Synthesis, cytotoxicity and pro-apoptosis activity of isoquinoline quinones

Article abstract of DOI:10.1007/s00044-017-1985-8

Mansouramycins are newly isolated cytotoxic isoquinoline quinones from marine organism. To find novel anticancer agents, eighteen isoquinoline quinones 7a–7r as Mansouramycins analogs were designed and synthesized. Most of these compounds displayed modera

Full text of DOI:10.1007/s00044-017-1985-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1985-8
ORIGINAL RESEARCH
Synthesis, cytotoxicity and pro-apoptosis activity of isoquinoline
quinones
1 ●
2 ●
2
Hua Ni Chao Xia Yu Zhao
Received: 27 December 2016 / Accepted: 6 July 2017
Springer Science+Business Media, LLC 2017
©
Abstract Mansouramycins are newly isolated cytotoxic
isoquinoline quinones from marine organism. To find novel
anticancer agents, eighteen isoquinoline quinones 7a–7r as
Mansouramycins analogs were designed and synthesized.
Most of these compounds displayed moderate cytotoxicities
against MCF-7, A549, HCT116, and HepG2 cancer cell
lines at micromolar concentration. Compound 7a was found
to has the ability of inducing HepG2 cells apoptosis by
Hoechst33342 staining assay.
including the Caulibugulones, Cribrostatins, and Mansour-
amycins, were isolated from the marine sponges, marine
bryozoans and marine streptomycetes (Choi et al. 1993;
Brisson et al. 2007) (Fig. 1). Mansouramycin D showed
cytotoxicity against 36 cancer cell lines with a mean IC50
value up to 0.089 μM (Hawas et al. 2009). Cribrostatin 5
showed proliferation inhibitory to six cancer cell lines with
GI50 value from 45 to 360 nM (Brisson et al. 2007). These
results suggested potential value of isoquinoline quinones
as lead structures for the development of new anticancer
agents (Vasquez et al. 2010). The total synthesis of Man-
souramycin D have been completed involving intramole-
cular iminoannulation as a key ring closure step (Prakash
and Nagarajan 2014). However, to the best of our knowl-
edge, there is no structure–activity relationship (SAR) dis-
cussion on isoquinoline quinones. To fully understand the
●
●
Keywords Mansouramycins Isoquinoline quinones
●
●
Synthesis Cytotoxicity Apoptosis
influence of C-3 substitute groups R and C-7 substitute
1
Introduction
groups R on their cytotoxicities, we intend to design and
2
synthesize series of isoquinoline quinones (Scheme 1). In
this paper, we report the synthsis of these isoquinoline
quinones 7a–7r, their cytotoxicities against four cancer cell
lines. The effects of substitute groups R and R on their
cytotoxicities. Most of these compounds displayed moder-
ate cytotoxicities against MCF-7, A549, HCT116, and
HepG2 cancer cell lines at micromolar concentration.
Compound 7k showed the best cytotoxicities among these
compounds with IC50 values from 2.3 to 2.6 μM.
Despite the rapid development of target-specific anticancer
agents (Ling et al. 2014, 2015; Li et al. 2015), natural
derived compounds still play important roles in cancer
chemotherapy. Marine isoquinoline quinones alkaloids have
received lots of attention from the scientific community due
to their various biological activities (Hawas et al. 2009;
Pettit et al. 2000; Milanowski et al. 2004; Li et al. 2017;
Abdelwahab et al. 2014). These isoquinoline quinones,
1
2
*
Yu Zhao
zhaoyu@ntu.edu.cn
Results and discussion
Chemistry
1
2
Department of Pharmacy, The Affiliated Hospital of Nantong
University, Nantong 226001, People’s Republic of China
Synthesis of isoquinoline quinones by various methods have
been reported to date (Vasquez et al. 2009; Ferreira et al. 2003;
School of Pharmacy, Nantong University, Nantong 226001,
People’s Republic of China

Med Chem Res
Fig. 1 Marine derived
isoquinoline quinones
Scheme 1 Synthesis of isoquinoline quinines 7a–7r
Perez et al. 2000; Coppola et al. 2015; Zhang et al. 2016;
Prakash and Nagarajan 2015). Firstly, bromination of com-
mercially available 2,5-dihydroxybenzaldehyde 1 afforded 2-
bromo-3,5-dihydroxybenzaldehyde 2 in 86% yield. Then, both
hydroxyl groups of 2-bromo-3,6-dihydroxybenzaldehyde were
protected by a Methoxymethyl (MOM) group using MOM
chloride and diisopropylethylamine as a base to afford com-
pound 3 in 76% yield. The Sonogashira reaction with 3 and
alkyne using Pd(PPh ) (5 mol%), CuI (5 mol%), and N,N-
Dimethyl formamide (DMF) as solvent proceeded smoothly at
100 °C and yielded 67–74% of coupled products 4a–4d
(Scheme 1). The iminoannulation of 4a–4d was performed
3
4

Med Chem Res
with aqueous ammonia and potassium carbonate to give 5a–5d
in 77–83% yields. Subsequently, oxidation and deprotection
reactions of compounds 5a–5d using ammonium ceric nitrate
in one pot to afford 6a–6d. Nextly, without further purification,
compounds 6a–6d were allowed to react with amines or
thiophenols to give final eighteen products 7a–7r in 53–77%
yields.
The C-3 position of isoquinoline quinines scaffold
proved to be critical for their cytotoxicities. The introducing
of cyclopropyl group at C-3 position of 7n and 7o resulted
in 2–3-folds decrease in their cytotoxicities compared to
compound 7a, which suggested a phenyl group at C-3
position was favorable to their cytotoxicities. For com-
pounds 7a, 7b, and 7c having a methylamino groups at C-7
position, they showed almost the same cytotoxicities with
the average IC50 values 4.0, 4.7, and 3.5 μM, which indi-
cated that substituted patterns on C-3 phenyl group have no
influence on their cytotoxicities. For compounds 7f, 7g, 7h,
and 7o bearing a benzylamino groups at C-7 position, the
substituted groups at C-3 position have influence on their
cytotoxicities. Compound 7h with benzyl group at a C-3
position exhibited the best cytotoxicity with the average
IC50 values 5.3 μM, while compound 7o with cyclopropyl
group at a C-3 position possessed the worst cytotoxicity
with the average IC50 values 13.4 μM. For compounds 7c,
Biological evaluation
Cytotoxicities
With eighteen isoquinoline quinones in hand, four cancer
cell lines from various solid tumors, MCF-7, HCT-116,
HepG2, and A549 were used to preliminaryly screen their
cytotoxicities employing a 3-(4,5-Dimethylthiazol-2-yl)-
2
,5-diphenyltetrazolium bromide (MTT) assay by using
7e, 7h, 7j, and 7m bearing phenyl group at C-3 position, 7c
etoposide as control (Table 1). IC50 values were summarized
in Table 1 and represented the concentration inducing a 50%
decrease of cell growth after 3 days incubation. From the
IC50 values, it is clear that most of these compounds dis-
played cytotoxic effects on four cancer cells at micromolar
concentration.
showed the best cytotoxicities with IC50 values 3.5 μM,
which indicated small substituted group was favorable to
their cytotoxicities.
