Discovery of Aporphine Analogues as Potential Antiplatelet and Antioxidant Agents: Design, Synthesis, Structure–Activity Relationships, Biological Evaluations, and in silico Molecular Docking Studies

Article abstract of DOI:10.1002/cmdc.201800318

To explore the potential of aporphine alkaloids, a novel series of functionalized aporphine analogues with alkoxy (OCH₃, OC₂H₅, OC₃H₇) functional groups at C1/C2 of ring A and an acyl (COCH₃

Full text of DOI:10.1002/cmdc.201800318

DOI: 10.1002/cmdc.201800318
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Discovery of Aporphine Analogues as Potential
Antiplatelet and Antioxidant Agents: Design, Synthesis,
Structure–Activity Relationships, Biological Evaluations,
and in silico Molecular Docking Studies
Vashundhra Sharma+,[a] Pradeep K. Jaiswal+,[a] Surendra Kumar,[b] Manas Mathur,[c]
Ajit K. Swami,[c] Dharmendra K. Yadav,[b] and Sandeep Chaudhary*[a]
To explore the potential of aporphine alkaloids, a novel series
of functionalized aporphine analogues with alkoxy (OCH3,
OC2H5, OC3H7) functional groups at C1/C2 of ring A and an acyl
(COCH3 and COPh) or phenylsulfonyl (SO2Ph and SO2C6H4-3-
CH3) functionality at the N6 position of ring B of the aporphine
scaffold were synthesized and evaluated for their arachidonic
acid (AA)-induced antiplatelet aggregation inhibitory activity
and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scaveng-
ing antioxidant activity, with acetylsalicylic acid and ascorbic
acid as standard references, respectively. The preliminary struc-
ture–activity relationship related to AA-induced platelet aggre-
gation inhibitory activity results showed that the aporphine
analogues 1-[1,2,9,10-tetramethoxy-6a,7-dihydro-4H-dibenzo-
[de,g]quinolin-6(5H)-yl]ethanone and 1-[2-(benzyloxy)-1,9,10-tri-
methoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]etha-
none to be the best compounds of the series. Moreover, the
DPPH free-radical-scavenging antioxidant activity results dem-
onstrated that the aporphine analogues 1,2,9,10-tetramethoxy-
6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quino-
line, 2-ethoxy-1,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tet-
rahydro-4H-dibenzo[de,g]quinoline, 1-ethoxy-2,9,10-trimethoxy-
6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quino-
line,
2,9,10-trimethoxy-6-(methylsulfonyl)-1-propoxy-5,6,6a,7-
tetrahydro-4H-dibenzo[de,g]quinoline, and 1-(benzyloxy)-2,9,10-
trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo-
[de,g]quinoline were the best compounds of the series. More-
over, in silico molecular docking simulation studies of the
active analogues were also performed.
Introduction
1,2,3,4-Tetrahydroisoquinoline substructure 1 is present in the
basic tetracyclic framework of aporphine alkaloids 2. A large
number of aporphine alkaloids have been isolated from several
plant species (e.g., Hernandiaceae, Lauraceae, Annonaceae,
etc.) and have been synthesized by several routes.[1] Both natu-
ral and synthetic aporphine alkaloids display a wide range of
pharmacological activities and also serve as leads for the devel-
opment of potential drug-discovery scaffolds. For example,
natural/synthetic aporphines have been identified as antimicro-
bial,[2a] antiviral,[2b,c] and acetyl cholinesterase inhibitors;[2d] anti-
malarial agents;[2e,f] central nervous system receptor li-
gands;[1c,2h] anti-Alzheimer agents;[1c,2d–f,g,h] and potent dopa-
mine D1/D2 agonists.[2i] Additionally, their characteristic tetracy-
clic motif with different levels of oxidation on both aromatic
rings results in a diverse range of interesting biological activi-
ties, including antimalarial,[3a] serotonergic,[3b] anticancer,[3c] vas-
orelaxing[3d] and cytotoxic activities.[3e] Moreover, literature re-
ports reveal that natural and semisynthetic aporphines 3–14
show excellent antioxidant[4] and antiplatelet activities[5]
(Figure 1).
On the other hand, cyclic/acyclic ester/amide analogues 15
and sulfonamide analogues 16 display promising antioxidant
activities (e.g., exifone, 2,4-dihydroxy-7-methoxy-1,4-benzoxa-
zin-3-one, benzo[1,3]oxazine, benzo[1,4]oxazine analogues,
etc.)[6] and antiplatelet activities (e.g., acetylsalicylic acid (Aspir-
in), tirofiban, sulfinpyrazone, clopidogrel, etc.).[7]
[a] V. Sharma,+ Dr. P. K. Jaiswal,+ Prof. S. Chaudhary
Laboratory of Organic & Medicinal Chemistry, Department of Chemistry,
Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur
302017 (India)
E-mail: schaudhary.chy@mnit.ac.in
Thus, we anticipated that the combination of these two moi-
eties, that is, 3–14 and 15–16, in part or in their entire molecu-
lar architectures, might display promising antiplatelet and anti-
oxidant activities; we designed novel aporphine analogues 17
and 18 (Figure 2). Moreover, a literature survey revealed that
there is no detailed systematic study of the structure–activity
relationship (SAR) of synthetic aporphines having an amide/
sulfonamide substructure as antiplatelet and antioxidant
agents until now.
[b] Dr. S. Kumar, Dr. D. K. Yadav
College of Pharmacy, Gachon University of Medicine and Science, Incheon
(South Korea)
[c] Dr. M. Mathur, Dr. A. K. Swami
Department of Advance Molecular Microbiology, Seminal Applied Sciences
Pvt. Ltd., Jaipur 302015 (India)
[+] These authors contributed equally to this work.
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/cmdc.201800318.
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Figure 1. Basic structures of aporphine alkaloids 2, aporphine alkaloids 3–7 having antioxidant activity, and aporphine alkaloids 8–14 having antiplatelet activ-
ity.
on their preliminary arachidonic acid (AA)-induced
platelet aggregation inhibitory activity and 2,2-di-
phenyl-1-picrylhydrazyl (DPPH) free-radical-scaveng-
ing antioxidant activity taking ascorbic acid and ace-
tylsalicylic acid as standard drug references, respec-
tively. To the best of our knowledge, this is the first
report of the synthesis, SAR, and antiplatelet and an-
tioxidant activity of novel racemic aporphine ana-
logues 27a–s. We also report in silico molecular
docking simulation studies of the active analogues.
Results and Discussion
In our endeavor to develop non-peptide-based anti-
platelet agents; we recently reported that the inhibi-
tion of cyclooxygenase-1 (COX-1) was the key target
in the development of novel platelet aggregation in-
hibitors.[8a] As acetylsalicylic acid, tirofiban, sulfinpyr-
Figure 2. Designed strategy and the basic structures of aporphine alkaloids 2, functional-
ized amides 15, functionalized sulfonamides 16, and designed aporphine–amide/sulfona-
mide hybrid prototypes 17 and 18.
azone, and clopidogrel are well-established potent
platelet-aggregation inhibitors that contain amide/
sulfonamide moieties and as natural/semisynthetic
Therefore, in our search for potent antiplatelet/antioxidant
agents, we report the synthesis of aporphines 27a–s as ana-
logues of prototypes 17 and 18 having structural modifications
at C1/C2 of ring A and amide/sulfonamide functionality at the
N6 position of ring B along with their SAR studies with respect
aporphine analogues 3–7 were reported to show promising
antioxidant activities, we envisaged that aporphines having
these scaffolds would also show potent activities.
