Novel hybrids from lamellarin D and combretastatin A 4 as cytotoxic agents

Article abstract of DOI:10.1016/j.ejmech.2009.09.017

A new series of hybrids of lamellarin D and combretastatin A 4, 1,2-diphenyl-5,6-dihydropyrrolo [2,1-a] isoquinolines, were designed as cytotoxic agents based on principles of combination in medicinal chemistry and taking the parent compounds' different anti-proliferative mechanisms into consideration. Twenty-two novel hybrids were synthesized through a convenient route, with a key step of core pyrrole formation and evaluated for their anti-proliferative activities in vitro against K-562, A-549, SMMC-7721, SGC-7901 and HCT-116 cancer cell lines. The results showed that some hybrids had good anti-proliferative activities in low IC₅₀ ranges.

Full text of DOI:10.1016/j.ejmech.2009.09.017

European Journal of Medicinal Chemistry 45 (2010) 11–18
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Novel hybrids from lamellarin D and combretastatin A 4 as cytotoxic agents
,
Li Shen a, Xiaochun Yang b, Bo Yang b, Qiaojun He b, Yongzhou Hu a
*
a ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
b Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of hybrids of lamellarin D and combretastatin A 4, 1,2-diphenyl-5,6-dihydropyrrolo [2,1-a]
isoquinolines, were designed as cytotoxic agents based on principles of combination in medicinal
chemistry and taking the parent compounds’ different anti-proliferative mechanisms into consideration.
Twenty-two novel hybrids were synthesized through a convenient route, with a key step of core pyrrole
formation and evaluated for their anti-proliferative activities in vitro against K-562, A-549, SMMC-7721,
SGC-7901 and HCT-116 cancer cell lines. The results showed that some hybrids had good anti-prolifer-
ative activities in low IC50 ranges.
Received 13 October 2008
Received in revised form
31 July 2009
Accepted 10 September 2009
Available online 16 September 2009
Keywords:
Hybrids
Ó 2009 Elsevier Masson SAS. All rights reserved.
Combretastatin A 4
Lamellarin D
Anti-proliferative
Cytotoxic
1. Introduction
2. Hybrids design
Lamellarin D (Fig. 1), first isolated from marine prosobranch
mollusk Lamellaria sp. [1], is a potent Topo I inhibitor [2] and has
the ability to reverse multidrug resistance [3] and induce
apoptosis through mitochondria mediated pathway [4] towards
a large panel of cancer cell lines [5,6]. Lots of work and reviews
on total synthesis, mechanism and modification of lamellarins
have been reported up till now [6–9]. Combretastatin A4, a cis-
stilbene natural product obtained from African willow tree
Combretum caffrum [10], has potent anti-mitotic activity in
binding with colchicines [11] and inhibits polymerization of
microtubules [12]. Its soluble pro-drug CA4P is currently under
Phase II clinical evaluation in the USA as an agent used in
combination treatment of various multi-drug resistant solid
tumors [13].
Based on the two different types of anti-proliferative mecha-
nism, novel hybrids of lamellarin D and combretastatin A4,
1,2-diphenyl-5,6- dihydropyrrolo [2,1-a] isoquinoline derivatives,
were designed and synthesized as cytotoxic agents, which were
evaluated for their anti-proliferation activities in vitro against
various human cancer cell lines.
Banwell et al. reported their work on developing 4,5-diaryl-
1H-pyrrole-2-carboxylates as combretastatin A 4 and lamellarin T
hybrids [14]. Although both being members in the lamellarin family,
lamellarin D is a much more typical representative than lamellarinT,
and it is the most extensively studied one in lamellarins. Lamellarin
D
incorporates a
2H[1]benzopyrano[40,3’:4,5]pyrrolo[2,1-a]iso-
quinolinone core. Researches revealed that if ring B was disposed,
the two aryl rings A and F of lamellarin D could be fixed in a cis-
relationship to each other, being a combretastatin A 4-like cis-stil-
bene substructure. It is worthwhile to design and synthesize novel
hybrids which not only combine important pharmacophore struc-
tures of lamellarin D and combretastatin A 4, but also retain both
cytotoxic and anti-mitotic activities.
We sought to design hybrids whose aryl units would closely
relate to the substituted patterns of lamellarin D. Firstly, we over-
lapped the 3D structures of the model hybrid with combretastatin
A4 by using Hyperchem software, and found ring F and A in model
hybrid molecule matched well with the relevant ring A and B
of combretastatin A4 (Fig. 2). This type of analysis allowed
the assessment of the 1,2-diphenyl-5,6-dihydropyrrolo [2,1-a]iso-
quinoline as a scaffold for preparing new antitumor agents.
Although Bailly and co-worker reported that the planarity of the
hexacyclic chromophore is important [2], our foregoing study
revealed that D5,6 double bond or single bond didn’t affect the
* Corresponding author. Tel./fax: þ86 571 88208460.
E-mail address: huyz@zju.edu.cn (Y. Hu).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.09.017

12
L. Shen et al. / European Journal of Medicinal Chemistry 45 (2010) 11–18
(9a–e) with phenacyl bromides (10a–l). As a result, twenty-three
hybrids (Table 1) were synthesized and confirmed. All compounds
were novel except 11v [15], which served as a reference compound
for synthesis as well as analysis studies.
4. Biological studies and discussion
The synthesized hybrids (11a–w) were measured for their
growth inhibitory activity in vitro against five human cancer cell
lines, including leukemia K-562, lung carcinoma A-549, hepato-
cellular carcinoma SMMC-7721, gastric carcinoma SGC-7901 and
colon carcinoma HCT-116. Taxol was employed as a positive control.
The results are summarized in Table 1.
Fig. 1. Structures of Lamellarin D and Combretastatin A 4.
The results of in vitro antitumor activity evaluation revealed that
eleven 1,2-diphenyl-5,6-dihydropyrrolo [2,1-a] isoquinolines
exhibited anti-proliferative activities against the tested five human
cancer cell lines with varied potency, comparing with the reference
compound taxol. 11c, with isopropoxy groups at 8 and 14 positions
and OH at 20 and 21 positions, showed the most effective activity
against all the five human cancer cells with the IC50 value around
result of the overlap. 1,2-diphenyl-5,6-dihydropyrrolo [2,1-a]
isoquinolines with different substituted groups on ring A, E and F
were chosen as prototypical hybrids of lamellarin D and com-
bretastatin A4.
3. Synthetic studies
10 mM, and 11i, without isopropoxy groups at 8 and 14 positions or
On the basis of the synthesis studies on lamellarins, a conve-
nient N-ylide-mediate pyrrole formation strategy [15–18] involving
dihydroisoquinoline hydrochlorides and phenacyl bromides was
adopted, with the corresponding benzaldehydes as starting mate-
rials (Scheme 1).
OH group at 21 position, showed slightly weaker activity than 11c.
Meanwhile, 11b and 11c, both with isopropoxy group at 8 position,
methoxy group at 9 and 13 positions, and OH group at 20 and
21 positions, showed potent activities against K562 and HCT-116
cells. Compounds 11a and 11n, with methoxy groups at 8, 9, 13, 14
and 15 positions and OH group at 21 position, showed favorable
activities against K562 and HCT-116 cells. 11g, with bromo atom at
20 position showed good activity towards K562, SMMC-7721 and
SGC-7901 cells.
The results revealed that hybrids bearing polyaromatic scaffold
and the structure features of lamellarin D showed more potent
activities. The presence of methoxy group (11g, 11i and 11n) rather
than isopropxy group (11h, 11j and 11m) at 8 position was favorable
for anti-proliferative activity, except 11a, which showed only
a slight decrease in activity relative to 11b, whose 8-methoxy group
was replaced by isopropoxy group. However, replacing the
methoxy group by an isopropxy group at both 8 and 14 positions, as
examplied by 11d and 11c, could improve the anti-proliferative
activity significantly. Comparing with 11i, the activity of 11k was
significantly decreased. Besides, 11p, 11s and 11t almost completely
The lack of symmetry in the cis-stilbene substructure domain
and substituted groups raised issues about whether a step-by-step
synthetic strategy was possible; therefore, benzaldehydes (1a–d)
were reduced to phenylmethanols (2a–d) and then converted to
phenylacetic acids (4a–d) by chlorination, cyanation and hydro-
lyzation [19]. Other benzaldehydes (5a–b) were converted to
corresponding nitroalkenes (6a–b) via Henry reaction [20] and
then reduced to phenylethanamines (7a–b) [21]. Reaction of
amines (7a–b) with phenylacetic acids (4a–d) yielded amides
(8a–e), followed by Bischler–Napieralski cyclization to afford
3,4-dihydroisoquinoline hydrochlorides (9a–e). Another compo-
nent phenacyl bromides (10a–l) were prepared by bromination of
substituted acetophenones using enzyltrimethylammonium tri-
bromide [17]. Finally, the target hybrids (11a–w) were synthesized
by cyclization of 1-benzyl-3,4-dihydroisoquinoline hydrochlorides
Fig. 2. Overlay of the model hybrid (11n) and Combretastatin A 4.

L. Shen et al. / European Journal of Medicinal Chemistry 45 (2010) 11–18
13
Scheme 1. Reagents: (a) KBH4, MeOH, rt; (b) (i) SOCl2, CH2Cl2, 0 ꢀC; (ii) NaCN, CH3CN, reflux; (c)KOH, EtOH, reflux; (d) MeNO2, NH4Ac, HOAc, ultrasonic; (e) BF3ꢁEt2O, NaBH4, THF,
reflux; (f) heat, 180 ꢀC;(g) POCl3, toluene, 80 ꢀC; (h) NaHCO3, CH3CN, reflux.
lost their activities, indicating that deletion of 13-methoxy and
15-methoxy groups greatly decreased the anti-proliferative
activity. Replacing the hydroxyl group with bromo or chloro at
20 position, as from 11i to 11e or 11g, reduced the anti-proliferative
activity. It could be concluded that not only the 13 and 15-methoxy
groups were crucial, but the 20-hydroxyl group was important,
consisting with Alvarez and co-worker’s work [22]. Our study on
selective de-protection and derivativation of the phenol group on
position 8, 14, 18, 20 or 21, as well as further mechanism research
were still in progress.