In general, compounds 7a and 7k displayed the best
cytotoxicities among these compounds with IC50 values
from 1.9 to 7.2 μM, which were better than those of eto-
poside. Compounds 7q and 7r which bearing sulfur ether
groups showed less cytotoxicities than amines, which
indicated amino-substitution was favorable to their cyto-
toxicities. The amino-substitutions had practically sig-
nificant effects on their cytotoxicities, methylamine, and
morpholine substitute groups were favorable to the cyto-
toxicities. These compounds showed no selectivity for these
four cancer cell lines.
Table 1 In vitro cytotoxicities of compounds 7a–7r
Compd
IC50 ± SD (μM)
MCF7 A549
a
HCT116 HepG2
Average
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
a
b
c
7.2 ± 0.4 3.6 ± 0.3 3.3 ± 0.1 1.9 ± 0.1 4.0 ± 0.3
5.7 ± 0.6 5.5 ± 0.4 5.1 ± 0.3 2.5 ± 0.3 4.7 ± 0.1
4.6 ± 0.1 2.7 ± 0.4 2.8 ± 0.1 4.0 ± 0.1 3.5 ± 0.4
44.2 ± 2.1 14.4 ± 2.4 10.1 ± 1.6 15.2 ± 1.7 20.9 ± 1.4
11.9 ± 1.0 25.5 ± 2.4 12.1 ± 1.2 6.3 ± 0.3 13.9 ± 0.7
16.8 ± 0.9 8.9 ± 0.6 17.4 ± 0.8 5.5 ± 0.3 12.1 ± 0.5
12.7 ± 0.6 10.7 ± 0.6 5.7 ± 0.3 4.3 ± 0.2 8.3 ± 0.9
8.3 ± 0.7 4.9 ± 0.3 5.7 ± 0.4 2.4 ± 0.2 5.3 ± 0.1
46.1 ± 5.0 45.8 ± 5.4 12.1 ± 1.4 5.4 ± 3.4 27.3 ± 2.5
0.7 ± 0.1 8.5 ± 0.7 6.9 ± 0.8 1.1 ± 0.1 4.3 ± 0.3
2.6 ± 0.2 2.2 ± 0.1 2.2 ± 0.3 2.3 ± 0.2 2.3 ± 0.1
6.6 ± 0.4 6.6 ± 0.3 6.8 ± 0.4 4.8 ± 0.5 6.2 ± 0.4
7.1 ± 0.6 6.7 ± 0.8 7.1 ± 0.5 8.2 ± 0.6 7.3 ± 0.3
8.5 ± 0.5 8.7 ± 0.4 5.8 ± 0.6 6.2 ± 0.6 7.3 ± 0.9
20.4 ± 2.4 20.7 ± 1.7 5.9 ± 0.3 6.9 ± 0.4 13.4 ± 0.9
7.1 ± 0.5 9.2 ± 0.7 6.1 ± 0.8 4.0 ± 0.7 6.6 ± 0.5
34.6 ± 3.1 37.1 ± 2.5 26.6 ± 2.0 10.0 ± 1.1 27.1 ± 2.4
d
e
Apoptosis inducing assay
f
g
h
i
On the basis of the above results, further biological eva-
luations have been focused on compound 7a HepG2 cells
were stained with Hoechst33342 to verify the type of cell
death. Without compound 7a treatment, the nuclei of con-
trol cells showed uniform blue fluorescence, which indi-
cated the cells were healthy and the nuclei were intact (Fig.
j
k
l
2
a). However, after treatment with different concentration
m
n
o
p
q
r
of compound 7a (0.1, 5, and 10 μM) for 48 h, the number of
cells was significantly reduced, and most cells showed early
apoptosis with perinuclear chromatin condensation and late
apoptosis with nuclear dense chromatin of pneumocytes
(Fig. 2a). These results showed that 7a induced the cells
>100
>100
>100
27.6
>100
death occurred primarily through apoptosis in a dose-
dependent manner. The data collected from the manual
counting of cells with normal and apoptotic nuclear features
are shown in Fig. 2b.
Etoposide 4.8 ± 0.3 11.3 ± 0.1 8.7 ± 0.5 4.9 ± 0.1 7.4 ± 0.3
All experiments were independently performed at least three times
a
Average IC50 of four cancer cells IC50
s

Med Chem Res
Fig. 2 Nuclear morphology of HepG2 Cells Treated with Compound 7a in 0, 0.5, 5, and 10 μM, respectively for 48 h by Hoechst33342 staining
Experimental
Chemistry
nitrogen atmosphere. Then 4-methoxyphenylacetylene (648
mg, 4.91 mmol) was added slowly, and the mixture was
heated at 100 °C for 8 h. After completion of reaction
(indicated by TLC), reaction mixture was diluted with 50
Melting points (mp) were determined with a X5 melting
point apparatus (Yuhua, Gongyi, China). Commercial grade
reagents and solvents were used without further purifica-
tion, except where noted. Flash chromatography was per-
formed on silica gel (100–200 mesh, Yinlong, Yantai,
China). Thin layer chromatography (TLC) was performed
mL of CHCl and filtered with celite bed. Then, water (10
mL) was added to the diluted solution, which was then
3
extracted with CHCl (2 × 50 mL). The combined organic
3
layer was dried with anhydrous Na SO and concentrated
2
4
under vacuum and purified by column chromatography on
silica gel eluting with EtOAc/petroleum-ether (1:6 v/v) to
on precoated Merck silica Gel 60 F
plates (Merck,
54
afford 4a in 71% yield.