Several routes have been reported for the synthesis of apor-
phines and related alkaloids and similar scaffolds.[8b–d] There-
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Scheme 1. Reagents and conditions: a) 1,1’-carbonyldiimidazole, THF, RT, 20 h, 72–84%; b) PCl5, CH2Cl2, 08C to RT, 12 h; c) NaBH4, MeOH, 08C, 5 h; d) (Boc)2O,
DMAP, Et3N, CH2Cl2, RT, 12 h, 70–83%; e) Pd(OAc)2, ligand, K2CO3, (CH3)3CCOOH, DMSO, 1308C, 18 h, 73–92%.
fore, novel aporphine analogues 27a–s having structural modi-
fications at C1/C2 of ring A and at the N6 position of ring B
were prepared by using reported procedures[8e,f] (Schemes 1
and 2). The coupling of functionalized phenethylamine ana-
logues 19a–f with 2-(2-bromo-4,5-dimethoxyphenyl)acetic acid
(20) under standard peptide-coupling conditions gave amides
21a–f. Amides 21a–f were subjected to the Bischler–Napieral-
ski reaction[9] to afford cyclized imines 22a–f, which, without
further purification, were subjected to NaBH4 reduction to fur-
nish secondary amines 23a–f. Protection of these amines with
a tert-butoxycarbonyl (Boc) group furnished C1- and C2-func-
tionalized N6 carbamates 24a–f. Finally, N-Boc-protected apor-
phine analogues 25a–f (up to 94% yield) were prepared by
Pd-catalyzed direct biaryl coupling methodology (Scheme 1).[10]
N-Carbamate (i.e., N-Boc) aporphine analogues 25a–f were
used as the key precursors for the synthesis of novel aporphine
analogues 27a–s (Scheme 2). Hence, the synthesis of N6
amide/sulfonamide analogues 27a–o and 27q–s was achieved
by deprotection of the Boc group[8e] of 25a–f by using anhy-
drous ZnBr2 and subsequent N-alkylation with different alkyl/
aryl halides. In addition, the subsequent reductive amination
of secondary amine 26c with formaldehyde afforded N-methy-
lated aporphine analogue 27p (Scheme 2). All of these com-
pounds were well characterized by using 1H NMR, 13C NMR,
and FTIR spectroscopy and high-resolution (HR) ESI-MS. As ex-
pected, the NMR spectral data (1H NMR and 13C NMR) of the N-
acetyl analogues revealed a mixture of rotamers (see the Ex-
perimental Section).
COCH3, N-SO2CH3, and N-SO2C6H4-3-CH3 substituents in ring B,
respectively, were prepared; of these compounds, 27a (IC50 =
20.08ꢀ0.22 mgmLꢁ1) displayed higher AA-induced platelet ag-
gregation inhibitory activity than acetylsalicylic acid (IC50 =
21.34ꢀ1.09 mgmLꢁ1; Table 1, entry 1). Changing the N-COCH3
group to an N-SO2CH3 or N-SO2C6H4-3-CH3 group further de-
creased the activity (Table 1, entries 2 and 3). Then, higher ho-
mologues of 27a–c, that is, 27d (IC50 =29.78ꢀ0.31 mgmLꢁ1),
27 f, and 27g having an ethoxy group at the C2 position were
assessed, and we observed a similar decrease in the antiplate-
let activity upon changing the N-substituents from an acetyl
group to either a sulfonyl or (3-methylphenyl)sulfonyl group
(Table 1, entries 4, 6, and 7). Although N-benzoyl analogue 27e
(IC50 =25.83ꢀ0.26 mgmLꢁ1) displayed better antiplatelet activi-
ty than 27d, 27 f, and 27g, its antiplatelet activity was similar
to that of acetylsalicylic acid (Table 1, entry 5). The platelet ag-
gregation inhibitory activities of compounds 27h (IC50 =
101.83ꢀ1.08 mgmLꢁ1), 27i (IC50 =33.37ꢀ0.34 mgmLꢁ1), 27j
(IC50 =37.71ꢀ0.38 mgmLꢁ1),
and
27k
(IC50 =40.00ꢀ
0.48 mgmLꢁ1) having an N-sulfonyl substituent and an ethoxy/
propoxy group at the C2 position were drastically lower than
that of parent analogue 27a having an N-acetyl group
(Table 1, entries 8–11).
As we did not observe any noticeable improvement in the
activity upon increasing the length of the alkyl chain, we intro-
duced aromatic moieties at both the C1 and C2 positions. So,
we prepared 27l–p and 27q–s having benzyloxy groups at
C1/C2 of ring A and an N-acetyl, N-benzoyl, N-arylsulfonyl, or
N-methylsulfonyl group in ring B as aporphine analogues. As
expected, 27l showed better AA-induced platelet aggregation
inhibitory activity than 27m--o; moreover, the IC50 value of
27p having an N-CH3 group (IC50 =27.83ꢀ0.29 mgmLꢁ1), the
reduced form of 27l, was also promising relative to that of
acetylsalicylic acid (Table 1, entries 12–16).
Synthesized novel aporphines 27a–s having alkoxy (OCH3,
OC2H5, OC3H7) functional groups at C1/C2 of ring A along with
acyl (COCH3 and COPh)/phenylsulfonyl (SO2Ph and SO2C6H4-3-
CH3) functionality at the N6 position of ring B were evaluated
for their arachidonic acid (AA)-induced antiplatelet aggregation
inhibitory activity as well as their DPPH radical-scavenging anti-
oxidant activity taking acetylsalicylic acid and ascorbic acid as
standard references, respectively, by using a reported proce-
dure[11,12] (Tables 1 and 2).
Thus, it can be inferred that substitution of the N-acetyl
group with an N-benzoyl group does not have a beneficial
effect on antiplatelet activity. Analogue 27m (IC50 =58.13ꢀ
0.77 mgmLꢁ1), having two phenyl moieties, exhibited lower ac-
tivity than acetyl analogue 27l. Aporphine analogues 27q–s,
As depicted in Table 1, initially, compounds 27a, 27b, and
27c having OCH3 substituents at C1 and C2 of ring A and N-
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Scheme 2. Reagents and conditions: a) ZnBr2, CH2Cl2, RT, 24 h; b) R3Cl [R3 =COCH3, COPh, SO2CH3, SO2C6H4-3-CH3], Et3N, CH2Cl2, 08C, 3 h, 69–93%; c) aq.
HCHO, NaBH(OAc)3, CH2Cl2, RT, 24 h, 67%.
having a benzyloxy group at the C2 position and an N-acetyl
group, also follows the same trend, that is, 27q (IC50 =21.29ꢀ
0.25 mgmLꢁ1) was as active as acetylsalicylic acid and more
active than its N-sulfonyl counterparts (Table 1, entries 17 and
18).
ascorbic acid as a standard reference by using a reported pro-
tocol.[13] The results are shown in Table 1.
DPPH is a stable free radical that can easily be converted
into a stable molecule after the acceptance of an electron or
hydrogen radical. It is well documented that the DPPH radical-
scavenging antioxidant activity assay proceeds through a
single-electron-transfer (SET) or hydrogen-atom-transfer (HAT)
mechanism.[12a–c] The DPPH molecule shows a strong absorp-
tion band at l=515 nm in MeOH solution with a deep-purple
color and having an odd electron configuration. The deep-
purple color of the MeOH medium containing DPPH changes
to yellow in the presence of free-radical scavengers.[12d,e]
Quenching of the DPPH free radical can be correlated with the
structural architecture of the quenching molecule, and steric
hindrance, rigidity, and electron density are key factors that
may facilitate access of this molecule to the radical site of
DPPH, thus, to enhance the antioxidant activity.[12f,g]
Overall, on the basis of the above SAR study, two com-
pounds, that is, 27a and 27q, having OCH3 and OCH2Ph sub-
stituents at C1, a OCH3 substituent at the C2 position of ring A,
and an N-acetyl group, were the most active compounds of
the series and displayed greater antiplatelet activity than ace-
tylsalicylic acid. It can be interpreted that the N-acetyl ana-
logue of aporphines (i.e., compounds 27a, 27d, 27l, and 27q)
showed better platelet aggregation inhibitory activity than the
N-sulfonamide analogues. However, the position of the alkoxy
substituent at C1 and C2 of ring A is also responsible for the
antiplatelet activity. Similarly, the N-methyl group of aporphine
analogue 27p further reduced the antiplatelet activity.