´
Table 1
The structures and anti-proliferative activities of 1,2- diphenyl-5,6-dihydropyrrolo[2,1-a]isoquinolines.
6
R1
8
5
N
3
R5
9
MeO
R2
18
17
13
11
1
2
20
R6
R3
14
15
R4
21
R7
No.
R1
R2
R3
R4
R5
R6
–
R7
–
OH
OH
OH
OH
H
H
H
H
H
IC50(mmol/L)
A-549
K-562
SMMC -7721
SGC -7901
HCT -116
Taxol
11a
11b
11c
11d
11e
11f
11g
11h
11i
–
–
–
–
–
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2.28
99.4
>94.1
6.7
>105.7
>98.8
>93.6
>90.8
>86.4
23.3
>96.8
>116.7
>89.3
>85.1
>96.4
>91.5
>109.0
>96.2
>91.6
>108.8
>102.6
>73.5
>83.9
>76.7
1.16
–
3.34
4.37
OMe
OPr-i
OPr-i
OMe
OMe
OPr-i
OMe
OPr-i
OMe
OPr-i
OMe
OMe
OPr-i
OMe
OPr-i
OMe
OMe
OPr-i
OMe
OMe
OPr-i
OMe
OPr-i
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
H
OMe
OMe
OPr-i
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OPr-i
OMe
OMe
OPr-i
OMe
OPr-i
OMe
OMe
H
OH
14.1
4
2.7
43.9
>94.1
10.9
>99.4
>94.1
11.4
5.8
1.4
0.7
OH
OH
OH
Cl
Cl
Br
H
>105.7
>98.8
>93.6
8.8
>86.4
5.3
>105.7
>98.8
>93.6
17.5
>86.4
15
>105.7
>98.8
>93.6
1.2
15.4
22.7
>105.7
>98.8
>93.6
>90.8
>86.4
13.8
OMe
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
H
OMe
H
H
H
H
Br
OH
OH
OH
OMe
OMe
OMe
OMe
OMe
H
H
H
H
OPr-i
OMe
OMe
11j
11k
11l
H
H
>96.8
3.1
>89.3
83.3
22
19.6
>109.0
37.1
>91.6
>108.8
>102.6
59.8
46.7
>96.8
>116.7
>89.3
>85.1
>96.4
>91.5
>109.0
>96.2
>91.6
>108.8
>102.6
>73.5
>83.9
>76.7
>96.8
34.5
>89.3
>85.1
3.2
>91.5
>109.0
>96.2
>91.6
>108.8
>102.6
21
>116.7
>89.3
>85.1
>96.4
>91.5
>109.0
>96.2
>91.6
>108.8
>102.6
>73.5
>83.9
>76.7
OPr-i
OPr-i
OH
OH
OH
F
F
F
F
11m
11n
11o
11p
11q
11r
11s
11t
H
OMe
OMe
H
OMe
OMe
OMe
OPr-i
OMs
OMs
OMs
H
11u
11v
11w
OMe
OMe
OMe
OMe
OMe
OMe
H
H
>83.9
>76.7
>83.9
>76.7

14
L. Shen et al. / European Journal of Medicinal Chemistry 45 (2010) 11–18
5. Conclusions
6.1.3. Phenylacetic acids (4a–d)
The title compounds were prepared according to literature
procedures [19] from appropriate benzaldehyde by reduction,
chlorination, cyanation and hydrolyzation.
A new series of hybrids from lamellarin D and combretastatin
A 4, 1,2- diphenyl-5,6-dihydropyrrolo [2,1-a] isoquinolines, were
designed as cytotoxic agents and synthesized through a convenient
route. Some of the hybrids exhibited anti-proliferative activity in
vitro against human cancer cell lines, K-562, A-549, SMMC-7721,
SGC-7901 and HCT-116. The results revealed that the hybrids
closely resembling structure features of lamellarin D showed
potent activities and the hydroxyl group at position 20 and the
methoxy groups at positions 9, 13 and 15 are crucial for activity.
Additional studies related to these analogues are in progress.
6.1.3.1. 2-(4-Isopropoxy-3-methoxyphenyl)acetic acid (4a). Yield
49% (4 steps); Mp 67–69 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 1.33
(d, 6H, J ¼ 6.4 Hz, –CH(CH3) 2), 3.75 (s, 2H, –CH2COOH), 3.86 (s, 3H,
3-OCH3), 4.49 (m, 1H, –CH(CH3)2), 6.79 (d, 1H, J ¼ 8.4 Hz, 6-Ar–H),
6.81 (s, 1H, 2-Ar–H), 6.84 (d, 1H, J ¼ 8.4 Hz, 5-Ar–H), 8.80 (s, 1H,
–CH2COOH).
6.1.3.2. 2-(4-Methoxyphenyl)acetic acid (4b). Yield 60% (4 steps);
Mp 85–88 ꢀC; 1H NMR (CDCl3, 400 MHz)
3.74 (s, 3H, 14-OCH3), 6.84 (dd, 2H, J ¼ 6.0 Hz, J ¼ 2.0 Hz, 3-Ar–H,
5-Ar–H), 6.96 (dd, 2H, 3J ¼ 6.0 Hz, 4J ¼ 2.0 Hz, 2-Ar–H, 6-Ar–H),
12.21 (s, 1H, –CH2COOH).
d
3.49 (s, 2H, –CH2COOH),
3
4
6. Experimental
6.1. Chemistry
Melting points were determined on a Bu¨chi B-540 melting
apparatus and uncorrected. Infrared spectra were recorded using
KBr plates on a Bruker Vector 22 FTIR instrument. 1H NMR spectra
and 13C NMR spectra were recorded on a Bruker AM-400 FT spec-
6.1.3.3. 2-(3,4-Dimethoxyphenyl)acetic
acid
(4c). Yield
71%
(4 steps); Mp 96–98 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
3.50 (s, 2H,
–CH2COOH), 3.72 (s, 3H, 4-OCH3), 3.75 (s, 6H, 3-OCH3, 5-OCH3), 6.52
(d, 1H, J ¼ 8.4 Hz, 6-Ar–H), 6.81 (s, 1H, 2-Ar–H), 6.86 (d, 1H,
J ¼ 8.4 Hz, 5-Ar–H), 10.30 (s, 1H, –CH2COOH).
trometer. Chemical shifts values were expressed in d ppm with TMS
as an internal standard. Elemental analysis was performed on
a Flash EA-1112 elemental analyzer. Mass spectra, ESI (positive)
were recorded on a Finnigan LCQ DECA XP plus using direct flow
injections. Reactions were run in ovendried glassware and distilled
solvents. Common reagents and intermediates were purified by
established procedures [23]. Thin layer chromatographic analysis
were carried out on silica gel plates made from silica gel H and
HF254 using 0.5% aqueous CMC-Na as adsorbent, while flash chro-
matographic purifications were conducted on silica gel (200–
300 mesh).
6.1.3.4. 2-(3,4,5-Trimethoxyphenyl)acetic acid (4d). Yield 68%
(4 steps); Mp 118–120 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 3.58 (s, 2H,
–CH2COOH), 3.76 (s, 3H, 3-OCH3), 3.83 (s, 3H, 3-OCH3), 6.52 (s, 2H,
2-Ar–H, 6-Ar–H), 9.60 (s, 1H, –CH2COOH).
6.1.4. Ethanamides (8a–e)
Phenylacetic acid
4 (1.0 mmol) and phenylethanamines 7
(1.1 mmol) were mixed and stirred at 180 ꢀC for 4 h under nitrogen
atmosphere. The mixture was cooled down and dissolved in
CH2Cl2 (20 mL). Then the solution was washed with 1 M HCl
(20 mL), saturated aqueous NaHCO3 (30 mL), brine (20 mL) and
dried over Na2SO4. The solvent was removed in vacuo to get the
crude product, which was recrystallized form methanol to get
a white solid.
6.1.1. Nitroalkenes (6a–b)
The title compounds were prepared according to literature
procedures [19] from appropriate veratraldehyde and isovanillin in
95–97% yield as yellow solids. 6a, mp: 137–140 ꢀC (lit [24]. mp:
142–144 ꢀC). 6b, mp: 114–117 ꢀC (lit [25] mp: 115–115.5 ꢀC).
6.1.4.1. N-(3,4-Dimethoxyphenethyl)-2-(3,4,5-trimethoxyphenyl)
acetamide (8a). Yield 54%; Mp 103–105 ꢀC; 1H NMR (CDCl3,
6.1.2. Phenylethanamines (7a–b)
400 MHz)
d
2.73 (t, 2H, J ¼ 7.2 Hz, –CH2CH2N–), 3.41–3.46 (m, 4H,
To the stirred suspension of NaBH4 (1.44 g, 30.7 mmol) in dry
THF (50 mL) at 0 ꢀC, was injected boron trifluoride diethyl etherate
(6 mL, 47.3 mmol), and a solution of nitroalkene 6 (8 mmol) in THF
(20 mL) subsequently. Ice bath was then removed and the mixture
was heated to 80 ꢀC, stirred for 4 h, cooled down and ice water
(30 mL) was added, followed by the addition of conc. HCl (8 ml).
The mixture was then refluxed for another 1 h, cooled down and
THF was evaporated under reduced pressure. The remaining
residue was washed with ether (20 mL) and the pH value was
adjusted to 12 by NaHCO3. After extraction with ether (3 ꢂ 20 mL),
the ether layer was combined and dried over Na2SO4. Evaporation
of the solvent under reduced pressure yielded the amines as pale
yellow oils.