2
1
1
Darmstadt, Germany). H nuclear magnetic resonance
NMR) spectra were recorded in CDCl solution (if not
Dark brown solid; mp 64–66 °C; H NMR (CDCl , 400
3
(
MHz) δ = 10.67 (s, 1H, CHO), 7.54 (d, J = 8.0 Hz, 2H,
ArH), 7.28 (d, J = 8.0 Hz, 1H, ArH), 7.13 (d, J = 8.0 Hz,
1H, ArH), 6.89 (d, J = 8.0 Hz, 2H, ArH), 5.23–5.21 (m, 4H,
–CH –), 3.83 (s, 3H, –OCH ), 3.55(s, 3H, –CH ), 3.51(s,
3
otherwise stated) with a Bruker DRX-400 instrument at 400
1
3
MHz, with Me Si as internal standard. C NMR spectra
4
were recorded with the same instrument at 100 MHz under
the same conditions. Full scan mass spectra of the com-
pounds were acquired in the range 50–800 m/z with an
Agilent 500MS Ion trap mass spectrometer equipped with
an electrospray ionization source.
Compound 3 was prepared according to the literature
procedure from commercially available 2,5-dihydrox-
ybenzaldehyde 1 in 65% yields in two steps (Little and
Porco 2012).
2
3
3
1
3
3H, –CH3); C NMR (CDCl , 100 MHz): δ = 190.3
3
(C=O), 154.1(ArC), 153.3(ArC), 139.2(ArC), 132.2(ArC),
132.1(ArC), 129.3(ArC), 129.2(ArC), 126.4(ArC), 122.5
(ArC), 119.6(ArC), 117.3(ArC), 116.5(ArC), 100.2
(OCH O), 96.1(OCH O), 95.5(C≡C), 81.9(C≡C), 56.5
2
2
(OCH ), 56.4(OCH ), 55.6(OCH ); low resolution mass
3
3
3
+
spectrometry (LRMS) (ESI-TOF) (m/z) [M+H] calcd for
C H O 356.1, found 356.1.
2
0 20 6
Synthetic procedure for synthesis of 4a–4d
3,6-Bis-methoxymethoxy-2-p-tolylethynyl-benzaldehyde
4b)
(
3
,6-Bis-methoxymethoxy-2-(4-methoxy-phenylethynyl)-
1
benzaldehyde (4a)
Dark brown solid, yield 72%; mp 71–74 °C; H NMR
CDCl , 400 MHz) δ = 10.67 (s, 1H, CHO), 7.49 (d, J =
(
3
To a solution of compound 3 (1.0 g, 3.27 mmol) in DMF (5
8.0 Hz, 2H, ArH), 7.27 (d, J = 8.0 Hz, 2H, ArH), 7.17(d,
mL) was added CuI (32 mg, 0.16 mmol), Pd(PPh ) (189
J = 8.0 Hz, 2H, ArH), 5.24 (s, 4H, –CH –), 3.55(s, 3H,
–CH ), 3.51(s, 3H, –CH ), 2.38 (s, 3H, –CH ); C NMR
3 3 3
3
4
2
1
3
mg, 0.16 mmol) and Na CO (5.19 g, 4.91 mmol) under
2
3

Med Chem Res
(
(
1
CDCl , 100 MHz): δ = 190.3(C=O), 153.3(ArC), 153.2
ArC), 139.1(ArC), 131.7(ArC), 131.7(ArC), 129.2(ArC),
29.2(ArC), 126.6(ArC), 122.5(ArC), 119.9(ArC), 117.1
The crude product was purified by column chromatography
3
(EtOAc/petroleum-ether 1:10 v/v) to afford 5a in 83% yield.
1
Dark brown solid; mp 107–109 °C; H NMR (CDCl ,
3
(
(
ArC), 116.7(ArC), 100.6(OCH O), 96.0(OCH O), 95.5
400 MHz): δ = 9.64 (s, 1H, ArH), 8.30 (s, 1H, ArH), 8.12
(d, J = 8.0 Hz, 2H, ArH), 7.17(d, J = 8.0 Hz, 1H, ArH),
2
2
C≡C), 81.9(C≡C), 56.5(OCH ), 56.4(OCH ), 21.6(CH );
3
3
3
+
LRMS (ESI-TOF) (m/z) [M+H] calcd for C H O
3
7.05–7.03(m, 3H, ArH), 5.36 (s, 4H, –CH –), 3.88(s, 3H,
2
0
20
5
2
1
3
40.1, found 340.1.
–OCH ), 3.57–3.54(m, 6H, –OCH ); C NMR (CDCl3,
3 3
1
00 MHz): δ = 158.8(ArC), 151.6(ArC), 148.6(ArC), 147.3
(ArC), 146.7(ArC), 138.6(ArC), 136.9(ArC), 129.6(ArC),
29.5(ArC), 126.9(ArC), 126.8(ArC), 120.4(ArC), 112.6
3
,6-Bis-methoxymethoxy-2-phenylethynyl-benzaldehyde (4c)
1
1
Dark brown oil, yield 74%; H NMR (CDCl , 400 MHz) δ
(ArC), 110.2(ArC), 108.7(ArC), 95.2(OCH O), 95.1
3
2
=
7
(
10.67 (s, 1H, CHO), 7.60 (d, J = 8.0 Hz, 2H, ArH),
.37–7.35 (m, 3H, ArH), 7.30(d, J = 8.0 Hz, 1H, ArH), 7.16
d, J = 8.0 Hz, 1H, ArH), 5.24 (s, 4H, –CH –), 3.56(s, 3H,
(OCH O), 56.4(OCH ), 56.3(OCH ), 55.3(OCH ); LRMS
2
3
3
3
+
(ESI-TOF) (m/z) [M + H] calcd for C H NO 355.1,
20 21 5
found 355.1.
2
1
3
–
CH ), 3.51(s, 3H, –CH ); C NMR (CDCl , 100 MHz):
3 3 3
δ = 190.3(C=O), 153.3(ArC), 153.0(ArC), 139.2(ArC),
31.7(ArC), 131.6(ArC), 129.2(ArC), 129.1(ArC), 126.3
ArC), 122.1(ArC), 119.9(ArC), 117.13(ArC), 117.1(ArC),
5,8-Bis-methoxymethoxy-3-p-tolyl-isoquinoline (5b)
1
(
1
Brown solid; yield 80%; mp 112–113 °C; H NMR (CDCl ,
3
1
00.6(OCH O), 96.0(OCH O), 95.4(C≡C), 82.1(C≡C),
400 MHz): δ = 9.69 (s, 1H, ArH), 8.39 (s, 1H, ArH), 8.10
(d, J = 8.0 Hz, 2H, ArH), 7.35(d, J = 8.0 Hz, 2H, ArH),
7.21(d, J = 8.0 Hz, 1H, ArH), 7.06(d, J = 8.0 Hz, 1H, ArH),
2
2
5
6.5(OCH ), 56.4(OCH ); LRMS (ESI-TOF) (m/z) [M
3 3
+
+
H] calcd for C H O 326.1, found 326.1.