Synthesized novel racemic aporphines 27a–s were also
screened for their preliminary antioxidant activity by using the
DPPH free-radical-scavenging antioxidant activity assay taking
Initially, in vitro antioxidant screening of novel aporphine an-
alogues 27a–c having OCH3 substituents at the C1/C2 posi-
tions of ring A and an N-acetyl, N-sulfonyl, or N-(3-methylphe-
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Table 1. In vitro AA-induced platelet aggregation inhibitory activity and in vitro DPPH radical-scavenging antioxidant activity of synthesized aporphine an-
alogues 27a–s.
Entry
Compound
R1
R2
R3
IC50 [mgmLꢁ1
Antiplatelet[a,b]
]
Antioxidant[c,d]
1
2
3
4
5
6
7
8
27a
27b
27c
27d
27e
27 f
27g
27h
27i
27j
27k
27l
27m
27n
27o
27p
CH3
CH3
CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH3
COCH3
SO2CH3
SO2C6H4-3-CH3
COCH3
COPh
SO2CH3
SO2C6H4-3-CH3
SO2CH3
SO2C6H4-3-CH3
SO2CH3
SO2C6H4-3-CH3
COCH3
COPh
SO2CH3
SO2C6H4-3-CH3
CH3
COCH3
SO2CH3
SO2C6H4-3-CH3
–
20.08ꢀ0.22
31.19ꢀ0.29
57.29ꢀ0.74
29.78ꢀ0.31
25.83ꢀ0.26
44.97ꢀ0.67
103.64ꢀ1.01
101.83ꢀ1.08
33.37ꢀ0.34
37.71ꢀ0.38
40.00ꢀ0.48
28.81ꢀ0.37
58.13ꢀ0.77
71.88ꢀ0.08
78.67ꢀ0.88
27.83ꢀ0.29
21.29ꢀ0.25
41.97ꢀ0.44
96.02ꢀ0.97
21.34ꢀ1.09
–
70.69ꢀ0.68
10.18ꢀ0.10
21.97ꢀ0.22
30.08ꢀ0.34
88.36ꢀ0.79
5.87ꢀ0.07
103.11ꢀ1.01
7.08ꢀ0.10
96.13ꢀ0.74
5.13ꢀ0.07
29.31ꢀ0.30
11.71ꢀ0.14
23.14ꢀ0.29
4.36ꢀ0.09
44.87ꢀ0.36
19.63ꢀ0.22
41.58ꢀ0.39
14.53ꢀ0.31
50.08ꢀ0.45
–
9
10
11
12
13
14
15
16
17
18
19
20
21
27q
27r
27s
CH2Ph
CH2Ph
CH2Ph
–
CH3
CH3
–
–
acetylsalicylic acid
ascorbic acid
–
–
4.57
[a] Platelets were incubated along with either a tested compound or 0.5% DMSO at 378C for 60 s, and then AA (100 mm) was added to accelerate aggrega-
tion. Acetylsalicylic acid was a positive control. Values are expressed as the mean of six separations. [b] The data represent the mean of three independent
determinations. [c] Results are expressed as meanꢀSD (n=3). [d] DPPH radical-scavenging activities are expressed as IC50 concentrations of the com-
pounds required to inhibit 50% of the radicals and the maximum inhibition values, and the positive control for the DPPH assay was ascorbic acid. Values
in boldface indicate compounds with high activity.
nyl)sulfonyl group at the N6 position were assessed, and it was
observed that 27a (IC50 =70.69ꢀ0.68 mgmLꢁ1) having OCH3
substituents at both the C1/C2 positions along with an N-
acetyl group displayed lower potency than ascorbic acid
(IC50 =4.57 mgmLꢁ1; Table 1, entry 1). However, 27b (IC50 =
10.18ꢀ0.10 mgmLꢁ1) having an N-sulfonyl group showed sig-
nificantly higher antioxidant activity than 27a (Table 1,
entry 2). Upon changing to an N-arylsulfonyl group, that is,
compound 27c (IC50 =21.97ꢀ0.22 mgmLꢁ1), a further decrease
in the antioxidant activity was observed (Table 1, entry 3).
Similar trends were observed upon analyzing 27d–k having
ethoxy/propoxy groups at the C1/C2 positions along with an
N-acetyl, N-benzoyl, N-methylsulfonyl, or N–arylsulfonyl group
at the N6 position (Table 1, entries 4–11). Whereas analogues
We were also interested to study the effect of the aromatic
ring at the C1/C2 positions of ring A. Therefore, we prepared
aporphine analogues 27l–s having an N-acetyl, N-benzoyl, N-
methylsulfonyl, or N-arylsulfonyl group at the N6 position
(Table 1, entries 12–19). Compound 27l (IC50 =11.71ꢀ
0.14 mgmLꢁ1) having a benzyloxy group at the C2 position and
an N-acetyl group showed promising antioxidant activity. How-
ever, changing the acetyl group to a methylsulfonyl group at
the N6 position had a profound effect on the antioxidant activ-
ity, as observed in the case of 27n (IC50 =4.36ꢀ0.09 mgmLꢁ1),
which showed higher activity than ascorbic acid (IC50 =
4.57 mgmLꢁ1). Thus, 27n was found to be the best compound
of the series. The activity decreased if a benzoyl or arylsulfonyl
group was introduced at the N6 position [27m, IC50 =(23.14ꢀ
0.29) mgmLꢁ1; 27o, IC50 =(44.87ꢀ0.36) mgmLꢁ1; Table 1, entries
13 and 15]. In addition, the tertiary amine analogue, that is, N-
methylaporphine 27p (IC50 =19.63ꢀ0.22 mgmLꢁ1), exhibited
lower antioxidant activity (Table 1, entry 16). We did not ob-
serve an incremental effect in the activity upon reversing the
position of the aromatic substituent at the C1/C2 positions, as
in compounds 27q–s (Table 1, entries 17–19). However, 27r
(IC50 =14.53ꢀ0.31 mgmLꢁ1) having an N-SO2CH3 group showed
27 f
(IC50 =5.87ꢀ0.07 mgmLꢁ1),
27h
(IC50 =7.08ꢀ
0.10 mgmLꢁ1), and 27j (IC50 =5.13ꢀ0.07 mgmLꢁ1) displayed ex-
cellent antioxidant potency similar to that of the standard
drug (Table 1, entries 6, 8, and 10), other analogues, as in com-
pounds 27d (IC50 =30.08ꢀ0.34 mgmLꢁ1), 27e (IC50 =88.36ꢀ
0.79 mgmLꢁ1), 27g (IC50 =103.11ꢀ1.01 mgmLꢁ1), 27i (IC50 =
96.13ꢀ0.74 mgmLꢁ1), and 27k (IC50 =29.31ꢀ0.30 mgmLꢁ1),
displayed poor potency (Table 1, entries 4–5, 7, 9 and 11).
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promising antioxidant activity relative to 27q (IC50 =41.58ꢀ
0.39 mgmLꢁ1) and 27s (IC50 =50.08ꢀ0.45 mgmLꢁ1).
terms of root-mean-square-deviation (RMSD) values in be-
tween the co-crystallized ligand and the redocked poses. The
RMSD values were found to be 0.6563 and 1.1420 for the
2OYE and 3MNG proteins, respectively, which suggested that
the docking program parameters could be used for docking of
our synthesized compounds (Figure 3).
