquinolines 3cej
yield 57%). 3f: 1H NMR (400 MHz, CDCl3)
d 7.71e7.60 (m, 1H), 7.57e
7.47 (m, 2H), 7.46e7.38 (m, 1H), 6.91 (d, J ¼ 8.0 Hz, 1H), 6.02 (s, 2H),
To a solution of arylisoquinolone 5a or 5b (0.3 mmol) in DMF
(2.0 mL) was added NaH (28.8 mg, 1.2 mmol) under ice bath. Then
the reaction mixture was stirred for 1 h at room temperature.
Alkylbromide (0.6 mmol) was added and stirred overnight. The
post-processing for obtaining 3ced was different from that of 3eej.
For 3ced, the reaction was quenched with water and filtered. The
precipitate was washed with water and petroleum ether. Then the
precipitation was dissolved in PE/EtOAc (1:1) and filtered, the
filtrate was evaporated to give 3ced. For 3eej, the reaction was
quenched with water and extracted with EtOAc. The organic layers
were washed with water and brine, dried with Na2SO4, and
concentrated. The residue was separated on silica gel to give pure
products 3eej.
5.00 (t, J ¼ 5.4 Hz, 1H), 4.69 (d, J ¼ 5.5 Hz, 2H), 3.99 (s, 6H), 3.54 (s,
6H). 13C NMR (100 MHz, CDCl3)
d 158.3, 150.9, 148.1, 147.8, 145.3,
144.9,135.8, 133.5, 123.1, 120.1, 119.1,114.5, 109.6, 108.4,106.8, 102.2,
101.2, 65.1, 61.8, 57.1, 54.0. HRMS (EI) calcd for C22H23NO7 413.1475
(Mþ), found 413.1480. IR (KBr): 1564 (C]N).
4.1.6. 3-(Benzo[d] [1,3]dioxol-5-yl)-1-(3,3-dimethoxypropoxy)-7,8-
dimethoxyisoquinoline (3g)
3-Bromo-1,1-dimethoxypropane (109.8 mg, 0.6 mmol) and 5b
(97.5 mg, 0.3 mmol) were used to give a white solid 3g (69.2 mg,
yield 54%). 3g: 1H NMR (500 MHz, CDCl3)
d 7.70e7.64 (m, 2H), 7.54
(d, J ¼ 8.9 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J ¼ 8.9 Hz, 1H), 6.93 (d,
J ¼ 8.5 Hz,1H), 6.04 (s, 2H), 4.88 (t, J ¼ 5.8 Hz, 1H), 4.71 (t, J ¼ 6.3 Hz,
2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.44 (s, 6H), 2.29 (q, J ¼ 6.2 Hz, 2H). 13
C
4.1.2. 3-(3,4-Dimethoxyphenyl)-7,8-dimethoxy-1-(oxiran-2-
ylmethoxy)isoquinoline (3c)
NMR (125 MHz, CDCl3) d 158.8, 150.7, 148.1, 147.7, 145.1, 135.6, 133.7,
123.2, 120.1, 118.7, 114.5, 109.2, 108.4, 106.9, 102.5, 101.2, 62.4, 61.8,
57.0, 53.5, 32.6. HRMS (EI) calcd for C23H25NO7 427.1631 (Mþ),
found 427.1631. IR (KBr): 1570 (C]N).
1-Bromo-2,3-epoxypropane (82.2 mg, 0.6 mmol) and 5a
(102.3 mg, 0.3 mmol) were used to give a white solid 3c (99.2 mg,
yield 83%). 3c: 1H NMR (400 MHz, CDCl3)
d7.74e7.62 (m, 2H), 7.58e
7.48 (m, 2H), 7.47e7.38 (m, 1H), 6.97 (d, J ¼ 8.2 Hz, 1H), 4.90 (dd,
J ¼ 12.2, 2.7 Hz, 1H), 4.65 (dd, J ¼ 12.1, 5.0 Hz, 1H), 4.01 (s, 3H), 3.99
4.1.7. 1-Butoxy-3-(3,4-dimethoxyphenyl)-7,8-dimethoxyisoquinoline
(3h)
(s, 6H), 3.95 (s, 3H), 3.58 (t, J ¼ 3.9 Hz, 1H), 3.02e2.90 (m, 2H). 13
C
NMR (100 MHz, CDCl3)
d
158.4, 150.9, 149.4, 149.1, 145.2, 135.8,
1-Bromobutane (82.2 mg, 0.6 mmol) and 5a (102.3 mg, 0.3 mmol)
132.1,123.1, 119.3,118.9,114.3,111.3,109.6, 66.3, 61.9, 57.1, 56.0, 50.2,
45.0. HRMS (EI) calcd for C22H23NO6 397.1525 (Mþ), found 397.1517.
IR (KBr): 1568 (C]N).