19 18 5
5
.40–5.38 (m, 4H, –CH –), 3.59–3.58(m, 6H, –CH ), 2.46
2 3
1
3
2
-Cyclopropylethynyl-3,6-bis-methoxymethoxy-
(s, 3H, –CH3); C NMR (CDCl , 100 MHz): δ = 151.6
3
benzaldehyde (4d)
(ArC), 148.5(ArC), 147.3(ArC), 146.7(ArC), 138.5(ArC),
1
36.9(ArC), 130.5(ArC), 129.6(ArC), 129.5(ArC), 126.9
1
Dark brown oil, yield 67%; H NMR (CDCl , 400 MHz):
(ArC), 126.8(ArC), 120.4(ArC), 112.6(ArC), 110.2(ArC),
108.7(ArC), 95.2(OCH O), 95.1(OCH O), 56.4(OCH ),
56.3(OCH ), 21.3(CH ); LRMS (ESI-TOF) (m/z) [M + H]
3
δ = 10.57 (s, 1H, CHO), 7.31–7.33 (d, J = 8.0 Hz, 1H,
ArH), 7.12–7.14 (d, J = 8.0 Hz, 1H, ArH), 5.21 (s, 4H,
2
2
3
+
3
3
–
CH –), 3.52(s, 3H, –CH ), 3.50(s, 3H, –CH ), 3.50(m, 1H,
calcd for C H NO 339.1, found 339.1.
20 21 4
2
3
3
1
3
–
CH–), 0.92–0.94(m, 4H, –CH –); C NMR (CDCl , 100
2
3
MHz): δ = 192.2(C=O), 166.0(ArC), 150.4(ArC), 126.7
5,8-Bis-methoxymethoxy-3-phenyl-isoquinoline (5c)
(
(
(
ArC), 122.4(ArC), 121.6(ArC), 116.0(ArC), 114.6
1
OCH O), 95.9(OCH O), 95.4(C≡C), 95.2(C≡C), 56.4
Brown solid; yield 83%; mp 78–80 °C; H NMR (CDCl ,
2
2
3
OCH ), 56.4(OCH ), 10.6(CH ), 9.2(CH ), 0.89(CH);
400 MHz): δ = 9.68 (s, 1H, ArH), 8.39 (s, 1H, ArH), 7.52
(d, J = 8.0 Hz, 2H, ArH), 7.20(d, J = 8.0 Hz, 2H, ArH),
3
3
2
2
+
LRMS (ESI-TOF) (m/z) [M+H] calcd for C H O
1
6 18 5
2
90.1, found 290.1.
Synthetic procedure for synthesis of 5a–5d
7.07–7.05(m, 3H, ArH), 5.38–5.36 (m, 4H, –CH –),
2
1
3
3
.55–3.57(m, 6H, –CH3); C NMR (CDCl , 100 MHz):
3
δ = 151.6(ArC), 148.6(ArC), 147.4(ArC), 146.5(ArC),
38.6(ArC), 136.9(ArC), 129.6(ArC), 129.5(ArC), 127.2
1
5
,8-Bis-methoxymethoxy-3-(4-methoxy-phenyl)-
(ArC), 126.9(ArC), 126.8(ArC), 120.4(ArC), 112.6(ArC),
110.2(ArC), 108.7(ArC), 95.2(OCH O), 95.1(OCH O),
isoquinoline (5a)
2
2
5
6.4(OCH ), 56.3(OCH ); LRMS (ESI-TOF) (m/z) [M +
3 3
+
An oven-dried 25 mL round-bottomed flask equipped with a
Teflon-coated magnetic stirring bar was charged with 4a
H] calcd for C H NO 325.1, found 325.1.
19 19 4
(
600 mg, 1.68 mmol) and K CO3 (468 mg, 3.36 mmol),
5,8-Bis-methoxymethoxy-3-cyclopropyl-isoquinoline (5d)
2
1
0 mL of ethanol and 3 mL of aqueous ammonia (37%
ammonia in water). The reaction mixture was refluxed for
h. The complete conversion of starting material was
1
Brown solid; yield 77%; mp 115–117 °C; H NMR (CDCl ,
3
8
400 MHz): δ = 9.48 (s, 1H, ArH), 7.78 (s, 1H, ArH), 6.94
observed by TLC. The reaction was allowed to cool to room
temperature, poured into ice and extracted with CHCl3
(d, J = 8.0 Hz, 2H, ArH), 5.35–5.33 (m, 4H, –CH –),
2
3.55–3.53(m, 6H, –CH ), 2.23–2.21(m, 1H, –CH–),
3
1
3
(
10 mL). The organic layer was washed with 10 mL of
1.13–1.12(m, 2H, –CH –), 1.06–1.04(m, 2H, –CH –);
C
2
2
water and 5 mL of brine, dried over anhydrous sodium
sulfate and solvent was removed under reduced pressure.
NMR (CDCl , 100 MHz): δ = 156.6(ArC), 148.5(ArC),
147.0(ArC), 145.9(ArC), 130.2(ArC), 119.9(ArC), 112.4
3

Med Chem Res
(
(
9
ArC), 110.5(ArC), 107.5(ArC), 95.2(OCH O), 94.9
163.6(N–C), 149.2(ArC), 148.3(ArC), 141.3(ArC), 140.1
(ArC), 135.1(ArC), 129.8(ArC), 129.7(ArC), 127.7(ArC),
127.6(ArC), 127.2(ArC), 115.2(ArC), 101.0(=CH), 29.3
2
OCH O), 56.3(OCH ), 56.2(OCH ), 17.3(CH), 9.5(CH ),
2
3
3
2
+
.4(CH ); LRMS (ESI-TOF) (m/z) [M + H] calcd for
2
+
C H NO 289.1, found 289.1.