On the basis of the above results, it was observed that the
N-methylsulfonyl substituent in aporphine analogues 27b,
27 f, 27h, 27j, and 27n played a crucial role in antioxidant ac-
tivity, and these compounds were the most active compounds
of the series. Analogues 27c, 27g, 27i, 27k, 27o, and 27s
having an N-arylsulfonyl group and aporphine analogues 27a,
27d, 27e, 27l, 27m, and 27q having an N-acetyl or N-benzoyl
group displayed lower antioxidant activity. Hence, it can be
speculated that the higher electronegativity of the sulfur atom
in the N-methylsulfonyl-containing aporphine analogues,
which is able to accumulate electron density (the N-arylsulfo-
nylaporphines have lower electron density owing to the pres-
ence of the electron-withdrawing aryl substituent despite the
presence of the electron-donating methyl substituent), restricts
delocalization of the bonds; as a result, the free electrons are
not available to quench the DPPH radical, and this might be a
plausible reason for the good antioxidant activity.
With the insight obtained from the binding interaction of
the co-crystallized ligand, we further docked and analyzed the
binding interaction of compounds 27a and 27q (Figure 4).
These compounds exhibited better platelet aggregation inhibi-
tion activity than acetylsalicylic acid (a standard reference used
as a platelet aggregation inhibitor). The docking results for
compound 27q showed a high binding affinity represented by
a total docking score of 7.4851 (Figure 4a). Compound 27q
forms H-bonds to the polar, uncharged, and nucleophilic Ser-
530 (2.31 ꢁ) and p–p interactions with hydrophobic Tyr-355. In
the docking pose, the binding-site residues within a radius of
3 ꢁ from the bound compound are aliphatic and hydrophobic
Ile-89, Ile-517, Ile-523, Leu-93, Leu-352, Leu-359, Leu-531, Val-
116, Val-349, Ala-527, and Gly-526; aromatic and hydrophobic
Tyr-348, Tyr-355, Tyr-385, Phe-381, Phe-518, and Trp-387; basic,
polar, and positively charged Arg-120; and polar, uncharged,
and nucleophilic Ser-353 and Ser-530.
We then performed in silico molecular docking simulation
studies by exploring the binding interactions, and we predict-
ed the binding affinities of selected synthesized aporphine an-
alogues that were active, in addition to those of the reference
standard, acetylsalicylic acid, and ascorbic acid, with the pro-
tein targets [2OYE, i.e., indomethacin-(R)-a-ethylethanolamide
bound to cyclooxygenase-1, and 3MNG, i.e., dithiothreitol
bound with human peroxiredoxin 5] (Tables 2 and 3). The bind-
ing affinities were measured as the “total” docking score. The
reliability of the docking program parameters was measured in
Similarly, the docking results for compound 27a also
showed good binding affinity in the total score of 5.9304 and
a H-bond length of 1.71 ꢁ to polar, uncharged, and nucleophil-
ic Ser-530 (Figure 4b). The compound also displayed a p–p in-
teraction with hydrophobic Tyr-355 (aromatic, hydrophobic).
Table 2. Comparison of the binding affinities of active aporphine analogues 27a and 27q with that of acetylsalicylic acid as the standard drug reference
against antiplatelet target protein (PDB ID: 2OYE).
Compound
Total
docking
score
Residues in the binding site within 3 ꢁ of ligand
Residues involved
in H-bonds
IM8
27a
27q
10.5285 Ile-89, Val-116, Arg-120, Val-349, Tyr-355, Ser-353, Leu-384, Phe-518, Met-522, Ile-523, Glu-524, Gly- Glu-524 (2.04 ꢁ), Tyr-355
526, Ala-527, Ser-530 (2.12 ꢁ), Trp-387 (3.26 ꢁ)
5.9304 Tyr-348, Val-349, Leu-352, Ser-353, Tyr-355, Leu-359, Tyr-385, Trp-387, Ile-517, Phe-518, Ile-523, Ala- Ser-530 (1.71 ꢁ), Tyr-355 (p–p)
527, Ser-530, Leu-531
7.4851 Ile-89, Leu-93, Val-116, Arg-120, Tyr-348, Val-349, Leu-352, Ser-353, Tyr-355, Leu-359, Phe-381, Tyr- Ser-530 (2.31 ꢁ), Tyr-355 (p–p)
385, Trp-387, Ile-517, Phe-518, Ile-523, Gly-526, Ala-527, Ser-530, Leu-531
acetylsalicylic 4.9713 Tyr-348, Val-349, Leu-352, Phe-381, Leu-384, Tyr-385, Trp-387, Gly-526, Ala-527, Ser-530
acid
Ser-530 (1.84 ꢁ), Tyr-355
(2.08 ꢁ)
Table 3. Comparison of the binding affinities of promising antioxidant-active aporphine analogues with that of ascorbic acid as the standard drug against
an antioxidant target protein (PDB ID: 3MNG).
Compound
Docking Residues in the binding site within 3 ꢁ of the ligand
score
Residues involved
in H-bonds
DID
27b
27 f
27h
27j
3.5321 Pro-40, Thr-44, Pro-45, Gly-46, Cys-47, Phe-120, Arg-127, Thr-147
2.9735 Pro-40, Pro-45, Gly-46, Lys-49, Leu-116, Phe-120, Arg-127, Thr-147, Leu-149
4.4967 Pro-40, Pro-45, Gly-46, Phe-120, Arg-127, Thr-147, Leu-149
3.9514 Pro-40, Thr-44, Pro-45, Gly-46, Lys-49, Leu-116, Phe-120, Arg-127, Thr-147, Leu-149 Arg-127 (2.59 ꢁ)
5.1878 Pro-40, Pro-45, Gly-46, Leu-116, Ile-119, Phe-120, Arg-127, Thr-147, Leu-149
4.6290 Pro-45, Gly-46, Lys-49, Arg-127, Thr-147, Gly-148, Leu-149
Arg-127 (1.96 ꢁ), Thr-44 (2.62 ꢁ)
Arg-127 (2.43, 2.65 ꢁ)
Gly-46 (3.71 ꢁ)
Arg-127 (2.62, 2.12 ꢁ),Thr-147 (1.98 ꢁ)
Gly-46 (2.55 ꢁ), Lys-49 (2.31 ꢁ)
27l
27n
4.7335 Pro-45, Gly-46, Lys-49, Phe-120, Arg-127, Thr-147, Gly-148, Leu-149
Gly-46 (2.53 ꢁ), Lys-49 (2.26 ꢁ)
ascorbic acid 4.2924 Pro-40, Thr-44, Pro-45, Gly-46, Cys-47, Leu-116, Arg-127, Thr-147
Thr-44 (1.90 ꢁ), Gly-46 (2.06 ꢁ), Thr-147 (1.97 ꢁ)
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Figure 3. Protein targets a) 2OYE and b) 3MNG having docking scores, that is, RMSDs, of 0.6563 and 1.1420 for co-crystallized IM8 and DID, respectively.
Figure 5. Docking results for acetylsalicylic acid showing a docking score of
4.9713 and the formation of two H-bonds to polar, uncharged, and nucleo-
philic Ser-530 (1.84 ꢁ) and the OH group of Tyr-355 (2.08 ꢁ).
Figure 4. Docking results for compounds a) 27q and b) 27a having total
docking scores of 7.4851 and 5.9304, respectively.
logues 27a and 27q showed better antiplatelet activity owing
In the docking pose, the binding-site residues within a
radius of 3 ꢁ from the bound compound were aliphatic, hydro-
phobic Ile-517, Ile-523, Leu-352, Leu-359, Leu-531, Val-349, and
Ala-527; aromatic, hydrophobic Tyr-348, Tyr-355, Tyr-385, Phe-
518, and Trp-387; and polar, uncharged, nucleophilic Ser-353
and Ser-530. Furthermore, the binding interaction and binding
affinities of compounds 27q and 27a were compared with
that of acetylsalicylic acid.
to the fact that it had greater binding affinity than acetylsali-
cylic acid.
Following the redocking approach, the synthesized apor-
phine analogues showing good activity (i.e., 27b, 27 f, 27h,
27j, 27l, and 27n) were selected for docking into the binding
site of the antioxidant target protein (PDB ID: 3MNG), and the
binding affinities were compared with that of ascorbic acid as
a standard drug.