–CH2CH2N–, –CH2CO–), 3.80 (d, 9H, N–Ph–3-OCH3, 2-Ph–3-OCH3,
2-Ph–5-OCH3), 3.84 (s, 3H, N–Ph–4-OCH3), 3.89 (s, 3H, 2–Ph–4-
OCH3), 5.42 (s, 1H, –NHCO–), 6.53 (dd, 1H, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz,
N–Ph–6-Ar–H), 6.61 (d, 1H, 4J ¼ 2.0 Hz, N–Ph–2-Ar–H), 6.36 (s, 2H,
2–Ph–2-Ar–H, 2–Ph–6-Ar–H), 6.83 (s, 1H, N–Ph–5-Ar–H).
6.1.4.2. N-(3-Isopropoxy-4-methoxyphenethyl)-2-(3,4,5-trimethox-
yphenyl) acetamide (8b). Yield 44%; Mp 104–109 ꢀC; 1H NMR
(CDCl3, 400 MHz)
d
1.37 (d, 6H, J ¼ 6.0 Hz, N–Ph–3-OCH(CH3)2),
2.73 (t, 2H, J ¼ 7.2 Hz, –CH2CH2N–), 3.41–3.46 (m, 4H, –CH2CH2N–,
–CH2CO–), 3.80 (d, 6H, 2-Ph–3-OCH3, 2-Ph–5-OCH3), 3.84 (s, 3H,
N–Ph–4-OCH3), 3.89 (s, 3H, 2-Ph–4-OCH3), 4.52 (m, 1H, N–Ph–3-
OCH(CH3)2), 5.42 (s, 1H, –NHCO–), 6.53 (dd, 1H, 3J ¼ 8.0 Hz,
4J ¼ 2.0 Hz, N–Ph–6-Ar–H), 6.61 (d, 1H, 4J ¼ 2.0 Hz, N–Ph–2-Ar–H),
6.36 (s, 2H, 2–Ph–2-Ar–H, 2–Ph–6-Ar–H), 6.83 (s, 1H, N–Ph–5-
Ar–H).
6.1.2.1. 2-(3,4-Dimethoxyphenyl)ethanamine(7a). Yield 86%; 1H
NMR (CDCl3, 400 MHz)
d
2.87 (t, 2H, J ¼ 7.6 Hz, –CH2CH2NH2), 3.08
(t, 2H, J ¼ 7.6 Hz, –CH2CH2NH2), 3.84 (s, 3H, 4-OCH3), 3.86 (s, 3H,
3-OCH3), 4.88 (s, 2H, –CH2CH2NH2).
6.1.4.3. 2-(4-Isopropoxy-3-methoxyphenyl)-N-(3-isopropoxy-4-
methoxyphenethyl) acetamide (8c). Yield 64%; Mp 77–80 ꢀC; 1H
6.1.2.2. 2-(3-Isopropoxy-4-methoxyphenyl)ethanamine (7b). Yield
54%; 1H NMR (CDCl3, 400 MHz)
d
1.28 (d, 6H, J ¼ 6.0 Hz,
NMR (CDCl3, 400 MHz)
d
1.31 (d, 6H, J ¼ 6.0 Hz, 2-Ph–4-
OCH(CH3)2), 1.33 (d, 6H, J ¼ 6.0 Hz, N–Ph–3-OCH(CH3)2), 2.63 (t, 2H,
J ¼ 7.2 Hz, –CH2CH2N–), 3.38–3.44 (m, 4H, –CH2CH2N–, –CH2CO–),
3.77 (s, 3H, 2-Ph–3-OCH3), 3.80 (s, 3H, N–Ph–4-OCH3), 4.42–4.51
3-OCH(CH3)2), 2.82 (t, 2H, J ¼ 7.6 Hz, –CH2CH2NH2), 2.98 (t, 2H,
J ¼ 7.6 Hz, –CH2CH2NH2), 3.83 (s, 3H, 4-OCH3), 4.43 (m, 1H,
3-OCH(CH3)2), 4.78 (s, 2H, –CH2CH2NH2).

L. Shen et al. / European Journal of Medicinal Chemistry 45 (2010) 11–18
15
4
(m, 2H, 2-Ph–4-OCH(CH3)2, N–Ph–3-OCH(CH3)2), 5.51 (s, 1H,
–NHCO–), 6.51 (dd, 1H, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, N–Ph–6-Ar–H),
6.64–6.71 (m, 4H, Ar–H), 6.81 (d, 1H, J ¼ 7.2 Hz, N–Ph–2-Ar–H).
60-Ar–H), 7.11 (s, 1H, 8-Ar–H), 7.20 (d,1H, J ¼ 2 Hz, 20 -Ar–H), 7.61
(s, 1H, 5-Ar–H), 13.59 (s, 1H, Hþ).
6.1.5.5. 6,7-Dimethoxy-1-(4-methoxybenzyl)-3,4-dihydroisoquino-
6.1.4.4. N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl) acet-
line hydrochloride (9e). Yield 98%; Mp 133–138 ꢀC; 1H NMR
amide(8d). Yield 54%; Mp 120–124 ꢀC; 1H NMR (CDCl3, 400 MHz)
(DMSO-d6, 400 MHz)
d
2.98 (t, 2H, J ¼ 8.0 Hz, –CH2CH2N–), 3.69
d
2.67 (t, 2H, J ¼ 7.2 Hz, –CH2CH2N–), 3.42–3.47 (m, 4H, –CH2CH2N–,
(s, 3H, 7-OCH3), 3.72 (s, 3H, 6-OCH3), 3.83 (t, 2H, J ¼ 8.0 Hz,
–CH2CO–), 3.82 (s, 6H, N–Ph–3-OCH3, 2-Ph–3-OCH3), 3.85 (s, 3H,
N–Ph–4-OCH3), 3.87 (s, 3H, 2-Ph–4-OCH3), 5.42 (s, 1H, –NHCO–),
6.52 (dd, 1H, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, N–Ph–6-Ar–H), 6.61 (d, 1H,
4J ¼ 2.0 Hz, N–Ph–2-Ar–H), 6.66–6.71 (m, 3H, N–Ph–5-Ar–H, 2-Ph–
–CH2CH2N–), 3.87 (s, 3H, 40-OCH3), 4.52 (s, 2H, 1-Ph–CH2–), 6.90
(dd, 2H, 3J ¼ 6.0 Hz, J ¼ 2.0 Hz, 30-Ar–H, 50-Ar–H), 7.06 (dd, 2H,
4
3J ¼ 6.0 Hz, J ¼ 2.0 Hz, 20-Ar–H, 60-Ar–H), 7.12 (s, 1H, 8-Ar–H), 7.58
4
(s, 1H, 5-Ar–H), 13.75 (s, 1H, Hþ).
3
2-Ar–H, 2-Ph–6-Ar–H), 6.80 (d, 1H, J ¼ 8.0 Hz, 2-Ph–5-Ar–H).
6.1.6. Phenacyl bromides (10a–l)
6.1.4.5. N-(3,4-Dimethoxyphenethyl)-2-(4-methoxyphenyl)
acet-
The title compounds 10 were prepared form appropriate
commercial acetophenones by bromination according to literature
procedurses [17] in 45–90% yield.
amide (8e). Yield 70%; Mp 125–127 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
2.66 (t, 2H, J ¼ 7.2 Hz, –CH2CH2N–), 3.41–3.47 (m, 4H, –CH2CH2N–,
–CH2CO–), 3.82 (s, 3H, N–Ph–3-OCH3), 3.86 (s, 3H, N–Ph–4-OCH3),
3.88 (s, 3H, 2-Ph–4-OCH3), 5.42 (s, 1H, –NHCO–), 6.52 (dd, 1H,
3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, N–Ph–6-Ar–H), 6.64 (d, 1H, 4J ¼ 2.0 Hz,
N–Ph–2-Ar–H), 6.72 (d, 1H, 3J ¼ 8.0 Hz, N–Ph–5-Ar–H), 6.83(dd, 2H,
3J ¼ 6.0 Hz, 4J ¼ 2.0 Hz, 2-Ph–3-Ar–H, 2-Ph–5-Ar–H), 6.97 (dd, 2H,
6.1.7. Dihydropyrrolo [2,1-a] isoquinolines (11a–w)
Phenacyl bromides 10 (25 mmol) and NaHCO3 (100 mmol) was
added in portion to a solution of dihydroisoquinoline hydrochloride
9 (25 mmol) in anhydrous acetonitrile (15 mL) at room tempera-
ture. The mixture was stirred under refluxing for 8 h. The solvent
was removed in vacuo. The residue was dissolved in EtOAc (40 mL),
washed with brine (20 mL) and dried over Na2SO4. The solvent was
evaporated to obtain a residue, which was purified by silica gel
column chromatography (petroleum ether/EtOAc 1:1, with 1% of
methanol), gave pure compounds 11.
3J ¼ 6.0 Hz, J ¼ 2.0 Hz, 2-Ph–2-Ar–H, 2-Ph–6-Ar–H).
4
6.1.5. Dihydroisoquinoline hydrochlorides (9a–e)
POCl3 (2.8 mL, 30 mmol) was added slowly to a solution of
ethanamide 8 (3 mmol) in dry toluene (15 mL) at room tempera-
ture. The mixture was heated to 80 ꢀC and stirred for 4 h at that
temperature, then cooled down and cold petroleum ether (20 mL)
was added without stirring. The suspension was cooled in ice-bath
for 2 h, the supernatant liquid was decanted and the remaining
crude product was recrystallized from ether to obtain a white solid.