(NCH ), 21.5(CH ); HRMS (ESI-TOF) (m/z) [M + H]
1
6
19
4
3
3
calcd for C H N O 279.1128, found 279.1128
1
7 14 2 2
Synthetic procedure for synthesis of 6a–6d
3-Phenyl-7-methylamino-isoquinoline-5,8-dione (7c)
To a solution of 5a (150 mg, 0.42 mmol) in CH CN (5 mL)
3
1
was added CAN (690 mg, 1.26 mmol). The mixture was
allowed to stir 2 h at room temperature. Then, EtOAc (10
mL) was added. The mixture was washed with 10 mL of
water and 5 mL of brine, dried over anhydrous sodium
sulfate and solvent was removed under reduced pressure to
give a brown oil 6a. This crude material was then used for
next step.
Red solid; yield 77%; mp 184–186 °C; H NMR (CDCl ,
3
400 MHz): δ = 9.34 (s, 1H, ArH), 8.41 (s, 1H, ArH), 8.21
(d, J = 8.0 Hz, 2H, ArH), 7.55–7.53 (m, 2H, ArH), 5.86(s,
1H, ArH), 3.00–3.01(d, J = 8.0 Hz, 3H, –CH3); C NMR
(CDCl , 100 MHz): δ = 181.1(C=O), 180.7(C=O), 163.6
(N–C), 149.2(ArC), 148.8(ArC), 148.3(ArC), 140.2(ArC),
1
3
3
137.8(ArC), 130.8(ArC), 129.1(ArC), 129.0(ArC), 127.7
(
ArC), 127.6(ArC), 115.6(ArC), 101.1(=CH), 29.3(NCH );
3
+
Synthetic procedure for synthesis of 7a–7r
HRMS (ESI-TOF) (m/z) [M + H] calcd for C H N O
16 12 2 2
264.0899, found 264.0902
3
-(4-Methoxy-phenyl)-7-methylamino-isoquinoline-5,8-
dione (7a)
3-(4-Methoxy-phenyl)-7-tert-butylamino-isoquinoline-5,8-
dione (7d)
The residue was diluted with 5 mL of 1,2-dimethox-
ymethane. The reaction mixture was then cooled to 0 °C
and 33% wt. absolute ethanolic solution of methyl amine
1
Red solid; yield 67%; mp 207–209 °C; H NMR (CDCl ,
3
400 MHz): δ = 9.23 (s, 1H, ArH), 8.28 (s, 1H, ArH), 8.16
(d, J = 8.0 Hz, 2H, ArH), 7.03(d, J = 8.0 Hz, 2H, ArH),
6.06(s, 1H, ArH), 3.89(s, 3H, –OCH ), 1.47(s, 9H, –CH );
(
1.35 mL, 1.26 mmol) was added dropwise. Then it was
allowed to stir at room temperature. After complete con-
version was observed in TLC. After removing the solvent in
reduced pressure, the reaction mixture was poured in 10 mL
of water and extracted with ethyl acetate (3 × 50 mL). The
organic layer was washed with water (20 mL) and brine
3
3
1
3
C NMR (CDCl , 100 MHz): δ = 181.3(C=O), 181.0
3
(C=O), 163.0(N–C), 162.0(ArC), 148.4(ArC), 146.3(ArC),
139.8(ArC), 130.4(ArC), 129.3(ArC), 129.2(ArC), 129.1
(ArC), 122.0(ArC), 111.4(ArC), 111.3(ArC), 103.0(=CH),
55.5(OCH ), 52.1(C(CH ) ), 28.2(3 × CH ); HRMS (ESI-
(
20 mL), dried over anhydrous sodium sulfate and the
3
3 3
3
+
solvent was removed under reduced pressure. The crude
TOF) (m/z) [M + H] calcd for C H N O 336.1474,
20 20 2 3
product was purified by column chromatography to give 7a
found 336.1477
in 74% yield for two steps.
1
Red solid; mp 191–192 °C; H NMR (CDCl , 400 MHz):
3-Phenyl-7-tert-butylaminoisoquinoline-5,8-dione (7e)
3
δ = 9.24 (s, 1H, ArH), 8.30 (s, 1H, ArH), 8.16 (d, J = 8.0
Hz, 2H, ArH), 7.03 (d, J = 8.0 Hz, 2H, ArH), 5.81 (s, 1H,
1
Red solid; yield 69%; mp 203–204 °C; H NMR (CDCl ,
3
1
3
ArH), 3.89 (s, 3H, –OCH ), 2.97(s, 3H, –CH ); C NMR
400 MHz): δ = 9.30 (s, 1H, ArH), 8.37 (s, 1H, ArH), 8.19
(d, J = 8.0 Hz, 2H, ArH), 7.52 (d, J = 8.0 Hz, 2H, ArH),
3
3
(
(
CDCl , 100 MHz): δ = 181.3(C=O), 180.7(C=O), 163.2
N–C), 162.0(ArC), 149.3(ArC), 148.3(ArC), 140.0(ArC),
3
1
3
6.08(s, 1H, ArH), 1.48(s, 9H, –CH3); C NMR (CDCl3,
100 MHz): δ = 181.4(C=O), 181.0(C=O), 163.5(N–C),
163.0(ArC), 148.3(ArC), 146.2(ArC), 140.0(ArC), 137.8
(ArC), 130.7(ArC), 129.1(ArC), 129.0(ArC), 127.6(ArC),
127.5(ArC), 122.7(ArC), 115.4(ArC), 103.1(=CH), 52.1(C
1
(
2
30.5(ArC), 129.3(ArC), 129.3(ArC), 128.9(ArC), 122.0
ArC), 114.4(ArC), 114.3(ArC), 101.0(=CH), 55.4(OCH3),
9.2(NCH ); high resolution mass spectrum (HRMS) (ESI-
3
+
TOF) (m/z) [M + H] calcd for C H N O 294.1004,
1
7 14 2 3
+
found 294.1000.
(CH ) ), 28.3(3 × CH ); HRMS (ESI-TOF) (m/z) [M + H]
3
3
3
calcd for C H N O 306.1368, found 307.1436.