were used to give a white solid 3h (83.5 mg, yield 70%). 3h: 1H NMR
(400 MHz, CDCl3)
d
7.72 (d, J ¼ 2.0 Hz, 1H), 7.68 (dd, J ¼ 8.4, 2.0 Hz,
1H), 7.53e7.48 (m, 1H), 7.48 (s, 1H), 7.38 (d, J ¼ 8.9 Hz, 1H), 6.96 (d,
J ¼ 8.4 Hz,1H), 4.65 (t, J ¼ 6.5 Hz, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.94 (s,
3H), 3.93 (s, 3H), 2.00e1.88 (m, 2H), 1.71e1.56 (m, 2H), 1.03 (t,
4.1.3. 3-(Benzo[d] [1,3]dioxol-5-yl)-7,8-dimethoxy-1-(oxiran-2-
ylmethoxy)isoquinoline (3d)
J ¼ 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 159.3,150.7,149.3,149.0,
145.5, 145.3, 135.8, 132.4, 123.0, 119.1, 118.8, 114.6, 111.2, 109.6, 108.9,
66.0, 61.7, 57.1, 56.0, 55.9, 31.2, 19.6, 14.0. HRMS (EI) calcd for
1-Bromo-2,3-epoxypropane (82.2 mg, 0.6 mmol) and 5b
(97.5 mg, 0.3 mmol) were used to give a white solid 3d (91.4 mg,
C
23H27NO5 397.1889 (Mþ), found 397.1895. IR (KBr): 1522 (C]N).
yield 80%). 3d: 1H NMR (400 MHz, CDCl3)
d7.67e7.61 (m, 2H), 7.56e
7.52 (m, 1H), 7.51 (s, 1H), 7.49e7.40 (m, 1H), 6.92 (d, J ¼ 8.6 Hz, 1H),
6.04 (s, 2H), 4.94 (dd, J ¼ 12.2, 3.0 Hz, 1H), 4.61 (dd, J ¼ 12.2, 5.6 Hz,
1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.63e3.55 (m, 1H), 3.04e2.93 (m, 2H).
4.1.8. 3-(3,4-Dimethoxyphenyl)-7,8-dimethoxy-1-(pentyloxy)
isoquinoline (3i)
1-Bromopentane (90.6 mg, 0.6 mmol) and 5a (102.3 mg,
0.3 mmol) were used to give a white solid 3i (75.3 mg, yield 61%). 3i:
13C NMR (125 MHz, CDCl3)
d
158.3, 150.9, 148.1, 147.8, 145.2, 144.9,
135.7, 133.5, 123.2, 120.0, 119.1, 114.4, 109.8, 108.4, 106.8, 101.2, 66.5,
62.0, 57.1, 50.3, 45.0. HRMS (EI) calcd for C21H19NO6 381.1212 (Mþ),
found 381.1203.
1H NMR (400 MHz, CDCl3)
d
7.73 (d, J ¼ 2.1 Hz, 1H), 7.69 (dd, J ¼ 8.4,
2.2 Hz,1H), 7.55e7.50 (m,1H), 7.50 (s,1H), 7.40 (d, J ¼ 8.9 Hz,1H), 6.97
(d, J ¼ 8.3 Hz,1H), 4.65 (t, J ¼ 6.5 Hz, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.95
(s, 6H), 2.06e1.90 (m, 2H),1.66e1.54 (m, 2H),1.51e1.40 (m, 2H), 0.97
4.1.4. 1-(2,2-Dimethoxyethoxy)-3-(3,4-dimethoxyphenyl)-7,8-
dimethoxyisoquinoline (3e)
(t, J ¼ 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 159.2, 150.7, 149.3,
149.0, 145.4, 145.3, 135.8, 132.3, 123,0, 118.9, 118.8, 114.6, 111.2, 109.5,
108.9, 66.3, 61.8, 57.1, 56.0, 55.9, 28.8, 28.6, 22.6,14.1. HRMS (EI) calcd
for C24H29NO5 411.2046 (Mþ), found 411.2046. IR (KBr): 1562 (C]N).