6.1.7.1. 4-(8,9-Dimethoxy-1-(3,4,5-trimethoxyphenyl)-5,6-dihy-
dropyrrolo[2,1-a]isoquinoline-2-yl)benzene-1,2-diol
(11a). Yield
50%; Mp 133–137 ꢀC; IR (KBr): 3566, 3525, 2955, 2931, 2855, 1602,
1582, 1558, 1541, 1508, 1489, 1465, 1457, 1437, 1212, 1120, 864, 845;
6.1.5.1. 6,7-Dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihy-
1H NMR (CD3COCD3, 400 MHz)
d
3.03 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–
droisoquinoline hydrochloride (9a). Yield 93%; Mp 108–113 ꢀC; 1H
), 3.34 (s, 3H, 9-OCH3), 3.71 (s, 6H, 13-OCH3, 15-OCH3), 3.74 (s, 3H,
14-OCH3), 3.76 (s, 3H, 8-OCH3), 4.10 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–),
6.55 (dd, 2H, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, 18-Ar–H, 10-Ar–H), 6.63 (d, 1H,
J ¼ 8.0 Hz, 19-Ar–H), 6.65 (s, 2H, 12-Ar–H, 16-Ar–H), 6.73 (d, 1H,
J ¼ 2.0 Hz, 22-Ar–H), 6.83 (s, 1H, 7-Ar–H), 6.88 (s, 1H, 3-H); 13C NMR
NMR (DMSO-d6, 400 MHz)
d
2.96 (t, 2H, J ¼ 8.0 Hz, –CH2CH2N–),
3.71 (s, 3H, 7-OCH3), 3.75 (s, 3H, 6-OCH3), 3.82 (s, 6H, 30-OCH3, 50-
OCH3), 3.86 (t, 2H, –CH2CH2N–), 3.87 (s, 3H, 40-OCH3), 4.47 (s, 2H,
1-Ph–CH2–), 6.87 (s, 1H, 60-Ar–H), 7.11 (s, 1H, 8-Ar–H), 7.20 (s, 1H,
20-Ar–H), 7.61 (s, 1H, 5-Ar–H), 12.97 (s, 1H, Hþ).
(CD3COCD3, 100 MHz)
d 44.28, 54.38, 55.23, 55.58, 59.80, 77.89,
78.16, 78.42, 107.44, 108.43, 111.94, 114.88, 114.90, 117.76, 118.68,
119.21, 122.27, 123.87, 124.36, 125.88, 128.05, 133.15, 137.04, 142.95,
144.47, 147.14, 147.65,153.55; Anal. Calcd for C29H29NO7: C, 69.17; H,
5.80; N, 2.78; O, 22.24; Found C, 69.09; H, 5.73; N, 2.71%. MS (ESI):
m/e 504 (Mþ).
6.1.5.2. 6-Isopropoxy-7-methoxy-1-(3,4,5-trimethoxybenzyl)-3,4-
dihydroisoquinoline hydrochloride (9b). Yield 96%; Mp 95–102 ꢀC;
1H NMR (CDCl3, 400 MHz)
d
1.37 (d, 6H, J ¼ 6.0 Hz, 6-OCH(CH3)2),
3.04 (t, 2H, J ¼ 6 Hz, –CH2CH2N–), 3.38 (s, 3H, 40-OCH3), 3.71 (s, 6H,
30-OCH3, 50-OCH3), 3.86 (s, 3H, 7-OCH3), 4.11 (t, 2H, J ¼ 6.0 Hz,
–CH2CH2N–), 4.52 (m, 1H, 6-OCH(CH3)2), 4.46 (s, 2H, 1-Ph–CH2–),
6.75 (s, 1H, 60-Ar–H), 7.08 (s, 1H, 8-Ar–H), 7.18 (s, 1H, 20-Ar–H), 7.61
(s, 1H, 5-Ar–H), 13.27 (s, 1H, Hþ).
6.1.7.2. 4-(8-Isopropoxy-9-methoxy-1-(3,4,5-trimethoxyphenyl)-5,6-
dihydropyrrolo[2,1-a]isoquinoline-2-yl)benzene-1,2-diol (11b). Yield
32%; Mp 141–144 ꢀC; IR (KBr): 3630, 3518, 2933, 2833, 1601, 1544,
1535, 1438, 1411, 1257, 1211, 1116; 1H NMR (CD3COCD3, 400 MHz)
6.1.5.3. 6-Isopropoxy-1-(4-isopropoxy-3-methoxybenzyl)-7-
d
1.19 (d, 6H, J ¼ 6.0 Hz, 8-OCH(CH3)2), 2.95 (t, 2H, J ¼ 6.4 Hz,
methoxy-3,4-dihydroisoquinoline hydrochloride (9c). Yield 97%; 1H
–CH2CH2N–), 3.29 (s, 3H, 9-OCH3), 3.67 (s, 6H, 13-OCH3, 15-OCH3),
3.72 (s, 3H, 14-OCH3), 4.05 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 4.43 (m,
1H, 8-OCH(CH3)2), 6.53 (s, 2H, 12-Ar–H, 16-Ar–H), 6.55 (s, 1H,
10-Ar–H), 6.56 (d, 1H, J ¼ 8.0 Hz, 18-Ar–H), 6.60 (d, 1H, J ¼ 8.0 Hz,
19-Ar–H), 6.69 (d,1H, J ¼ 1.2 Hz, 22-Ar–H), 6.77 (s,1H, 7-Ar–H), 6.84
(s,1H, 3-H), 7.52 (s,1H, 20-Ph–OH), 7.64 (s, 1H,19-Ph–OH); 13C NMR
NMR (DMSO-d6, 400 MHz)
d
1.21 (d, 6H, J ¼ 6.0 Hz, 6-OCH(CH3)2),
1.26 (d, 6H, J ¼ 6.0 Hz, 40-OCH(CH3)2), 2.96 (t, 2H, J ¼ 6.4 Hz,
–CH2CH2N–), 3.26 (s, 3H, 7-OCH3), 3.65 (s, 3H, 50-OCH3), 4.09 (t, 2H,
J ¼ 6.4 Hz, –CH2CH2N–), 4.41 (m, 1H, 6-OCH(CH3)2), 4.51 (m, 1H,
40-OCH(CH3)2), 6.53 (s, 1H, 8-Ar–H), 6.67 (d, J ¼ 1.6 Hz, 20-Ar–H),
3
4
6.75 (dd, 1H, J ¼ 8.0 Hz, J ¼ 1.2 Hz, 60-Ar–H), 6.94 (d, 1H, J ¼ 8 Hz,
(CD3COCD3, 100 MHz) d 21.60, 44.28, 54.35, 55.56, 59.71, 71.01,
50-Ar–H), 13.27 (s, 1H, Hþ).
107.86, 108.43, 114.80, 114.85, 116.65, 117.80, 118.82, 119.15, 122.94,
123.92, 124.42, 125.88,128.07,133.20, 137.09,142.96,144.48,145.04,
149.12, 153.60; Anal. Calcd for C31H33NO7: C, 70.04; H, 6.26; N, 2.63;
O, 21.07; Found C, 70.12; H, 6.20; N, 2.59%. MS (ESI): m/e 532 (Mþ).
6.1.5.4. 1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-3,4-dihy-
droisoquinoline hydrochloride (9d). Yield 96%; Mp 106–115 ꢀC; 1H
NMR (DMSO-d6, 400 MHz)
d
2.98 (t, 2H, J ¼ 8.0 Hz, –CH2CH2N–),
3.69 (s, 3H, 7-OCH3), 3.73 (s, 3H, 6-OCH3), 3.81 (s, 3H, 30-OCH3), 3.83
(t, 2H, –CH2CH2N–), 3.87 (s, 3H, 40-OCH3), 4.52 (s, 2H, 1-Ph–CH2–),
6.90 (d, 1H, 3J ¼ 8.4 Hz, 50-Ar–H), 6.96 (dd, 1H, 3J ¼ 8.4 Hz, 4J ¼ 2 Hz,
6.1.7.3. 4-(8-Isopropoxy-1-(4-isopropoxy-3-methoxyphenyl)-9-
methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-yl)benzene-1,2-
diol (11c). Yield 32%; Mp 137 ꢀC (dec.); IR (KBr): 3463, 3322, 2926,

16
L. Shen et al. / European Journal of Medicinal Chemistry 45 (2010) 11–18
2854, 1687, 1602, 1524, 1509, 1268, 1173, 1133, 816, 182, 746, 611; 1H
NMR (CD3COCD3, 400 MHz)
1.18 (d, 6H, J ¼ 6.0 Hz, 8-OCH(CH3)2),
400 MHz)
d
3.06 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 3.41 (s, 3H,
d
9-OCH3), 3.71 (s, 6H, 13-OCH3, 15-OCH3), 3.86 (s, 3H, 8-OCH3), 3.87
(s, 3H, 14-OCH3), 4.11 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 6.56 (s, 2H,
12-Ar–H, 16-Ar–H), 6.62 (s, 1H, 7-Ar–H), 6.70 (s, 1H, 10-Ar–H), 6.87
(s, 1H, 3-H), 7.08 (d, 2H, J ¼ 8.4 Hz, 18-Ar–H, 22-Ar–H), 7.33 (d, 2H,
1.24 (s, 3H, 14-OCH(CH3)2), 1.26 (s, 3H, 14-OCH(CH3)2), 2.95 (t, 2H,
J ¼ 6.0 Hz, –CH2CH2N–), 3.26 (s, 3H, 9-OCH3), 3.65 (s, 3H, 13-OCH3),
4.08 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 4.42 (m, 1H, 8-OCH(CH3)2), 4.50
(m, 1H, 14-OCH(CH3)2), 6.52 (dd, 1H, 3J ¼ 8.4 Hz, 4J ¼ 2.0 Hz, 18-Ar–
H), 6.55 (s, 1H, 10-Ar–H), 6.58 (d, 1H, J ¼ 8.0 Hz, 19-Ar–H), 6.66
(d, 1H, J ¼ 1.6 Hz, 12-Ar–H), 6.76 (dd, 1H, 3J ¼ 8.0 Hz, 4J ¼ 1.2 Hz,
16-Ar–H), 6.77 (s, 1H, 22-Ar–H), 6.81 (s, 1H, 3-H), 6.83 (s, 1H, 7-Ar–
H), 6.94 (d, 1H, J ¼ 8.0 Hz,), 7.51 (s, 1H, 21-Ph–OH), 7.57 (s, 1H,
J ¼ 8.4 Hz, 19-Ar–H, 21-Ar–H); 13C NMR (CDCl3, 100 MHz)
d 29.39,
44.79, 55.18, 55.89, 56.15, 60.97, 107.34, 107.88, 111.03, 118.21,
118.63, 119.16, 121.81, 122.84, 124.04, 126.65, 129.20, 131.18, 132.06,
134.37, 136.69, 146.96, 147.35, 153.38; Anal. Calcd for C29H28BrNO5:
C, 63.28; H, 5.13; Br, 14.52; N, 2.54; O, 14.53; Found C, 63.25; H, 5.15;
N, 2.51%. MS (ESI): m/e 550 (Mþ).