1
9 18 2 2
3
-p-Tolyl-7-methylamino-isoquinoline-5,8-dione (7b)
3
-(4-Methoxy-phenyl)-7-phenylamino-isoquinoline-5,8-
1
Red solid; yield 71%; mp 197–199 °C; H NMR (CDCl ,
dione (7f)
3
4
00 MHz): δ = 9.30 (s, 1H, ArH), 8.37 (s, 1H, ArH), 8.11
1
(
d, J = 8.0 Hz, 2H, ArH), 7.35–7.33(m, 2H, ArH), 5.85(s,
Red solid; yield 53%; mp 199–201 °C; H NMR (CDCl ,
3
1
3
1
H, ArH), 2.99–2.97(m, 3H, –CH ), 2.46(s, 3H, –CH );
C
400 MHz): δ = 9.34 (s, 1H, ArH), 8.30 (s, 1H, ArH), 8.18
(d, J = 8.0 Hz, 2H, ArH), 7.44 (d, J = 8.0 Hz, 1H, ArH),
3
3
NMR (CDCl , 100 MHz): δ = 181.2(C=O), 180.8(C=O),
3

Med Chem Res
7
7
3
.31 (d, J = 8.0 Hz, 2H, ArH), 7.28–7.26 (m, 3H, ArH),
122.0(ArC), 114.4(ArC), 114.1(ArC), 102.0(=CH), 55.5
+
.05 (d, J = 8.0 Hz, 2H, ArH), 6.48(s, 1H, ArH), 3.90(s,
(OCH ), 46.9(PhCH ); HRMS (ESI-TOF) (m/z) [M + H]
3
2
1
3
H, –OCH3); C NMR (CDCl , 100 MHz): δ = 182.7
calcd for C H N O 370.1317, found 370.1322.
23 18 2 3
3
(
C=O), 181.1(C=O), 162.1(N–C), 148.5(ArC), 145.3
(
ArC), 141.4(ArC), 138.4(ArC), 136.1(ArC), 135.0(ArC),
1
(
1
29.2(ArC), 129.1(ArC), 129.0(ArC), 127.8(ArC), 127.6
ArC), 127.5(ArC), 124.3(ArC), 121.5(ArC), 121.4(ArC),
14.4(ArC), 113.2(ArC), 103.5(=CH), 55.4(OCH3);
3-Pheny-7-benzylamino-l-isoquinoline-5,8-dione (7j)
1
Red solid; yield 75%; mp 197–198 °C; H NMR (CDCl ,
3
+
HRMS (ESI-TOF) (m/z) [M + H] calcd for C H N O
400 MHz): δ = 9.31 (s, 1H, ArH), 8.36 (s, 1H, ArH), 8.18
(d, J = 8.0 Hz, 2H, ArH), 7.53–7.51 (m, 3H, ArH),
2
2 16 2 3
3
56.1161, found 356.1163.
7.38–7.37 (m, 2H, ArH), 7.36–7.34 (m, 2H, ArH), 7.26 (s,
3
-p-Tolyl-7-phenylamino-isoquinoline-5,8-dione (7g)
1H, ArH), 5.89(s, 1H, ArH), 4.41 (d, J = 4.0 Hz, 2H,
1
3
–
CH –); C NMR (CDCl , 100 MHz): δ = 181.4(C=O),
2 3
1
Red solid; yield 62%; mp 207–209 °C; H NMR (CDCl ,
4
180.1(C=O), 163.7(N–C), 148.4(ArC), 148.0(ArC), 140.0
(ArC), 137.8(ArC), 135.4(ArC), 130.8(ArC), 122.7(ArC),
129.7(ArC), 129.2(ArC), 129.0(ArC), 128.7(ArC), 128.4
(ArC), 127.7(ArC), 127.3(ArC), 127.0(ArC), 126.6(ArC),
3
00 MHz): δ = 9.38 (s, 1H, ArH), 8.36 (s, 1H, ArH), 8.13
(
d, J = 8.0 Hz, 2H, ArH), 7.47 (d, J = 8.0 Hz, 2H, ArH),
7
1
.37–7.35 (m, 3H, ArH), 7.34-7.32 (m, 2H, ArH), 6.51(s,
1
3
H, ArH), 2.47(s, 3H, -CH3); C NMR (CDCl , 100 MHz):
115.4(ArC), 102.1(=CH), 46.9(PhCH ); HRMS (ESI-TOF)
3
2
+
δ = 182.5(C=O), 181.0(C=O), 163.8(N-C), 148.5(ArC),
45.3(ArC), 141.4(ArC), 139.5(ArC), 136.9(ArC), 135.0
ArC), 130.2(ArC), 129.8(ArC), 129.5(ArC), 129.1(ArC),
27.6(ArC), 127.2(ArC), 126.3(ArC), 123.3(ArC), 123.0
ArC), 114.9(ArC), 114.6(ArC), 103.5(=CH), 22.5(CH );
(m/z) [M + H] calcd for C H N O 341.1290, found
2
2 17 2 2
1
(
1
(
340.1209.
3-(4-Methoxy-phenyl)-7-morpholin-4-yl-isoquinoline-5,8-
dione (7k)
3
+
HRMS (ESI-TOF) (m/z) [M+H] calcd for C H N O
2
2 16 2 2
3
40.1212, found 341.1281.
1
Red solid; yield 64%; mp 219–221 °C; H NMR (CDCl ,
3
3
-Phenyl-7-phenylamino-isoquinoline-5,8-dione (7h)
400 MHz): δ = 9.24 (s, 1H, ArH), 8.23 (s, 1H, ArH), 8.16
(
d, J = 8.0 Hz, 2H, ArH), 7.04 (d, J = 8.0 Hz, 2H, ArH),
1
Red solid; yield 65%; mp 183–185 °C; H NMR (CDCl ,
6.10(s, 1H, ArH), 3.94–3.92 (m, 2H, –CH –), 3.90–3.89
3
2
4
00 MHz): δ = 9.39 (s, 1H, ArH), 8.38 (s, 1H, ArH), 8.20
(m, 2H, –CH –), 3.89 (s, 3H, –OCH ), 3.63–3.61 (m, 4H,
2 × –CH –); C NMR (CDCl , 100 MHz): δ = 182.4
2
3
1
2 3
3
(
d, J = 8.0 Hz, 2H, ArH), 7.53 (d, J = 8.0 Hz, 3H, ArH),
7
1
1
.48–7.46 (m, 2H, ArH), 7.31–7.29 (m, 3H, ArH), 6.49(s,
(C=O), 182.0(C=O), 162.3(N–C), 161.9(ArC), 153.4
(ArC), 148.9(ArC), 138.5(ArC), 130.3(ArC), 129.2(ArC),
129.0(ArC), 123.9(ArC), 114.6(ArC), 114.2(ArC), 113.4
(ArC), 111.2(=CH), 66.5(CH ), 66.3(CH ), 55.5(OCH ),
1
3
H, ArH); C NMR (CDCl , 100 MHz): δ = 182.3(C=O),
3
81.1(C=O), 163.8(N–C), 148.5(ArC), 145.3(ArC), 139.6
(
1
(
1
ArC), 137.8(ArC), 136.9(ArC), 130.9(ArC), 129.8(ArC),
29.5(ArC), 129.3(ArC), 129.0(ArC), 127.7(ArC), 127.3
ArC), 126.3(ArC), 123.5(ArC), 123.0(ArC), 122.5(ArC),
15.2(ArC), 103.6(=CH); HRMS (ESI-TOF) (m/z) [M +
2
2
3
+
49.2(CH ), 49.0(CH ); HRMS (ESI-TOF) (m/z) [M+H]
2 2
calcd for C H N O 351.1345, found 351.1334.