The docking results for acetylsalicylic acid showed a compa-
ratively lower binding affinity indicated by a docking score of
4.9713 and formed two H-bonds to polar, uncharged, and nu-
cleophilic Ser-530 (1.84 ꢁ) and the OH group of Tyr-355
(2.08 ꢁ) (Figure 5). In the docking pose, the binding-site resi-
dues within a radius of 3 ꢁ from the bound acetylsalicylic acid
were aliphatic, hydrophobic Leu-352, Leu-384, Val-349, Gly-526,
and Ala-527; aromatic, hydrophobic Tyr-348, Tyr-385, Phe-381,
and Trp-387; and polar, uncharged, nucleophilic Ser-530.
Chemical analysis of the binding of the amino acid residues for
compounds 27a and 27q and acetylsalicylic acid revealed that
these compounds bind to hydrophobic and hydrophilic resi-
dues, and the hydrophobic residues stabilize in the binding
pocket and the H-bond network is established by hydrophilic
residues.
The docking results for selected active compounds revealed
good binding affinity. Among the selected compounds, 27j
displayed the highest binding affinity in terms of docking
score (5.1878). Compound 27j forms two H-bonds to Arg-127
(2.62 and 2.12 ꢁ) and Thr-147 (1.98 ꢁ) (Figure 6a). In the dock-
ing pose, the binding-site residues within a radius of 3 ꢁ from
the bound compound were cyclic, hydrophobic Pro-40 and
Pro-45; aliphatic, hydrophobic Gly-46, Leu-116, Leu-149, and
Ile-119; aromatic, hydrophobic Phe-120; basic, polar, and posi-
tively charged Arg-127; and polar, uncharged, and nucleophilic
Thr-147.
Similarly, compounds 27n, 27l, 27 f, 27h, and 27b showed
good binding affinity in terms of docking scores of 4.7335,
4.6290, 4.4967, 3.9514, and 2.9735, respectively (Figures 6b–d
and 7). For all of the compounds, the common binding amino
acid residues within a radius of 3 ꢁ from the bound com-
pounds were cyclic, hydrophobic Pro-45; aliphatic, hydropho-
bic Gly-46 and Leu-149; polar, positively charged Lys-49 and
Arg-127; and polar uncharged, nucleophilic Thr-147. These
compounds showed multiple H-bonds to binding amino acid
residues.
Furthermore, comparison of the binding amino acid residues
revealed that the majority of the interacting residues belonged
to hydrophobic amino acids. Thus, the presence of hydropho-
bic residues imparts greater stability and inhibition activity
than the standard reference (i.e., acetylsalicylic acid). The dock-
ing results allowed us to infer that synthesized aporphine ana-
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Figure 6. Docking scores of a) 27j, b) 27n, c) 27l, and d) 27 f revealed good binding affinity in terms of docking scores of 5.1878, 4.7335, 4.6290, and 4.4967,
respectively.
Figure 7. Docking scores of a) 27h and b) 27b revealed binding affinity in terms of docking scores 3.9514 and 2.9735, respectively.
Furthermore, the binding interaction of ascorbic acid (dock-
ing score 4.2924) was explored, and we found similar binding-
interaction amino acid residues within a radius of 3 ꢁ that
comprised cyclic, hydrophobic Pro-40 and Pro-45; aliphatic, hy-
drophobic Gly-46 and Leu-116; polar, uncharged, and nucleo-
philic Thr-44, Thr-147, and Cys-47; and basic, polar, and posi-
tively charged Arg-127 (Figure 8). Moreover, after analyzing the
chemical nature of the binding-site amino acid residues, it was
revealed that these compounds have a propensity to form hy-
drophobic interactions and multiple H-bonds with the hydro-
philic residues of the target protein. Thus, comparison of the
binding affinities of the aporphine analogues with that of as-
corbic acid showed that these compounds have better antioxi-
Figure 8. Binding interactions of the standard drug ascorbic acid (docking
dant activity.
score=4.2924).
Conclusions
N6 position of the aporphine skeleton. The SAR study suggest-
ed that alkoxy substituents at the C1 and C2 positions of
ring A and the N6 substituent could be modified to develop
potent antiplatelet and antioxidant agents. In arachidonic acid
We herein disclosed the identification of novel aporphine ana-
logues as potent antiplatelet and antioxidant agents by struc-
tural manipulation on ring A (at the C1/C2 positions) and the
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induced platelet aggregation inhibitory activity, aporphine ana-
logues 1-[1,2,9,10-tetramethoxy-6a,7-dihydro-4H-dibenzo[de,g]-
quinolin-6(5H)-yl]ethanone (27a) and 1-[2-(benzyloxy)-1,9,10-
trimethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]-
ethanone (27q) (having an acetyl group at the N6 position, a
OCH3 or OCH2Ph substituent at C1, and a OCH3 substituent at
the C2 position of ring A) were the most active compounds of
the series. Moreover, in a preliminary 2,2-diphenyl-1-picrylhy-
drazyl (DPPH) free-radical antioxidant activity assay, aporphine
analogues 1,2,9,10-tetramethoxy-6-(methylsulfonyl)-5,6,6a,7-tet-
rahydro-4H-dibenzo[de,g]quinoline (27b), 2-ethoxy-1,9,10-tri-
methoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo-
[de,g]quinoline (27 f), 1-ethoxy-2,9,10-trimethoxy-6-(methylsul-
Synthesis
General procedure for the synthesis of 2-(2-bromophenyl)-
N-phenethylacetamide analogues 21a–f
A solution of 2-(2-bromo-4,5-dimethoxyphenyl)acetic acid (20;
10.0 mmol, 1 equiv) and 1,10-carbonyldiimidazole (10.0 mmol,
1 equiv) in anhydrous THF (25 mL) was stirred at room temperature
for 1 h. The mixture was then cooled at 08C and phenethylamine
analogue 19a–f (10.0 mmol, 1 equiv) was added, The mixture was
stirred at 08C for 4 h and then at room temperature overnight. The
mixture was concentrated under reduced pressure, and the ob-
tained residue was dissolved in EtOAc (20 mL) and washed sequen-
tially with 1n HCl (15 mL), water (2ꢂ25 mL), satd. NaHCO3 solution
(2ꢂ15 mL), and brine (30 mL). The organic layer was dried (anhy-
drous Na2SO4) and concentrated under reduced pressure. The re-
sultant crude products were purified by recrystallization (EtOAc/
hexane 20:80, v/v) or by flash column chromatography (silica gel,
hexane/EtOAc 9:1), which furnished the 2-(2-bromophenyl)-N-phe-
nethylacetamide analogue (2–84% yield).
fonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline
(27h),
2,9,10-trimethoxy-6-(methylsulfonyl)-1-propoxy-5,6,6a,7-tetra-
hydro-4H-dibenzo[de,g]quinoline (27j), and 1-(benzyloxy)-
2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-di-
benzo[de,g]quinoline (27n) (methylsulfonyl substituent at the
N6 position with a OCH3 or OC2H5 substituent at C1 and a
OCH3, OC3H7, or OCH2Ph substituent at C2 of ring A) were the
most active compounds of the series. Our results showed that
the substituent at the N6 position played a very important role
in antiplatelet and antioxidant activity. Interestingly, it was pos-
sible, through structural modifications, to synthesize potent
aporphines showing both activities, as displayed by aporphine
analogue 1-[1-(benzyloxy)-2,9,10-trimethoxy-6a,7-dihydro-4H-
dibenzo[de,g]quinolin-6(5H)-yl]ethanone (27l) in our study. In
addition, to check the binding interaction and docking score,
in silico molecular docking studies were also performed for the
reference standard and the promising active analogues for an-
tiplatelet and antioxidant activities. Moreover, the SAR effects
related to modification at C1/C2 of ring A and the N6 position
of ring B provided the necessary aspects for any future under-
taking to understand the role of different functional groups at
specific positions in active analogues for their therapeutic po-
tential. Succinctly, these lead compounds are considered
worthy of further structural optimization and development as
potential antiplatelet and antioxidant agents.