20-Ph–OH); 13C NMR (CD3COCD3, 100 MHz)
d 21.56, 44.28, 46.16,
54.23, 55.30, 70.47, 107.89, 112.18, 114.80, 114.98, 115.11, 115.62,
115.70, 116.64, 116.81, 117.82, 118.59, 119.23, 121.94, 122.27, 122.63,
123.11, 123.32, 124.01, 124.31, 125.90, 127.10, 128.26, 130.93, 145.10,
150.87, 189.23; Anal. Calcd for C32H35NO6: C, 72.57; H, 6.66; N, 2.64;
O, 18.13; Found C, 72.68; H, 6.57; N, 2.67%. MS (ESI): m/e 531 (Mþ).
6.1.7.8. 2-(4-Bromophenyl)-8-isopropoxy-9-methoxy-1-(3,4,5-trime-
thoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (11h). Yield
56%; Mp 89–92 ꢀC; IR (KBr): 2973, 2934, 2833, 1738, 1703, 1655,
1580, 1490, 1410, 1231, 1126, 1008, 831, 780, 760, 627, 650; 1H
NMR (CDCl3, 400 MHz)
d
1.35 (d, 6H, J ¼ 6.0 Hz, 8-OCH(CH3)2),
6.1.7.4. 4-(1-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-5,6-dihy-
3.04 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 3.38 (s, 3H, 9-OCH3), 3.71 (s,
6H, 13-OCH3, 15-OCH3), 3.86 (s, 3H, 14-OCH3), 4.11 (t, 2H,
J ¼ 6.0 Hz, –CH2CH2N–), 4.49 (m, 1H, 8-OCH(CH3)2), 6.56 (s, 2H,
12-Ar–H, 16-Ar–H), 6.63 (s, 1H, 7-Ar–H), 6.71 (s, 1H, 10-Ar–H),
6.86 (s, 1H, 3-H), 7.08 (d, 2H, J ¼ 8.8 Hz, 18-Ar–H, 22-Ar–H), 7.32
(d, 2H, J ¼ 8.8 Hz, 19-Ar–H, 21-Ar–H); Anal. Calcd for
C31H32BrNO5: C, 64.36; H, 5.58; Br, 13.81; N, 2.42; O, 13.83; Found
C, 64.40; H, 5.59; N, 2.41%. MS (ESI): m/e 578 (Mþ).
dropyrrolo[2,1-a]isoquinoline-2-yl)benzene-1,2-diol
(11d). Yield
33%; Mp 229–238 ꢀC; IR (KBr): 2975, 2933, 2834, 1536, 1507, 1255,
1228, 1173, 1136, 1111, 1035, 955, 865, 471; 1H NMR (CDCl3,
400 MHz)
d
3.05 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 3.37 (s, 3H, 9-
OCH3), 3.72 (s, 3H, 13-OCH3), 3.86 (s, 3H, 8-OCH3), 3.89 (s, 3H, 14-
OCH3), 4.08 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 4.98 (s, 1H, 20-Ph–OH),
5.00 (s, 1H, 21-Ph–OH), 6.62 (s, 1H, 10-Ar–H), 6.65 (dd, 1H,
3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, 19-Ar–H), 6.69 (s, 2H, 7-Ar–H, 12-Ar–H), 6.72
(d, 1H, J ¼ 8.0 Hz, 15-Ar–H), 6.78 (s, 1H, 7-Ar–H), 6.86–6.87 (m, 2H,
16-Ar–H, 22-Ar–H), 6.88 (s, 1H, 3-H), 6.90 (d, 1H, 3J ¼ 8.0 Hz,
6.1.7.9. 4-(8,9-Dimethoxy-1-(3,4,5-trimethoxyphenyl)-5,6-dihy-
dropyrrolo[2,1-a]isoquinoline-2-yl)phenol (11i). Yield 62%; Mp 136–
138 ꢀC; IR (KBr): 3560, 3502, 2998, 2959, 2934, 2835, 1602, 1581,
1505, 1406, 1268, 1233, 1214, 1121, 845, 796; 1H NMR (CDCl3,
4J ¼ 2.0 Hz, 18-Ar–H). 13C NMR (CD3COCD3, 100 MHz)
d 21.53, 44.22,
54.32, 55.52, 59.65, 71.02, 107.88, 108.47, 114.79, 116.71, 117.74,
118.76, 119.13, 122.91, 123.83, 124.28, 125.83, 128.07, 133.12, 136.16,
137.11, 142.90, 144.42, 145.02, 149.12, 153.54, 232.19, 250.10; Anal.
Calcd for C28H27NO6: C, 71.02; H, 5.75; N, 2.96; O, 20.27; Found C,
71.10; H, 5.72; N, 2.98%. MS (ESI): m/e 474 (Mþ).
400 MHz)
d
3.06 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 3.42 (s, 3H,
9-OCH3), 3.69 (s, 6H, 13-OCH3, 15-OCH3), 3.85 (s, 3H, 8-OCH3), 3.86
(s, 3H, 14-OCH3), 4.09 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 4.87 (s, 1H,
20-Ph–OH), 6.57 (s, 2H, 12-Ar–H, 16-Ar–H), 6.66 (s, 1H, 10-Ar–H),
6.68 (d, 2H, J ¼ 8.8 Hz, 19-Ar–H, 21-Ar–H), 6.69 (s, 1H, 7-Ar–H), 6.80
(s, 1H, 3-H), 7.06 (d, 2H, J ¼ 8.8 Hz, 18-Ar–H, 22-Ar–H); 13C NMR
6.1.7.5. 2-(4-Chlorophenyl)-8,9-dimethoxy-1-(3,4,5-trimethox-
yphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (11e). Yield 70%; Mp
167–169 ꢀC; IR (KBr): 2994, 2937, 2836, 1580, 1509, 1492, 1465,
(CD3Cl3, 100 MHz)
d 29.46, 44.68, 55.17, 55.88, 56.10, 60.95, 107.37,
108.03, 111.07, 115.03, 117.75, 118.61, 122.09, 123.82, 124.07, 126.18,
127.83, 129.08, 132.52, 136.36, 146.77, 147.26, 153.17, 153.76; Anal.
Calcd for C29H29NO6: C, 71.44; H, 6.00; N, 2.87; O, 19.69; Found C,
71.49; H, 5.98; N, 2.85%. MS (ESI): m/e 488 (Mþ).
1408, 1275, 1216, 1124, 1007, 841; 1H NMR (CDCl3, 400 MHz)
d 3.06
(t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 3.41 (s, 3H, 9-OCH3), 3.71 (s, 6H,
13-OCH3, 15-OCH3), 3.86 (s, 3H, 8-OCH3,), 3.87 (s, 3H, 14-OCH3), 4.11
(t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 6.56 (s, 2H, 12-Ar–H, 16-Ar–H), 6.62
(s, 1H, 7-Ar–H), 6.70 (s, 1H, 10-Ar–H), 6.87 (s, 1H, 3-H), 7.13 (d, 2H,
J ¼ 8.4 Hz, 18-Ar–H, 22-Ar–H), 7.18 (d, 2H, J ¼ 8.4 Hz, 19-Ar–H,
21-Ar–H); Anal. Calcd for C29H28ClNO5: C, 68.84; H, 5.58; Cl, 7.01; N,
2.77; O, 15.81; Found C, 68.83; H, 5.60; N, 7.02%. MS (ESI): m/e 507
(Mþ).
6.1.7.10. 4-(8-Isopropoxy-9-methoxy-1-(3,4,5-trimethoxyphenyl)-
5,6-dihydropyrrolo[2,1-a]isoquinoline-2-yl)phenol (11j). Yield 58%;
Mp 147–150 ꢀC; IR (KBr): 3563, 3504, 3442, 2974, 2935, 2867, 2833,
1737, 1702, 1504, 1407, 1268, 1229, 1212, 1118, 993, 798, 775, 561; 1H
NMR (CDCl3, 400 MHz)
d
1.34 (d, 6H, J ¼ 6.0 Hz, 8-OCH(CH3)2), 3.03
(t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 3.38 (s, 3H, 9-OCH3), 3.69 (s, 6H,
13-OCH3, 15-OCH3), 3.85 (s, 3H, 14-OCH3), 4.08 (t, 2H, J ¼ 6.4 Hz,
–CH2CH2N–), 4.49 (m, 1H, 8-OCH(CH3)2), 6.57 (s, 2H, 12-Ar–H,
16-Ar–H), 6.66 (s, 1H, 10-Ar–H), 6.67 (d, 2H, J ¼ 8.8 Hz, 19-Ar–H,
21-Ar–H), 6.71 (s, 1H, 7-Ar–H), 6.79 (s, 1H, 3-H), 7.05 (d, 2H,
J ¼ 8.8 Hz, 18-Ar–H, 22-Ar–H); Anal. Calcd for C31H33NO6: C, 72.21;
H, 6.45; N, 2.72; O,18.62; Found C, 72.19; H, 6.46; N, 2.71%. MS (ESI):
m/e 516 (Mþ).