20 19 2 4
+
H] calcd for C H N O 326.1055, found 326.1059
2
1 14 2 2
3-p-Tolyl-7-morpholin-4-yl-isoquinoline-5,8-dione (7l)
3
-(4-Methoxy-phenyl)-7-benzylamino-isoquinoline-5,8-
1
dione (7i)
Red solid; yield 69%; mp 213–214 °C; H NMR (CDCl ,
3
4
00 MHz): δ = 9.26 (s, 1H, ArH), 8.26 (s, 1H, ArH), 8.07
1
Red solid; yield 71%; mp 205–207 °C; H NMR (CDCl ,
(d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH),
3
4
00 MHz): δ = 9.26 (s, 1H, ArH), 8.28 (s, 1H, ArH), 8.16
6.10(s, 1H, ArH), 3.89–3.87 (m, 4H, 2 × –CH –),
2
1
3
(
d, J = 8.0 Hz, 2H, ArH), 7.40–7.38 (m, 2H, ArH),
3.62–3.60 (m, 4H, 2 × –CH –), 2.45 (s, 3H, –CH );
C
2
3
7
8
2
.36–7.34 (m, 2H, ArH), 7.26 (s, 1H, ArH), 7.03 (d, J =
NMR (CDCl , 100 MHz): δ = 182.4(C=O), 182.0(C=O),
3
.0 Hz, 2H, ArH), 5.87 (s, 1H, ArH), 4.41 (d, J = 8.0 Hz,
162.7(N–C), 153.3(ArC), 148.8(ArC), 141.2(ArC), 138.5
(ArC), 134.9(ArC), 129.8(ArC), 129.6(ArC), 127.5(ArC),
127.3(ArC), 124.4(ArC), 114.1(ArC), 111.2(=CH), 66.4
(CH ), 66.1(CH ), 49.2(CH ), 49.0(CH ), 21.3(CH );
1
3
H, –CH –), 3.89(s, 3H, –OCH ); C NMR (CDCl , 100
2
3
3
MHz): δ = 181.5(C=O), 180.7(C=O), 163.2(N–C), 162.0
ArC), 148.4(ArC), 148.1(ArC), 139.6(ArC), 135.5(ArC),
30.4(ArC), 129.7(ArC), 129.5(ArC), 129.3(ArC), 129.1
ArC), 128.9(ArC), 128.3(ArC), 127.7(ArC), 127.3(ArC),
(
1
(
2
2
2
2
3
+
HRMS (ESI-TOF) (m/z) [M + H] calcd for C H N O
20 19 2 3
335.1396, found 335.1386.

Med Chem Res
3
-Phenyl-7-morpholin-4-yl-isoquinoline-5,8-dione (7m)
3-Phenyl-7-p-tolylsulfanyl-isoquinoline-5,8-dione (7q)
1
1
Red solid; yield 71%; mp 188–189 °C; H NMR (CDCl ,
Red solid; yield 68%; mp 166–168 °C; H NMR (CDCl ,
3
3
4
00 MHz): δ = 9.29 (s, 1H, ArH), 8.31 (s, 1H, ArH), 8.18
400 MHz): δ = 9.23 (s, 1H, ArH), 8.18 (s, 1H, ArH), 8.09
(d, J = 8.0 Hz, 2H, ArH), 7.49–7.48 (m, 3H, ArH),
(
d, J = 8.0 Hz, 2H, ArH), 7.55–7.53 (m, 3H, ArH), 6.12(s,
1
4
H, ArH), 3.90–3.89(m, 4H, 2 × –CH –), 3.64–3.63 (m,
7.35–7.33 (m, 3H, ArH), 7.14 (d, J = 4.0 Hz, 2H, ArH),
2
1
3
13
H, 2 × –CH –); C NMR (CDCl , 100 MHz): δ = 182.3
2.35 (s, 3H, –CH3); C NMR (CDCl , 100 MHz): δ =
2
3
3
(
(
1
(
C=O), 182.1(C=O), 162.8(N–C), 153.3(ArC), 148.8
ArC), 138.6(ArC), 137.8(ArC), 130.7(ArC), 129.3(ArC),
29.1(ArC), 127.6(ArC), 127.3(ArC), 124.6(ArC), 114.5
178.1(C=O), 177.8(C=O), 162.6(N–C), 149.5(ArC), 149.3
(ArC), 147.3(ArC), 138.8(ArC), 138.5(ArC), 138.4(ArC),
137.5(ArC), 131.8(ArC), 131.7(ArC), 130.8(ArC), 130.1
(ArC), 130.0(ArC), 129.8(ArC), 129.0(ArC), 128.5(ArC),
ArC), 111.3(=CH), 66.4(CH ), 66.1(CH ), 49.2(CH ),
2
2
2
+
4
9.0(CH ); HRMS (ESI-TOF) (m/z) [M+H] calcd for
127.5(ArC), 124.2(ArC), 115.5(=CH), 21.3(CH ); HRMS
2
3
+
C H N O 321.1239, found 321.1233.
(ESI-TOF) (m/z) [M + H] calcd for C H NO S 357.0823,
1
9
17
2
3
2
15
2
found 357.0816.