2-(2-Bromo-4,5-dimethoxyphenyl)-N-(3,4-dimethoxyphenethyl)-
acetamide (21a): White solid (81%); Rf (MeOH/CH2Cl2 5:95)=0.52;
purification by flash column chromatography (deactivated silica
1
gel, MeOH/CH2Cl2 2:98); mp: 128–1308C; H NMR (400 MHz, CDCl3):
d=7.03 (s, 1H), 6.98 (d, J=8.4 Hz 1H), 6.91 (d, J=1.6 Hz, 1H), 6.85
(dd, J=2.0, 10.4 Hz, 1H), 5.75 (s, 1H), 4.15–4.10 (m, 12H), 3.86 (s,
2H), 3.74 (q, J=6.8 Hz, 2H), 2.98 ppm (t, J=6.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=169.9, 149.0, 148.8, 147.7, 131.1, 126.6, 120.7,
115.6, 114.8, 113.8, 111.8, 111.2, 56.3, 56.2, 56.2, 55.9, 43.7, 40.8,
35.0 ppm; FTIR (KBr): n˜max =3414, 2935, 1633, 1549, 1463, 1384,
1244, 1028 cmꢁ1; HRMS (ESI): m/z: calcd for C20H24BrNO5: 439.0838
[M+2]+; found: 439.0832.
2-(2-Bromo-4,5-dimethoxyphenyl)-N-(3-methoxy-4-propoxyphen-
ethyl)acetamide (21b): White solid (72%); Rf (MeOH/CH2Cl2
5:95)=0.60; purification by flash column chromatography (deacti-
vated silica gel, MeOH/CH2Cl2 2.5:97.5); mp: 100–1028C; 1H NMR
(400 MHz, CDCl3): d=6.98 (s, 1H), 6.76 (s, 1H), 6.72 (d, J=8.0 Hz
1H), 6.63–6.62 (m, 1H), 6.56–6.54 (m, 1H), 5.46 (s, 1H), 3.95–3.90
(m, 2H), 3.87–3.77 (m, 9H), 3.58 (s, 2H), 3.45 (q, J=6.8 Hz 2H), 2.68
(t, J=6.8 Hz, 2H), 1.84 (q, J=7.6 Hz, 2H), 1.02 ppm (t, J=7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=169.9, 149.6, 149.1, 147.3,
131.1, 126.7, 120.7, 115.6, 114.9, 113.8, 113.1, 112.4, 70.7, 56.3, 56.2,
56.1, 43.8, 40.9, 35.1, 22.6, 10.6 ppm; FTIR (KBr): n˜max =3300, 2930,
1638, 1511, 1465, 1338, 1260, 1027 cmꢁ1; HRMS (ESI): m/z: calcd for
C22H28BrNO5: 467.1151 [M+2]+; found: 467.1156.
Experimental Section
N-[4-(Benzyloxy)-3-methoxyphenethyl]-2-(2-bromo-4,5-dime-
thoxyphenyl)acetamide (21c): White solid (78%); Rf (MeOH/CH2Cl2
4:96)=0.55; purification by flash column chromatography (deacti-
vated silica gel, MeOH/CH2Cl2 2:98); mp: 125–1278C; 1H NMR
(400 MHz, CDCl3): d=7.44–7.42 (m, 2H), 7.38–7.27 (m, 2H), 6.96 (s,
1H), 6.82- 6.72 (m, 3H), 6.65(s, 1H), 6.52–6.49 (m, 1H), 5.45 (s, 1H),
5.12 (s, 2H), 3.87- 3.82 (m, 9H), 3.57 (s, 2H) 3.48–3.42 (m, 2H) 2.74–
2.67 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=169.9, 149.8,
149.0, 148.2, 146.9, 137.4, 131.8, 128.7, 127.9, 127.4, 126.7, 120.7,
115.6, 114.9, 114.2, 113.8, 112.4, 71.2, 56.3, 56.2, 56.0, 43.8, 40.8,
35.1 ppm; FTIR (KBr): n˜max =3387, 2900, 1635, 1510, 1463, 1384,
1265, 1030 cmꢁ1; HRMS (ESI): m/z: calcd for C26H28BrNO5: 515.1151
[M+2]+; found: 515.1155.
General methods
All glass apparatus were oven dried prior to use. Melting points
were taken in open capillaries with a Complab melting point appa-
ratus. Infrared spectra were recorded with a PerkinElmer FTIR Spec-
trum 2 spectrophotometer. H NMR and 13C NMR spectra were re-
1
corded with an ECS 400 MHz (JEOL) NMR spectrometer by using
CDCl3 and CD3SOCD3 as solvents and tetramethylsilane as an inter-
nal reference. Electrospray ionization mass spectrometry (ESI-MS)
and HRMS were recorded with an Xevo G2-S QToF (Waters, USA)
spectrometer. A microwave reactor (CEM Discover) was used for
the reactions. Column chromatography was performed over Merck
silica gel (particle size: 60–120 mesh and 230–400 mesh) procured
from Qualigens (India) and flash silica gel (particle size: 230–
400 mesh). All chemicals and reagents were obtained from Sigma–
Aldrich (USA), Merck (India), or Spectrochem (India) and were used
without further purification.
2-(2-Bromo-4,5-dimethoxyphenyl)-N-(3-ethoxy-4-methoxyphene-
thyl)acetamide (21d): White solid (84%); Rf (MeOH/CH2Cl2 5:95)=
0.55; purification by flash column chromatography (deactivated
silica gel, MeOH/CH2Cl2 3:97); mp: 119–1218C; 1H NMR (400 MHz,
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CDCl3): d=6.97(s, 1H), 6.70 (d, J=8.0 Hz 1H), 6.64–6.63 (m, 1H),
6.57–6.54 (m, 1H), 5.45 (s, 1H), 4.03 (q, J=7.2 Hz 2H), 3.86–3.82
(m, 9H), 3.57 (s, 1H), 3.44 (q, J=6.4 Hz, 2H), 2.67 (t, J=6.8 Hz, 2H),
1.44 ppm (t, J=7.2 Hz, 3H), 13C NMR (100 MHz, CDCl3): d=169.9,
149.0, 148.8, 148.5, 148.0, 131.1, 126.7, 120.7, 115.6, 114.9, 113.3,
111.6, 64.4, 56.3, 56.2, 56.1, 43.8, 40.9, 35.1, 14.9 ppm; FTIR (KBr):
n˜max =3300, 2930, 1638, 1511, 1465, 1338, 1260, 1027 cmꢁ1; HRMS
(ESI): m/z: calcd for C21H26BrNO5: 453.0994 [M+2]+; found:
453.0998.
23a–f cannot be stored for a long time, as they decompose if stored
for more than 24 h).
General procedure for the synthesis of N-Boc-protected 1-
(2-bromo-4,5-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquino-
line analogues 24a–f
iPr2NEt (6.00 mmol, 2 equiv), 4-(dimethylamino)pyridine (DMAP)
(0.01 g), and Boc2O (3.6 mmol, 1.2 equiv) were added to a stirred
solution of crude oily amine 23a–f (3.00 mmol, 1 equiv) in CH2Cl2
(15 mL) at room temperature, and the resulting mixture was stirred
for 18 h. The mixture was then quenched with aqueous NH4Cl
(2 mL), extracted with CH2Cl2 (3ꢂ50 mL) and water (20 mL), dried
(anhydrous Na2SO4), and concentrated under reduced pressure.
The resultant crude product was purified by flash column chroma-
tography (deactivated 100–200 mesh silica gel, 100% EtOAc),
which furnished Boc-protected 1-(2-bromo-3,4-dimethoxybenzyl)-
1,2,3,4-tetrahydroisoquinoline analogue 24a–f as a white crystal-
line solid in good yield (70–83%).