6.1.7.6. 2-(4-Chlorophenyl)-8-isopropoxy-9-methoxy-1-(3,4,5-trime-
thoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (11f). Yield 64%;
Mp 160–163 ꢀC; IR (KBr): 2975, 2934, 2835, 1580, 1491, 1407, 1231,
1135, 857, 829; 1H NMR (CDCl3, 400 MHz)
d
1.35 (d, 6H, J ¼ 6.0 Hz,
8-OCH(CH3)2), 3.04 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 3.38 (s, 3H, 9-
OCH3), 3.71 (s, 6H, 13-OCH3, 15-OCH3), 3.86 (s, 3H, 14-OCH3), 4.11 (t,
2H, J ¼ 6.0 Hz, –CH2CH2N–), 4.49 (m, 1H, 8-OCH(CH3)2), 6.56 (s, 2H,
12-Ar–H, 16-Ar–H), 6.63 (s, 1H, 7-Ar–H), 6.71 (s, 1H, 10-Ar–H), 6.86
(s, 1H, 3-H), 7.13 (d, 2H, J ¼ 8.8 Hz, 18-Ar–H, 22-Ar–H), 7.19 (d, 2H,
J ¼ 8.8 Hz, 19-Ar–H, 21-Ar–H); Anal. Calcd for C31H32ClNO5: C,
69.72; H, 6.04; Cl, 6.64; N, 2.62; O, 14.98; Found C, 69.71; H, 6.02; N,
2.62%. MS (ESI): m/e 534 (Mþ).
6.1.7.11. 4-(8,9-Dimethoxy-1-(4-methoxyphenyl)-5,6-dihy-
dropyrrolo[2,1-a]isoquinoline-2-yl)phenol (11k). Yield 26%; Mp
225–228 ꢀC; IR (KBr): 3457, 3006, 2936, 2836, 1611, 1543, 1503,
1467, 1258, 1245, 1213, 1123, 1032, 865, 835, 818, 794, 759; 1H NMR
(CDCl3, 400 MHz)
d
3.05 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 3.38 (s, 3H,
6.1.7.7. 2-(4-Bromophenyl)-8,9-dimethoxy-1-(3,4,5-trimethox-
yphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (11g). Yield 47%; Mp
173–176 ꢀC; IR (KBr): 2994, 2933, 2854, 2836, 1562, 1509, 1491,
1465, 1407, 1275, 1231, 1216, 1123, 1005, 855, 842; 1H NMR (CDCl3,
9-OCH3), 3.84 (s, 3H, 8-OCH3), 3.86 (s, 3H, 14-OCH3), 4.09 (t, 2H,
J ¼ 6 Hz, –CH2CH2N–), 4.61 (s, 1H, 20-Ph–OH), 6.58 (s, 1H, 10-Ar–H),
6.66 (d, 2H, J ¼ 8.0 Hz, 19-Ar–H, 21-Ar–H), 6.69 (s, 1H, 7-Ar–H), 6.79
(s, 1H, 3-H), 6.89 (d, 2H, J ¼ 8.8 Hz, 13-Ar–H, 15-Ar–H), 7.02 (d, 2H,

L. Shen et al. / European Journal of Medicinal Chemistry 45 (2010) 11–18
17
J ¼ 8.8 Hz, 18-Ar–H, 22-Ar–H), 7.24 (d, 2H, J ¼ 8.0 Hz, 12-Ar–H,
16-Ar–H); Anal. Calcd for C27H25NO4: C, 75.86; H, 5.89; N, 3.28; O,
14.97; Found C, 75.83; H, 5.90; N, 3.29%. MS (ESI): m/e 428 (Mþ).
8-OCH(CH3)2), 3.05 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 3.38 (s, 3H,
9-OCH3), 3.65 (s, 6H, 13-OCH3, 15-OCH3), 3.80 (s, 3H, 14-OCH3), 3.84
(s, 3H, 20-OCH3), 4.10 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 4.47 (m, 1H,
8-OCH(CH3)2), 6.51 (m, 2H, 10-Ar–H, 22-Ar–H), 6.58 (m, 1H, 18-Ar–
H), 6.68 (s, 2H, 12-Ar–H, 16-Ar–H), 6.72 (d, 1H, J ¼ 8.0 Hz, 19-Ar–H),
6.75 (s, 1H, 7-Ar–H), 6.79 (s, 1H, 3-H); Anal. Calcd for C32H35NO7: C,
70.44; H, 6.47; N, 2.57; O, 20.53; Found C, 70.51; H, 6.42; N, 2.59%.
MS (ESI): m/e 546 (Mþ).
6.1.7.12. 2-(3-Isopropoxy-4-methoxyphenyl)-8,9-dimethoxy-1-
(3,4,5-trimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline
(11l). Yield 54%; Mp 69–74 ꢀC; IR (KBr): 2971, 2935, 2833, 1603,
1579, 1508, 1464, 1408, 1261, 1232, 1124, 1030, 1009, 973, 844, 811,
795, 771; 1H NMR (CDCl3, 400 MHz)
d
1.18 (d, 6H, J ¼ 6.0 Hz,
21-OCH(CH3)2), 3.06 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 3.41 (s, 3H,
9-OCH3), 3.72 (s, 6H, 13-OCH3, 15-OCH3), 3.83 (s, 6H, 14-OCH3,
20-OCH3), 3.87 (s, 3H, 8-OCH3), 4.11 (m, 1H, 21-OCH(CH3)2), 4.12
(t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 6.62 (s, 2H, 12-Ar–H, 16-Ar–H), 6.63
(s, 1H, 10-Ar–H), 6.69 (s, 1H, 7-Ar–H), 6.70 (d, 1H, 4J ¼ 2.0 Hz, 22-Ar–
H), 6.79 (d, 1H, 3J ¼ 8.0 Hz, 19-Ar–H), 6.83 (s, 1H, 3-H), 6.89 (dd, 1H,
3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, 18-Ar–H); 13C NMR (CD3Cl3, 100 MHz)
6.1.7.16. 5-(8,9-Dimethoxy-1-(4-methoxyphenyl)-5,6-dihy-
dropyrrolo[2,1-a]isoquinoline-2-yl)-2-methoxyphenol (11p). Yield
19%; Mp 79–81 ꢀC; IR (KBr): 2997, 2935, 2835, 1610, 1509, 1491,
1466, 1274, 1240, 1214, 1174, 1126, 1033, 865, 838, 798; 1H NMR
(CDCl3, 400 MHz)
d
3.07 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 3.39 (s, 3H,
9-OCH3), 3.77 (s, 3H, 8-OCH3), 3.86 (s, 6H, 14-OCH3, 20-OCH3), 4.10
(t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 5.91 (s, 1H, 19-Ph–OH), 6.57 (s, 1H,
10-Ar–H), 6.63 (d, 1H, 4J ¼ 2.0 Hz, 22-Ar–H), 6.68 (m, 2H, 18-Ar–H,
19-Ar–H), 6.77 (s, 1H, 7-Ar–H), 6.18 (dd, 2H, 3J ¼ 8.8 Hz, 4J ¼ 2.0 Hz,
13-Ar–H, 15-Ar–H), 6.90 (s, 1H, 3-H), 7.15 (dd, 2H, 3J ¼ 8.8 Hz,
4J ¼ 2.0 Hz, 12-Ar–H, 16-Ar–H); Anal. Calcd for C28H27NO5: C, 73.51;
H, 5.95; N, 3.06; O, 17.49; Found C, 73.33; H, 5.92; N, 3.11%. MS (ESI):
m/e 458 (Mþ).
d
21.96, 22.08, 29.42, 44.70, 55.17, 55.88, 55.95, 56.14, 56.29, 60.84,
70.77, 107.25, 107.98, 111.05, 111.72, 115.23, 117.66, 118.54, 119.70,
122.05, 123.78, 123.96, 126.32, 128.19, 132.84, 136.48, 146.58,
146.80, 147.31,148.06, 153.38; Anal. Calcd for C33H37NO7: C, 70.82;
H, 6.66; N, 2.50; O, 20.01; Found C, 70.86; H, 6.61; N, 2.49%. MS
(ESI): m/e 560 (Mþ).