2-Bromo-1,1-dimethoxyethane (101.4 mg, 0.6 mmol) and 5a
(102.3 mg, 0.3 mmol) were used to give a white solid 3e (83.9 mg,
yield 65%). 3e: 1H NMR (400 MHz, CDCl3)
d 7.75e7.67 (m, 2H), 7.59e
7.51 (m, 2H), 7.43 (d, J ¼ 8.9 Hz, 1H), 6.98 (d, J ¼ 8.2 Hz, 1H), 5.01 (t,
J ¼ 5.4 Hz, 1H), 4.76e4.68 (m, 2H), 4.02 (s, 3H), 4.00 (s, 3H), 3.99 (s,
4.1.9. 1-(6-Bromohexyloxy)-3-(3,4-dimethoxyphenyl)-7,8-
dimethoxyisoquinoline (3j)
3H), 3.96 (s, 3H), 3.53 (s, 6H). 13C NMR (100 MHz, CDCl3)
d 158.4,
150.9, 149.1, 145.1, 135.9, 132.1, 123.0, 119.2, 118.9, 111.2, 109.6, 109.5,
102.2, 65.1, 61.8, 57.1, 56.0, 55.9, 53.9. HRMS (EI) calcd for
C
1,6-Dibromohexane (146.4 mg, 0.6 mmol) and 5a (102.3 mg,
0.3 mmol) were used to give a white solid 3j (70.7 mg, yield 51%).
23H27NO7 429.1788 (Mþ), found 429.1788. IR (KBr): 1566 (C]N).
3j: 1H NMR (400 MHz, CDCl3)
d 7.75e7.64 (m, 2H), 7.55e7.46 (m,

B. Li et al. / European Journal of Medicinal Chemistry 77 (2014) 204e210
209
2H), 7.39 (d, J ¼ 8.9 Hz, 1H), 6.96 (d, J ¼ 8.3 Hz, 1H), 4.64 (t,
J ¼ 6.4 Hz, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.93 (s, 6H), 3.43 (t,
J ¼ 6.8 Hz, 2H), 2.03e1.83 (m, 4H), 1.67e1.54 (m, 4H). 13C NMR
4.1.16. General procedure for the preparation of 4geh
To a solution of 4d or 4f (0.3 mmol) in DMF (2.0 mL) was added
NaH (28.8 mg, 1.2 mmol) under ice bath. Then the reaction mixture
was stirred for 1 h at room temperature. CH3I (0.6 mmol) was
added and stirred overnight. Then the reaction mixture was
quenched with water and extracted with EtOAc. The organic layers
were washed with water and brine, dried with Na2SO4, and
concentrated. The residue was separated through silica gel to give a
yellow oil 4g (107.6 mg, yield 84%) or 4h (120.2 mg, yield 97%).
(100 MHz, CDCl3)
d 159.2, 150.7, 149.3, 149.0, 145.4, 145.3, 135.8,
132.3, 123.0, 119.0, 118.8, 114.5, 111.2, 109.6, 108.9, 65.9, 61.7, 57.1,
56.0, 55.9, 33.8, 32.8, 29.0, 28.0, 25.6. HRMS (EI) calcd
for C25H30BrNO5 503.1307 (Mþ), found 503.1311. IR (KBr): 1562
(C]N).
4.1.10. General procedure for the preparation of 4ced
3c (119.1 mg, 0.3 mmol) and 3d (114.3 mg, 0.3 mmol) converted
to a white solid 4c (122.0 mg, yield 98%) and 4d (113.7 mg, yield
95%) after being eluted through silica gel with methylene dichlor-
ide and methanol (20:1), respectively.
4.1.17. 3-(Benzo[d] [1,3]dioxol-5-yl)-2-(1,3-dimethoxypropan-2-
yl)-7,8-dimethoxyisoquinolin-1(2H)-one (4g)
4g: 1H NMR (500 MHz, CDCl3)
d
7.32 (d, J ¼ 8.6 Hz, 1H), 7.18 (d,
J ¼ 8.6 Hz, 1H), 6.97 (d, J ¼ 1.7 Hz,1H), 6.95e6.90 (m, 1H), 6.89e6.84
(m, 1H), 6.24 (s, 1H), 6.04 (s, 2H), 4.46e4.36 (m, 1H), 4.26e4.05 (m,
2H), 3.98 (s, 3H), 3.95 (s, 3H), 3.88e3.75 (m, 2H), 3.23 (s, 6H). 13
C
4.1.11. 2-(1,3-Dihydroxypropan-2-yl)-3-(3,4-dimethoxyphenyl)-
NMR (125 MHz, CDCl3) d 161.5,151.4,149.6,147.8,147.4,142.9,132.3,
7,8-dimethoxyisoquinolin-1(2H)-one (4c)
4c: 1H NMR (400 MHz, DMSO)
d
7.49 (d, J ¼ 8.6 Hz, 1H), 7.32 (d,
J ¼ 8.7 Hz, 1H), 7.10 (s, 1H), 7.06e6.95 (m, 2H), 6.30 (s, 1H), 4.71 (s,
2H, OH), 4.18e3.96 (m, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.76 (s, 8H). 13
NMR (100 MHz, DMSO) 161.0, 151.3, 149.2, 148.8, 148.5, 144.0,
130.2, 123.5, 121.8, 120.3, 119.2, 110.4, 108.1, 107.7, 101.4, 77.3, 71.6,
61.6, 60.2, 58.8, 57.0. HRMS (EI) calcd for C23H25NO7 427.1631 (Mþ),
found 427.1626. IR (KBr): 1655 (C]O).