N-[3-(Benzyloxy)-4-methoxyphenethyl]-2-(2-bromo-4,5-dime-
thoxyphenyl)acetamide (21e): White solid (79%); Rf (MeOH/
CH2Cl2 5:95)=0.60; purification by flash column chromatography
(deactivated silica gel, MeOH/CH2Cl2 3:97); mp: 110–1128C; 1H NMR
(400 MHz, CDCl3): d=7.44–7.42 (m, 2H), 7.35 (t, J=14.8 Hz, 2H),
7.31–7.29 (m, 1H), 6.97 (s, 1H), 6.74–6.67 (m, 3H), 6.60–6.57 (m,
1H), 5.41 (s, 1H), 4.15–4.10 (m, 12H), 3.86 (s, 2H), 3.74 (q, J=
6.8 Hz, 2H), 2.98 ppm (t, J=6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=169.9, 149.0, 148.8, 148.5, 148.3, 137.2, 131.0, 128.7, 127.9,
127.5, 126.7, 121.4, 115.6, 114.9, 114.7, 113.8, 111.9, 71.1, 56.3, 56.2,
56.1, 43.9, 43.8, 40.8, 34.9 ppm; FTIR (KBr): n˜max =3387, 2930, 1635,
1513, 1463, 1384, 1260, 1029 cmꢁ1; HRMS (ESI): m/z: calcd for
C26H28BrNO5: 515.1151 [M+2]+; found: 515.1158.
tert-Butyl 1-(2-bromo-4, 5-dimethoxybenzyl)-6,7-dimethoxy-3,4-
dihydroisoquinoline-2(1H)-carboxylate (24a): White solid (76%);
Rf (MeOH/CH2Cl2 5:95)=0.55; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 3:97); mp: 123–
2-(2-Bromo-4,5-dimethoxyphenyl)-N-(4-ethoxy-3-methoxyphene-
thyl)acetamide (21 f): White solid (75%); Rf (MeOH/CH2Cl2 5:95)=
0.55; purification by flash column chromatography (deactivated
silica gel, MeOH/CH2Cl2 2:98); mp: 119–1218C; 1H NMR (400 MHz,
CDCl3): d=6.97 (s, 1H), 6.76 (s, 1H), 6.71 (d, J=7.6 Hz 1H), 6.63–
6.62 (m, 1H), 6.56–6.53 (m, 1H), 5.46 (s, 1H), 4.08- 4.03 (m, 2H),
3.90–3.81 (m, 9H), 3.57 (s, 2H), 3.45 (q, J=6.8 Hz, 2H), 2.68 (t, J=
6.8 Hz, 2H), 1.44 ppm (t, J=7.2 Hz, 3H), 13C NMR (100 MHz, CDCl3):
d=169.9, 149.4, 149.0, 148.8, 147.0, 131.1, 126.7, 120.7, 115.6,
114.9, 113.8, 112.8, 112.1, 64.4, 56.3, 56.2, 55.9, 43.8, 40.9, 35.1,
14.9 ppm; FTIR (KBr): n˜max =3297, 2930, 1636, 1551, 1464, 1337,
1213, 1164 cmꢁ1; HRMS (ESI): m/z: calcd for C21H26BrNO5: 453.0994
[M+2]+; found: 453.0999.
1
1258C; H NMR (400 MHz, CDCl3, mixture of rotamers): d=7.03 and
6.96 (m, 1H, both rotamers), 6.73 and 6.64 (m, 1H, both rotamers),
6.61 and 6.57 (m, 1H, both rotamers), 6.51–6.47 (m, 1H, both ro-
tamers), 5.39–5.35 and 5.25- 5.22 (m, 1H, both rotamers), 4.36–4.31
(m, 1H, both rotamers), 3.90–3.73 (m, 12H, both rotamers), 3.38–
3.18 (m, 2H, both rotamers), 3.05–2.85 (m, 2H, both rotamers),
2.65–2.61 (m, 1H, both rotamers), 1.37 and 1.16 ppm (m, 2+7=
9H, both rotamers); 13C NMR (100 MHz, CDCl3, major rotamers): d=
154.3, 148.6, 148.4, 147.9, 147.5, 130.4, 128.9, 126.7, 115.5, 114.4,
111.5, 110.1, 79.5, 56.4, 56.3, 56.0, 54.4, 42.2, 36.6, 28.5, 28.3,
28.1 ppm; FTIR (KBr): n˜max =3418, 1690, 1468, 1361, 1253, 1169,
1111 cmꢁ1; HRMS (ESI): m/z: calcd for C25H32BrNO6: 523.1413 [M+
2]+; found: 523.1418.
tert-Butyl
1-(2-bromo-4,5-dimethoxybenzyl)-6-methoxy-7-pro-
poxy-3, 4-dihydroisoquinoline-2(1H)-carboxylate (24b): White
solid (70%); Rf (MeOH/CH2Cl2 5:95)=0.65; purification by flash
column chromatography (deactivated silica gel, MeOH/CH2Cl2
General procedure for the synthesis of 1-(2-bromo-4,5-dime-
thoxybenzyl)-1,2,3,4-tetrahydroisoquinoline analogues
23a–f
1
2:98); mp: 120–1228C; H NMR (400 MHz, CDCl3, mixture of rotam-
Solid PCl5 (10.0 mmol, 2 equiv) was added in portions over a
10 min period to a stirred ice-cooled solution of 2-(2-bromophen-
yl)-N-phenethylacetamide analogue 21a–f (5.00 mmol, 1 equiv) in
dry CH2Cl2 (20 mL). The mixture was stirred at 08C for 1 h and then
at room temperature for 12 h. The mixture was poured onto a sa-
turated aqueous solution of NaHCO3 (30 mL) and was stirred for
1 h. The aqueous layer was extracted with CH2Cl2 (3ꢂ50 mL), and
the combined organic phase was sequentially washed with saturat-
ed NaHCO3 solution (2ꢂ20 mL) and brine (30 mL), dried (anhy-
drous Na2SO4), and concentrated under reduced pressure. Crude
imine 22a–f was immediately used in the next step.
ers): d=7.03 and 6.96 (m, 1H, both rotamers), 6.75 (m, 1H, both
rotamers), 6.63 and 6.61 (m, 1H, both rotamers), 6.57 and 6.51 (m,
1H, both rotamers), 5.36–5.34 and 5.26–5.16 (m, 1H, both rotam-
ers), 4.34–4.30 (m, 1H, both rotamers), 3.96–3.90 (m, 1H, both ro-
tamers), 3.84–3.78(m, 9H, both rotamers), 3.29–3.12 (m, 2H, both
rotamers), 3.02–2.49 (m, 3H, both rotamers), 2.02–1.53 (m, 3H,
both rotamers), 1.36 and 1.15 (m, 7+2=9H, both rotamers), 1.06–
0.94 ppm (m, 3H, both rotamers); 13C NMR (100 MHz, CDCl3, major
rotamer): d=154.3, 148.5, 148.4, 148.0, 147.0, 130.4, 128.9, 126.7,
115.5, 115.2, 114.4, 111.9, 111.9, 79.5, 70.9, 56.4, 56.3, 56.2, 54.4,
42.3, 36.6, 28.5, 28.3, 28.1 ppm; FTIR (KBr): n˜max =3416, 1685, 1512,
1415, 1385, 1260, 1164, 1098 cmꢁ1; HRMS (ESI): m/z: calcd for
C27H36BrNO6: 551.1726 [M+2]+; found: 551.1721.