3
-Cyclopropyl-7-methylamino-isoquinoline-5,8-dione (7n)
1
Red solid; yield 67%; mp 123–125 °C; H NMR (CDCl ,
3-(4-Methoxy-phenyl)-7-p-tolylsulfanyl-isoquinoline-5,8-
3
4
00 MHz): δ = 9.08 (s, 1H, ArH), 7.73 (s, 1H, ArH), 5.79
dione (7r)
(
s, 1H, ArH), 2.96 (d, J = 8.0 Hz, 3H, –CH ), 2.26 (m, 1H,
3
1
3
1
–
1
1
CH–), 1.26-1.22 (m, 4H, 2 × –CH –); C NMR (CDCl3,
Red solid; yield 72%; mp 171–173 °C; H NMR (CDCl ,
2
3
00 MHz): δ = 181.5(C=O), 180.8(C=O), 171.9(N–C),
49.2(ArC), 148.0(ArC), 139.0(ArC), 121.7(ArC), 116.4
400 MHz): δ = 9.20 (s, 1H, ArH), 8.13 (s, 1H, ArH), 8.08
(d, J = 8.0 Hz, 2H, ArH), 7.35–7.33 (m, 3H, ArH), 7.17 (d,
J = 4.0 Hz, 2H, ArH), 7.03 (d, J = 4.0 Hz, 2H, ArH), 3.90
(
ArC), 100.9(=CH), 29.2(CH ), 18.8(CH), 12.1(CH ), 12.0
3 2
+
13
(
CH ); HRMS (ESI-TOF) (m/z) [M + H] calcd for
(s, 3H, –OCH ), 2.37 (s, 3H, –CH ); C NMR (CDCl3,
2
3
3
C H N O 229.0972, found 229.0970.
100 MHz): δ = 179.3(C=O), 178.2(C=O), 165.8(N–C),
51.2(ArC), 148.8(ArC), 147.3(ArC), 137.2(ArC), 136.5
(ArC), 136.3(ArC), 133.5(ArC), 131.9(ArC), 131.5
ArC), 130.1(ArC), 130.0(ArC), 129.8(ArC), 129.6(ArC),
1
3 13 2 2
1
3
-Cyclopropyl-7-phenylamino-isoquinoline-5,8-dione (7o)
(
1
Red solid; yield 64%; mp 133–135 °C; H NMR (CDCl ,
128.5(ArC), 128.3(ArC), 127.1(ArC), 122.5(ArC), 116.3
3
4
00 MHz): δ = 9.17 (s, 1H, ArH), 7.74 (s, 1H, ArH), 7.29
(=CH), 55.5(OCH ), 22.5(CH ); HRMS (ESI-TOF) (m/z)
3
3
+
(
d, J = 8.0 Hz, 2H, ArH), 6.79 (d, J = 8.0 Hz, 1H, ArH),
[M + H]
calcd for C H NO S 387.0929, found
23 17 2
6
–
1
1
.73–6.71 (m, 2H, ArH), 6.46(s, 1H, ArH), 2.18 (m, 1H,
387.0934.
1
3
CH–), 1.29–1.25(m, 4H, 2 × –CH –); C NMR (CDCl3,
2
00 MHz): δ = 182.8(C=O), 181.1(C=O), 172.2(N–C),
48.3(ArC), 146.4(ArC), 129.8(ArC), 129.3(ArC), 129.1
Biological evaluation
(
ArC), 126.2(ArC), 122.9(ArC), 118.6(ArC), 116.2(ArC),
1
15.1(ArC), 115.0(ArC), 103.4(=CH), 18.9(CH), 12.3
Cell viability
+
(
CH ), 12.1(CH ); HRMS (ESI-TOF) (m/z) [M + H] calcd
2 2
for C H N O 291.1128, found 291.1125.
Human hepatocellular carcinoma (HepG2), human non-
small-cell lung tumor (A549), human colon carcinoma
(HCT-116), and human cervical carcinoma (HeLa) were
obtained from the Cell Bank of the Chinese Academy of
Sciences (Shanghai, China). All cell lines were cultured in a
1
8 14 2 2
3
-Cyclopropyl-7-morpholin-4-yl-isoquinoline-5,8-dione
(
7p)
1
Red solid; yield 73%; mp 166–168 °C; H NMR (CDCl ,
37 °C incubator with a 5% CO environment. Compounds
3
2
4
1
4
4
00 MHz): δ = 9.04 (s, 1H, ArH), 7.65 (s, 1H, ArH), 6.05(s,
were dissolved in Dimethyl sulfoxide (DMSO) with a
concentration of 10 mM. The final DMSO concentration in
the cell culture and cell viability tests is 0.05%. Cells were
H, ArH), 3.89–3.87 (m, 4H, 2 × –CH –), 3.60–3.58 (m,
2
H, 2 × –CH –), 2.24–2.22 (m, 1H, –CH–), 1.28–1.24(m,
2
1
3
3
H, 2 × –CH –); C NMR (CDCl , 100 MHz): δ = 182.5
seeded into 96-well plates at a concentration of 2 × 10 per
2
3
(
(
6
1
C=O), 182.1(C=O), 170.9(N–C), 153.4(ArC), 148.6
ArC), 137.4(ArC), 123.7(ArC), 115.4(ArC), 111.2(=CH),
well, cultured for 24 h, exposed to the compounds at various
concentrations for cancer cell viability experiments, cells
were cultured for 72 h and viability was determined through
the use of the MTT assay.
6.4(CH ), 66.2(CH ), 49.2(CH ), 49.1(CH ), 18.6(CH),
2 2 2 2
+
1.9(CH ), 11.7(CH ); HRMS (ESI-TOF) (m/z) [M + H]
2
2
calcd for C H N O 284.1234, found 285.1232.
1
6 16 2 3

Med Chem Res
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Fluorescence morphological examination
Hoechst 33342 staining was carried out according to the
procedure of literature (Ding et al. 2009). Cells were treated
with compound 7a in 0, 0.1, 5, and 10 μM for 48 h. Then
stained by incubating in PBS containing Hoechst 33342 (10
μg/mL) at 37 °C for 3 min in the dark. Then washed cells
with PBS three times. Stained cells were viewed under a
fluorescence microscope (Leica, German) with 200
magnification.
Conclusion
To find novel cytotoxic anticancer agents, we have prepared
eighteen isoquinoline quinones as natural Mansouramycins
analogs. Most of these compounds displayed cytotoxicities
against MCF-7, A549, HCT116, and HepG2 cancer cell
lines at micromolar concentration. Apoptosis of HepG2
cells induced by compound 7a was observed by
Hoechst33342 staining assay. The current study contributes
to understand the SAR and mechanisms of anticancer
activity of isoquinoline quinones, which would be helpful to
develop novel marine derived anticancer agents.
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Compliance with ethical standards
Conflict of interest The authors declare that they have no competing
interests.
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