C
d
132.3, 129.7, 122.3, 122.2, 120.3, 119.6, 113.8, 111.8, 107.0, 65.8, 61.2,
59.7, 56.9, 56.0, 55.8. HRMS (EI) calcd for C22H25NO7 415.1631 (Mþ),
found 415.1627. IR (KBr): 1647 (C]O).
4.1.18. 3-(benzo[d] [1,3]dioxol-5-yl)-2-(1,2-dimethoxyethyl)-7,8-
dimethoxyisoquinolin-1(2H)-one (4h)
4h: 1H NMR (500 MHz, CDCl3)
d
7.31 (d, J ¼ 8.6 Hz, 1H), 7.16 (d,
J ¼ 8.6 Hz, 1H), 6.92e6.82 (m, 3H), 6.20 (s, 1H), 6.03 (s, 2H), 5.63 (s,
4.1.12. 3-(Benzo[d] [1,3]dioxol-5-yl)-2-(1,3-dihydroxypropan-2-yl)-
1H), 4.01e3.85 (m, 8H), 3.32 (s, 3H), 3.27 (s, 3H). 13C NMR (125 MHz,
7,8-dimethoxyisoquinolin-1(2H)-one (4d)
CDCl3) d 161.6, 151.8, 150.0, 148.0, 147.4, 141.4, 131.8, 129.8, 121.9,
4d: 1H NMR (400 MHz, CDCl3)
d
7.35 (d, J ¼ 8.7 Hz, 1H), 7.20 (d,
120.3, 119.2, 108.2, 108.1, 101.5, 77.3, 74.5, 61.6, 59.0, 56.8, 56.5.
HRMS (EI) calcd for C22H23NO7 413.1475 (Mþ), found 413.1474. IR
(KBr): 1657 (C]O).
J ¼ 8.7 Hz, 1H), 6.88e6.85 (m, 1H), 6.83e6.79 (m, 2H), 6.34 (s, 1H),
6.04 (s, 2H), 4.40 (s,1H), 4.27e3.96 (m, 4H), 3.96 (s, 3H), 3.95 (s, 3H).
13C NMR (125 MHz, CDCl3)
d 163.0, 151.8, 149.5, 148.2, 147.9, 142.1,
132.0, 129.7, 123.0, 122.0, 120.1, 119.8, 109.6, 109.1, 108.5, 101.6, 62.9,
61.7, 61.0, 57.0. HRMS (EI) calcd for C21H21NO7 399.1318 (Mþ), found
399.1319. IR (KBr): 1649 (C]O).
4.1.19. 2-(3-(Benzo[d] [1,3]dioxol-5-yl)-7,8-dimethoxy-1-
oxoisoquinolin-2(1H)-yl)-2-methoxyacetaldehyde (4i)
To a solution of 4f (39.9 mg, 0.1 mmol) in CH2Cl2 (2.0 mL) Dess-
Martin periodinane (DMP) (84.8 mg, 0.2 mmol) was added and
stirred overnight. Then the reaction mixture was quenched with
methanol, neutralized by saturated sodium bicarbonate aqueous
solution and extracted with EtOAc. The organic layers were
washed with water and brine, dried with Na2SO4, and concen-
trated. The residue was separated through silica gel to give a white
4.1.13. General procedure for the preparation of 4eef
To a solution of 3e (128.9 mg, 0.3 mmol) or 3f (123.9 mg,
0.3 mmol) in acetone (5.0 mL) was added 10% HCl (5.0 mL) and
stirred overnight. After evaporating to remove acetone, the residue
was diluted with CH2Cl2 (50.0 mL), washed with saturated sodium
bicarbonate, dried with Na2SO4, and concentrated to afford a white
solid 4e (115.8 mg, yield 93%) or 4f (107.7 mg, yield 90%).