6.1.7.13. 8-Isopropoxy-2-(3-isopropoxy-4-methoxyphenyl)-9-
methoxy-1-(3,4,5-trimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a]iso-
quinoline (11m). Yield 50%; Mp 70–73 ꢀC; IR (KBr): 2974, 2932,
2834, 1579, 1551, 1536, 1506, 1408, 1382, 1371, 1262, 1231, 1125,
6.1.7.17. 2-(5-Fluoro-2-methoxyphenyl)-8,9-dimethoxy-1-(3,4,5-tri-
methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (11q). Yield
58%; Mp 75–79 ꢀC; IR (KBr): 2995, 2937, 2833, 1609, 1580, 1493,
1465, 1276, 1237, 1216, 1170, 1125, 1032, 842, 797, 743, 725; 1H NMR
1030, 1008, 960, 849, 772; 1H NMR (CDCl3, 400 MHz)
d
1.19 (d, 6H,
(CDCl3, 400 MHz)
d
3.06 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 3.43 (s, 3H,
J ¼ 6.0 Hz, 19-OCH(CH3)2), 1.36 (s, 3H, 8-OCH(CH3)2), 1.38 (s, 3H,
8-OCH(CH3)2), 3.05 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 3.39 (s, 3H,
9-OCH3), 3.84 (s, 6H, 13-OCH3, 15-OCH3), 3.84 (s, 6H, 14-OCH3,
20-OCH3), 4.13 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 4.15 (m, 1H,
19-OCH(CH3)2), 4.50 (m, 1H, 8-OCH(CH3)2), 6.63 (s, 2H, 12-Ar–H,
16-Ar–H), 6.65 (s, 1H, 10-Ar–H), 6.69 (s, 1H, 7-Ar–H), 6.72 (d, 1H,
4J ¼ 2.0 Hz, 22-Ar–H), 6.80 (d, 1H, 3J ¼ 8.0 Hz, 19-Ar–H), 6.83 (s, 1H,
3-H), 6.90 (dd, 1H, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, 18-Ar–H); 13C NMR
9-OCH3), 3.53 (s, 3H, 18-OCH3), 3.65 (s, 6H, 13-OCH3, 15-OCH3), 3.82
(s, 3H, 8-OCH3), 3.87 (s, 3H, 14-OCH3), 4.11 (t, 2H, J ¼ 6.0 Hz,
–CH2CH2N–), 6.53 (s, 2H, 12-Ar–H, 16-Ar–H), 6.69 (s, 1H, 10-Ar–H),
6.71 (m, 1H, 19-H), 6.78 (s, 1H, 7-Ar–H), 6.81 (m, 2H, 20-Ar–H,
22-Ar–H), 6.93 (s, 1H, 3-H); 13C NMR (CD3Cl3, 100 MHz)
d 29.42,
44.76, 55.27, 55.65, 55.85, 56.06, 60.93, 107.30, 107.64, 111.02, 111.16,
111.24, 112.64, 112.82, 117.69, 117.88, 119.70, 120.23, 122.03, 124.22,
125.70, 126.00, 132.57, 136.32, 146.89, 147.24, 152.87, 152.98, 155.76,
157.64; Anal. Calcd for C30H30FNO6: C, 69.35; H, 5.82; F, 3.66; N,
2.70; O, 18.48; Found C, 69.39; H, 5.79; N, 2.71%. MS (ESI): m/e 520
(Mþ).
(CD3Cl3, 100 MHz)
d 21.97, 22.17, 29.33, 29.72, 44.72, 55.15, 55.94,
56.14, 60.82, 70.77, 71.51, 107.67, 108.01, 111.75, 115.22, 115.60,
117.65, 118.56, 119.66, 122.47, 123.71, 123.84, 126.39, 128.27, 132.95,
136.48, 145.00, 146.88, 148.03, 148.77, 153.37; Anal. Calcd for
C35H41NO7: C, 71.53; H, 7.03; N, 2.38; O, 19.06; Found C, 71.49; H,
7.05; N, 2.39%. MS (ESI): m/e 588 (Mþ).
6.1.7.18. 2-(5-Fluoro-2-methoxyphenyl)-8-isopropoxy-1-(4-iso-
propoxy-3-methoxyphenyl)-9-methoxy-5,6-dihydropyrrolo[2,1-a]iso-
quinoline (11r). Yield 57%; Mp 65–68 ꢀC; IR (KBr): 2975, 2935,
2833, 1737, 1702, 1610, 1509, 1493, 1466, 1261, 1237, 1213, 1172, 1111,
6.1.7.14. 5-(8,9-Dimethoxy-1-(3,4,5-trimethoxyphenyl)-5,6-dihy-
dropyrrolo[2,1-a]isoquinoline-2-yl)-2-methoxyphenol (11n). Yield
19%; Mp 102–105 ꢀC; IR (KBr): 2996, 2937, 2835, 1603, 1580, 1508,
1491, 1465, 1408, 1274, 1234, 1215, 1234, 844, 796; 1H NMR (CDCl3,
1034, 941, 866, 560; 1H NMR (CDCl3, 400 MHz)
d 1.35 (t, 12H,
J ¼ 6.0 Hz, 8-OCH(CH3)2, 14-OCH(CH3)2), 3.03 (t, 2H, J ¼ 6.0 Hz,
–CH2CH2N–), 3.37 (s, 3H, 9-OCH3), 3.53 (s, 3H, 18-OCH3), 3.63 (s, 3H,
13-OCH3), 4.09 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 4.48 (m, 2H,
8-OCH(CH3)2, 14-OCH(CH3)2), 6.68 (m, 1H, 20-Ar–H), 6.70 (s, 1H, 10-
Ar–H), 6.77 (s, 1H, 7-Ar–H), 6.79 (m, 2H, J ¼ 2.0 Hz, 12-Ar–H, 19-Ar–
H), 6.82 (m, 1H, 22-Ar–H), 6.85 (dd, 1H, 3J ¼ 8.4 Hz, 4J ¼ 2.0 Hz,
16-Ar–H), 6.86 (d, 1H, 3J ¼ 8.4 Hz, 15-Ar–H), 6.93 (s, 1H, 3-H);Anal.
Calcd for C33H36FNO5: C, 72.64; H, 6.65; F, 3.48; N, 2.57; O, 14.66;
Found C, 72.60; H, 6.69; N, 2.55%. MS (ESI): m/e 546 (Mþ).
400 MHz)
d
3.08 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 3.42 (s, 3H,
9-OCH3), 3.65 (s, 6H, 13-OCH3, 15-OCH3), 3.80 (s, 3H, 14-OCH3), 3.84
(s, 6H, 8-OCH3, 20-OCH3), 4.11 (t, 2H, J ¼ 6.4 Hz, –CH2CH2N–), 5.45
(s, 1H, 21-Ph–OH), 6.58 (s, 1H, 10-Ar–H), 6.59 (s, 2H, 12-Ar–H,
16-Ar–H), 6.61 (dd,1H, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz,18-Ar–H), 6.66 (d,1H,
3J ¼ 8.0 Hz, 19-Ar–H), 6.73 (s, 1H, 7-Ar–H), 6.79 (s, 1H, 3-H), 6.87
(d, 4J ¼ 2.0 Hz, 22-Ar–H); 13C NMR (CD3Cl3, 100 MHz)
d 29.49, 44.78,
55.22, 55.88, 56.01, 56.14, 56.18, 56.30, 60.87, 60.93, 107.47, 107.66,
109.11, 111.03, 111.73, 119.85, 120.25, 122.11, 122.83, 123.37, 124.06,
125.05, 129.78, 131.86, 136.13, 142.73, 145.34, 146.81.147.24, 152.76;
Anal. Calcd for C30H31NO7: C, 69.62; H, 6.04; N, 2.71; O, 21.64; Found
C, 69.67; H, 6.05; N, 2.70%. MS (ESI): m/e 518 (Mþ).
6.1.7.19. 2-(5-Fluoro-2-methoxyphenyl)-8,9-dimethoxy-1-(4-
methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (11s). Yield
44%; Mp 151–153 ꢀC; IR (KBr): 3002, 2937, 2835, 1737, 1702, 1611,
1553, 1536, 1514, 1492, 1466, 1274, 1244, 1216, 1171, 1128, 1029, 880,
837, 801, 744, 732; 1H NMR (CDCl3, 400 MHz)
d
3.05 (t, 2H, J ¼ 6 Hz,
6.1.7.15. 5-(8-Isopropoxy-9-methoxy-1-(3,4,5-trimethoxyphenyl)-
5,6-dihydropyrrolo[2,1-a]isoquinolin-2-yl)-2-methoxyphenol
(11o). Yield 23%; Mp 147–150 ꢀC; IR (KBr): 2971, 2936, 2835, 1603,
1580, 1552, 1541, 1536, 1508, 1490, 1460, 1409, 1274, 1233, 1213,
–CH2CH2N–), 3.38 (s, 3H, 9-OCH3), 3.56 (s, 3H, 18-OCH3), 3.79 (s, 3H,
8-OCH3), 3.86 (s, 3H, 14-OCH3), 4.09 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–),
4.35 (m, 1H, 18-OCH(CH3)2), 6.64 (s, 1H, 10-Ar–H), 6.68 (s, 1H, 7-Ar–
H), 6.70 (m, 1H, 19-Ar–H), 6.77 (m, 1H, 20-Ar–H), 6.82 (m, 1H,
22-Ar–H), 6.85 (dd, 2H, 3J ¼ 8.4 Hz, 4J ¼ 2.0 Hz, 13-Ar–H, 15-Ar–H),
1124, 1033, 848; 1H NMR(CDCl3, 400 MHz)
d
1.34 (d, 6H, J ¼ 6.0 Hz,

18
L. Shen et al. / European Journal of Medicinal Chemistry 45 (2010) 11–18
4
6.93 (s, 1H, 3-H), 7.20 (dd, 2H, 3J ¼ 8.4 Hz, J ¼ 2.0 Hz, 12-Ar–H, 16-
Ar–H); Anal. Calcd for C28H26FNO4: C, 73.19; H, 5.70; F, 4.13; N, 3.05;
O, 13.93; Found C, 73.22; H, 5.68; N, 3.09%. MS (ESI): m/e 460 (Mþ).
2975, 2934, 2837, 1638, 1610, 1536, 1509, 1485, 1466, 1418, 1400,
1364, 1262, 1240, 1213, 1172, 1133, 1112, 1034, 985, 854; 1H NMR
(CD3COCD3, 400 MHz)
d
1.34 (d, 6H, J ¼ 6.0 Hz, 14-OCH(CH3)2), 1.38
(d, 6H, J ¼ 6.0 Hz, 8-OCH(CH3)2), 2.84 (s, 3H, 18-OSO2CH3), 3.04
(t, 2H, 5-CH2CH2N–), 3.28 (s, 3H, 9-OCH3), 3.37 (s, 3H, 21-OCH3),
3.67 (s, 3H, 13-OCH3), 3.87 (s, 3H, 20-OCH3), 4.12 (t, 2H, J ¼ 6.0 Hz,
–CH2–CH2–N), 4.48 (m, 2H, 14-OCH(CH3)2, 8-OCH(CH3)2), 6.50
(s, 1H, 10-Ar–H), 6.73 (s, 1H, 7-Ar–H), 6.74 (s, 1H, 19-Ar–H), 6.80 (dd,
1H, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, 16-Ar–H), 6.85 (d, 1H, 4J ¼ 2.0 Hz, 12-Ar–
H), 6.87 (d, 1H, 4J ¼ 2.0 Hz, 15-Ar–H), 6.88 (s, 1H, 22-Ar–H), 6.98 (s,
1H, 3-H);Anal. Calcd for C35H41NO9S: C, 64.50; H, 6.34; N, 2.15; O,
22.09; S, 4.92; Found C, 64.39; H, 6.30; N, 2.16%. MS (ESI): m/e 652
(Mþ).