solid 4i (13.9 mg, yield 35%). 4i: 1H NMR (400 MHz, CDCl3)
(s, 1H), 7.37 (d, J ¼ 8.6 Hz, 1H), 7.24 (d, J ¼ 8.6 Hz, 1H), 7.07e6.96
(m, 2H), 6.96e6.86 (m, 1H), 6.36 (s, 1H), 6.07 (s, 2H), 5.26 (s, 1H),
3.98 (s, 3H), 3.96 (s, 3H), 3.28 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 9.77
4.1.14. 3-(3,4-Dimethoxyphenyl)-2-(2-hydroxy-1-methoxyethyl)-
d
193.5, 160.4, 151.9, 150.0, 148.5, 147.9, 141.0, 132.0, 128.7, 122.2,
7,8-dimethoxyisoquinolin-1(2H)-one (4e)
4e: 1H NMR (400 MHz, CDCl3)
d
7.31 (d, J ¼ 8.7 Hz, 1H), 7.17 (d,
119.7, 119.4, 108.5, 108.1, 101.6, 87.3, 77.2, 61.7, 56.8, 56.4. HRMS (EI)
calcd for C21H19NO7 397.1162 (Mþ), found 397.1163. IR (KBr): 1657
(C]O).
J¼8.6Hz,1H),7.00e6.94(m,2H),6.93e6.88(m,1H),6.26(s,1H),5.46(s,
1H),4.17e4.00(m,2H),3.97(s,3H),3.92(s,6H),3.88(s,3H),3.20(s,3H).
13CNMR(100MHz,CDCl3)
d162.4,151.9,150.0,149.5,148.7,141.9,132.0,
128.7,121.8,120.2,119.6,112.5,110.9,108.2,90.9,63.9,61.6,56.9,56.4,
56.0, 55.9. HRMS (EI) calcd for C22H25NO7 415.1631 (Mþ), found
415.1623.IR(KBr):1664(C]O).
4.1.20. 3-(Benzo[d] [1,3]dioxol-5-yl)-7,8-dimethoxy-2-propyl-
isoquinolin-1(2H)-one (4j)
To a solution of 4b (109.5 mg, 0.3 mmol) in methanol (5.0 mL)
was added palladium 10% on carbon (10.0 mg), Hydrogen was then
bubbled into the solution and stirred overnight. The reaction
mixture was filtered through celite and the filtrate was evaporated
to give a white solid 4j (104.6 mg, yield 95%). 4j: 1H NMR (400 MHz,
4.1.15. 3-(benzo[d] [1,3]dioxol-5-yl)-2-(2-hydroxy-1-
methoxyethyl)-7,8-dimethoxyisoquinolin-1(2H)-one (4f)
4f: 1H NMR (400 MHz, CDCl3)
d
7.34 (d, J ¼ 8.6 Hz, 1H), 7.19 (d,
J ¼ 8.6 Hz, 1H), 6.88 (d, J ¼ 3.7 Hz, 3H), 6.26 (s, 1H), 6.05 (d,
J ¼ 1.6 Hz, 2H), 5.50 (d, J ¼ 5.6 Hz, 1H), 4.22e4.10 (m, 1H), 4.08e4.01
CDCl3)
d
7.29 (d, J ¼ 8.6 Hz, 1H), 7.16 (d, J ¼ 8.6 Hz, 1H), 6.87e6.80
(m, 3H), 6.22 (s, 1H), 6.03 (s, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 3.84 (t,
(m, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 3.29 (s, 1H, OH), 3.24 (s, 3H). 13
C
J ¼ 7.8 Hz, 2H), 1.69e1.52 (m, 2H), 0.74 (t, J ¼ 7.4 Hz, 3H). 13C NMR
NMR (125 MHz, CDCl3)
d
162.3, 151.9, 149.8, 148.1, 147.7, 141.5, 131.8,
(125 MHz, CDCl3) d 160.2, 151.0, 149.1, 147.4, 147.0, 140.9, 131.5,
129.8, 122.0, 120.3, 119.4, 109.7, 108.6, 108.3, 101.6, 90.8, 77.3, 63.7,
61.6, 56.8, 56.5. HRMS (EI) calcd for C21H21NO7 399.1318 (Mþ),
found 399.1314. IR (KBr): 1657 (C]O).
129.6, 122.4, 121.4, 119.5, 118.5, 109.0, 107.7, 106.7, 101.0, 61.2, 56.5,
46.5, 21.6,10.8. HRMS (EI) calcd for C21H21NO5 367.1420 (Mþ), found
367.1427.

210
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Acknowledgments
We gratefully acknowledge the financial support of this work by
the Ministry of Science and Technology (2012AA01A305), National
Major Project (2012ZX09301001-004 and 2013ZX09103001-001),
National Natural Science Foundation (81273435, 81302699 and
21373258).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.03.008.
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