6.1.7.20. 2-(5-Fluoro-2-isopropoxyphenyl)-8,9-dimethoxy-1-(4-
methoxyphenyl)-5,6-dihydropyrrolo[2,1-a] isoquinoline (11t). Yield
52%; Mp 120–122 ꢀC; IR (KBr): 2935, 2834, 1610, 1514, 1490, 1337,
1243, 1170, 1127, 1108, 1034; 1H NMR (CDCl3, 400 MHz)
d 1.19(d, 6H,
J ¼ 6.0 Hz, 18-OCH(CH3)2), 3.05 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 3.38
(s, 3H, 9-OCH3), 3.80 (s, 3H, 8-OCH3), 3.86 (s, 3H, 14-OCH3), 4.09
(t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 4.35 (m, 1H, 18-OCH(CH3)2), 6.60 (s,
1H, 10-Ar–H), 6.69 (s, 1H, 7-Ar–H), 6.74 (m, 1H, 20-Ar–H), 6.78 (m,
1H, 22-Ar–H), 6.89 (dd, 2H, 3J ¼ 8.4 Hz, 4J ¼ 2.0 Hz, 13-Ar–H, 15-Ar–
H), 7.03 (s, 1H, 3-H), 7.23 (dd, 2H, 3J ¼ 8.4 Hz, 4J ¼ 2.0 Hz, 12-Ar–H,
16-Ar–H);13C NMR (CD3Cl3, 100 MHz)
d 21.96, 29.53, 44.77, 55.18,
6.2. Biological procedures
55.33, 55.90, 71.15, 107.44, 111.09, 112.07, 112.25, 113.98, 116.01,
117.71, 117.89, 118.55, 119.37, 121.00, 122.48, 123.98, 125.46, 127.74,
129.17, 132.01, 146.61, 147.26, 151.15, 155.81, 157.70, 158.32; Anal.
Calcd for C30H30FNO4: C, 73.90; H, 6.20; F, 3.90; N, 2.87; O, 13.13;
Found C, 73.92; H, 6.19; N, 2.85%. MS (ESI): m/e 488 (Mþ).
The human cancer cell lines (K-562, A-549, SMMC-7721, SGC-
7901 and HCT-116) were obtained from Shanghai Institute of
Pharmaceutical Industry. To investigate the cell growth inhibition
activity of the compounds, we performed MTT assays. In brief,
exponentially growing cells were seeded into a 96-well plate and
incubated. After 24 h, drugs were added at given concentrations,
followed by incubation for 48 h. MTT was given to the wells at
a concentration of 2.5 mg mlꢃ1, and the cells were incubated for 4 h.
The formazan was solubilized by a lysis buffer (10% SDS in 0.1 N
HCl), and the absorbance read at 570 nm with a microplate reader
(Bio-Tek Instruments, Winooski, VT). The cell viabilities of each well
were compared with a blank. The concentration required for 50%
inhibition of cell viability (IC50) was calculated by Bliss method.
6.1.7.21. 5-Isopropoxy-2-(8-isopropoxy-1-(4-isopropoxy-3-methox-
yphenyl)-9-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-yl)-4-
methoxyphenyl methanesulfonate (11u). Yield 71%; Mp 70–74 ꢀC; IR
(KBr): 2976, 2931, 1605, 1508, 1365, 1261, 1211, 1174, 1111, 1030, 851,
517; 1H NMR (CDCl3, 400 MHz)
d
1.17 (d, 6H, J ¼ 6.0 Hz, 20-
OCH(CH3)2), 1.34 (d, 6H, J ¼ 6.0 Hz, 14-OCH(CH3)2), 1.37 (d, 6H,
J ¼ 6.0 Hz, 8-OCH(CH3)2), 2.82 (s, 3H, 18-OSO2CH3), 3.03 (t, 2H,
J ¼ 6.0 Hz, –CH2CH2N–), 3.36 (s, 3H, 9-OCH3), 3.41 (s, 3H, 21-OCH3),
3.66 (s, 3H, 13-OCH3), 4.11 (t, 2H, J ¼ 6.0 Hz, –CH2CH2N–), 4.15
(m, 1H, 20-OCH(CH3)2), 4.50 (m, 2H, 14-OCH(CH3)2, 8-OCH(CH3)2),
6.64 (s,1H,10-Ar–H), 6.68 (d,1H, 4J ¼ 1.6 Hz,12-Ar–H), 6.70(s,1H, 7-
Ar–H), 6.74 (d, 1H, 3J ¼ 8.0 Hz, 15-Ar–H), 6.81 (s, 1H, 19-Ar–H), 6.82
(dd, 1H, 3J ¼ 8.0 Hz, 4J ¼ 1.6 Hz, 16-Ar–H), 6.90 (s, 1H, 3-H); 13C NMR
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746.
(CDCl3, 100 MHz)
d 21.65, 21.82, 21.94, 22.10, 29.32, 29.64, 37.70,
44.82, 55.15, 55.55, 55.94, 71.42, 71.58, 104.94, 107.90, 110.26,
112.72, 114.115, 114.90, 115.76, 116.54, 117.74, 119.28, 120.02, 120.57,
122.29, 122.93, 123.77, 125.97, 129.54, 139.79, 145.21, 145.32, 145.87,
148.25, 148.87, 150.63; Anal. Calcd for C37H45NO9S: C, 65.37; H,
6.67; N, 2.06; O, 21.18; S, 4.72; C, 65.40; H, 6.69; N, 2.08%. MS (ESI):
m/e 680 (Mþ).
6.1.7.22. 2-(1-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-5,6-dihy-
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Mol. Pharmacol. 34 (1988) 200.
dropyrrolo[2,1-a]isoquinoline-2-yl)-4,5-dimethoxyphenyl
meth-
anesulfonate (11v). Yield 67%; Mp 176–178 ꢀC; IR (KBr): 3002, 2936,
2837, 1739, 1703, 1540, 1510, 1491, 1418, 1361, 1267, 1244, 1217, 1172,
1135, 869, 843, 529; 1H NMR (CDCl3, 400 MHz)
d
2.84 (s, 3H,
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[13]
.
An Oxigene0s report on http://www.oxigene.com/vascular/pipeline.asp
18-OSO2CH3), 3.06 (t, 2H, J ¼ 6.4 Hz, –CH2–CH2–N), 3.38 (s, 3H,
9-OCH3), 3.46 (s, 3H, 21-OCH3), 3.71 (s, 3H, 8-OCH3), 3.86 (s, 3H, 13-
OCH3), 3.87 (s, 3H, 20-OCH3), 3.87 (s, 3H, 14-OCH3), 4.12 (t, 2H,
J ¼ 6.4 Hz, –CH2–CH2–N), 6.50 (s, 1H, 10-Ar–H), 6.71 (s, 1H, 7-Ar–H),
6.72 (s, 1H, 19-Ar–H), 6.80 (dd, 1H, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, 16-Ar–H),
6.84 (s, 1H, 12-Ar–H), 6.86 (m, 1H, 15-Ar–H), 6.88 (s, 1H, 22-Ar–H),
(Clinical Research Progress of CA4P, June 2006)
[14]. M.G. Banwell, E. Hamel, D.C.R. Hockless, P. Verdier-Pinard, A.C. Willis,
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(2003) 1363.
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6.97 (s, 1H, 3-H); 13C NMR (CDCl3, 100 MHz)
d 29.49, 37.82, 44.85,
55.29, 55.65, 55.93, 55.98, 56.03, 56.15, 106.94, 107.45,111.15,111.33,
113.71, 114.11, 117.84, 119.26, 120.04, 120.61, 121.83, 123.08, 124.02,
125.96, 128.83, 139.97, 147.06, 147.15, 147.26, 147.41, 147.79, 149.00;
Anal. Calcd for C31H33NO9S: C, 62.51; H, 5.58; N, 2.35; O, 24.17; S,
5.38; Found C, 62.47; H, 560; N, 2.10%. MS (ESI): m/e 596 (Mþ).
´
[22]. D. Pla, A. Marchal, C.A. Olsen, A. Francesch, C. Cuevas, F. Albericio, M. Alvarez,
J. Med. Chem. 49 (2006) 3257.
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Butterworth -Heinemann, Oxford, New York, 2003.
[24]. N. Milhazes, R. Calheiros, M.P.M. Marques, J. Garrido, M.N.D.S. Cordeiro,
C. Rodrigues, S. Quinteira, C. Novais, L. Peixe, F. Borges, Bioorg. Med. Chem. 14
(2006) 4078.
6.1.7.23. 2-(8-Isopropoxy-1-(4-isopropoxy-3-methoxyphenyl)-9-
methoxy-5,6-dihydropyrrolo[2,1-a]isoquinolin-2-yl)-4,5-dimethox-
yphenyl methanesulfonate (11w). Yield 58%; Mp 80–83 ꢀC; IR (KBr):
[25]. N. Fujikawa, T. Ohta, T. Yamaguchi, T. Fukuda, F. Ishibashi, M. Iwao, Tetrahe-
dron 62 (2006) 594.