Sodium borohydride (5.20 mmol, 1.3 equiv) was added slowly in
three portions over a 10 min period to a stirred ice-cooled solution
of crude imine 22a–f (4.00 mmol, 1.0 equiv) in MeOH (15 mL) at
08C. The mixture was stirred at 08C for 1 h and then at room tem-
perature for 2 h. The mixture was cooled to 08C, diluted with
water (5 mL), and extracted with CH2Cl2 (3ꢂ50 mL). The combined
organic layer was washed with brine (25 mL), dried (anhydrous
Na2SO4), and concentrated under reduced pressure to afford the
crude product. Crude oily amine 23a–f was immediately used in
the next step without further purification (CAUTION: compounds
tert-Butyl 7-(benzyloxy)-1-(2-bromo-4,5-dimethoxybenzyl)-6-me-
thoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (24c): White
solid (83%); Rf (MeOH/CH2Cl2 5:95)=0.60; purification by flash
column chromatography (deactivated silica gel, MeOH/CH2Cl2
1
3:97); mp: 108–1108C; H NMR (400 MHz, CDCl3, mixture of rotam-
ers) 7.46–7.27 (m, 5H, both rotamers), 7.02 and 6.96 (m, 1H, both
rotamers), 6.77 (s, 1H, major rotamer), 6.63–6.47(m, 2H, both ro-
tamers), 5.31–4.95 (m, 3H, both rotamers), 4.36–4.32 (m, 1H, both
&
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rotamers), 3.91–3.76 (m, 9H, both rotamers), 3.35–3.13 and 3.06–
3.01 (m, 2H, both rotamers), 2.92- 2.71 and 2.63–2.50 (m, 3H, both
rotamers), 1.36 and 1.13 ppm (m, 7+2=9H, both rotamers);
13C NMR (100 MHz, CDCl3, major rotamer): d=154.3, 148.6, 148.5,
148.4, 146.6, 137.2, 130.5, 128.7, 127.9, 127.4, 127.4, 115.4, 115.0,
114.3, 113.1, 111.9, 79.5, 71.5, 56.4, 56.2, 54.2, 42.2, 38.9, 36.4, 28.5,
28.1 ppm; FTIR (KBr): n˜max =3418, 1689, 1513, 1408, 1387, 1252,
1163, 1104 cmꢁ1; HRMS (ESI): m/z: calcd for C31H36BrNO6: 599.1726
[M+2]+; found: 599.1722.
General procedure for the synthesis of biaryl-coupled N-pro-
tected 1,2,9,10-tetramethoxy-5,6,6a,7-tetrahydro-4H-diben-
zo[de,g]quinoline analogues 25a–f
Pd(OAc)2 (0.02 mmol, 20 mol%), ligand di-tert-butyl(methyl)phos-
phonium tetrafluoroborate (0.04 mmol, 40 mol%), K2CO3
(0.3 mmol, 3 equiv), and pivalic acid (0.04 mmol, 40 mol%) were
added to a solution of compound 24a–f (0.10 mmol, 1 equiv) in
DMSO (1.0 mL) in a microwave vial by purging with nitrogen, and
the mixture was irradiated in a microwave reactor in a sealed vial
for 5 min at 1358C. After cooling to room temperature, the mixture
was loaded onto deactivated silica gel column (100–200 mesh) and
eluted with EtOAc/hexanes (35:65, v/v) to afford desired N-protect-
ed 1,2,9,10-tetramethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]qui-
noline analogue 25a–f as a white solid in excellent yields (up to
73–92%).
tert-Butyl
1-(2-bromo-4,5-dimethoxybenzyl)-6-ethoxy-7-me-
thoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (24d): White
solid (72%); Rf (MeOH/CH2Cl2 5:95)=0.65; purification by flash
column chromatography (deactivated silica gel, MeOH/CH2Cl2
1
2:98); mp: 118–1208C; H NMR (400 MHz, CDCl3, mixture of rotam-
ers): d=7.03 and 6.96 (m, 1H, both rotamers), 6.73 and 6.65 (m,
1H, both rotamers), 6.61 and 6.57 (m, 1H, both rotamers), 6.52–
6.47 (m, 1H, both rotamers), 5.38–5.35 and 5.25- 5.22 (m, 1H, both
rotamers), 4.35–4.31 (m, 1H, both rotamers), 4.12–4.01 (m, 2H,
both rotamers), 3.86–3.72 (m, 9H, both rotamers), 3.39–3.32 and
3.29–3.18 (m, 2H, both rotamers), 3.05–3.00 and 2.95- 2.84 (m, 2H,
both rotamers), 2.80–2.72 and 2.64–2.53 (m, 1H, both rotamers),
1.47–1.43 (m, 3H, both rotamers), 1.38 and 1.17 ppm (m, 2+7=
9H, both rotamers); 13C NMR (100 MHz, CDCl3, major rotamer): d=
154.3, 148.6, 148.4, 147.8, 147.3, 130.5, 128.9, 126.7, 115.5, 115.1,
114.4, 112.9, 110.4, 79.5, 64.5 56.5, 56.3, 56.2, 42.3, 36.6, 28.5, 28.3,
28.1, 14.9 ppm; FTIR (KBr): n˜max =3415, 1687, 1503, 1384,
1033 cmꢁ1; HRMS (ESI): m/z: calcd for C26H34BrNO6: 537.1570 [M+
2]+; found: 537.1576.
tert-Butyl 1,2,9,10-tetramethoxy-6a,7-dihydro-4H-dibenzo[de,g]-
quinoline-6(5H)-carboxylate (25a): White solid (80%); Rf (EtOAc/
hexane 40:60)=0.65; purification by flash column chromatography
1
(deactivated silica gel, hexane/EtOAc 7:3); mp: 130–1328C; H NMR
(400 MHz, CDCl3): d=8.15 (s, 1H), 6.76 (s, 1H), 6.63 (s, 1H), 4.67–
4.39 (m, 5H), 3.92–3.89 (m, 9H), 3.65 (s, 3H), 2.97–2.74 (m, 4H),
2.65–2.62 (m, 1H), 1.49 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=
154.7, 152.0, 148.3, 147.4, 144.7, 130.2, 130.0, 128.2, 127.7, 125.9,
125.7, 124.2, 124.1, 111.7,110.9, 110.6,79.9, 60.1, 55.9, 55.9, 51.9,
51.8, 38.9, 34.8, 30.6, 29.7 28.6 ppm; FTIR (KBr): n˜max =3416, 2941,
1632, 1518, 1465, 1328, 1253, 1199, 1023 cmꢁ1; HRMS (ESI): m/z:
calcd for C25H31NO6: 442.2224 [M+H]+; found: 442.2229.
tert-Butyl 2,9,10-trimethoxy-1-propoxy-6a,7-dihydro-4H-diben-
zo[de,g]quinoline-6(5H)-carboxylate (25b): White solid (84%); Rf
(EtOAc/hexane 40:60)=0.60; purification by flash column chroma-
tography (deactivated silica gel, hexane/EtOAc 7:3); mp: 95–978C;
1H NMR (400 MHz, CDCl3): d=8.15 (s, 1H), 6.75 (s, 1H), 6.61 (s, 1H),
4.61 (s, 1H), 4.38(s, 1H), 3.91–3.85 (m, 9H), 3.81–3.75 (m, 2H), 3.55
(q, J=8.4 Hz, 1H), 2.90–2.61 (m, 4H), 1.76–1.69 (m, 2H), 1.48–1.46
(m, 9H), 0.92 ppm (t, J=7.6 Hz, 3H), 13C NMR (100 MHz, CDCl3): d=
154.8, 152.0, 148.2, 147.2, 144.0, 130.1, 129.9, 128.0, 125.9, 124.5,
112.1, 110.9, 110.6, 79.9, 74.9, 55.9, 55.9, 55.9, 52.0, 38.9, 35.2, 30.5,
28.7, 23.8, 10.5 ppm; FTIR (KBr): n˜max =3417, 2933, 1691, 1512,
1462, 1391, 1247, 1045 cmꢁ1; HRMS (ESI): m/z: calcd for C27H35NO6:
470.2537 [M+H]+; found: 470.2532.
tert-Butyl 6-(benzyloxy)-1-(2-bromo-4,5-dimethoxybenzyl)-7-me-
thoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (24e): White
solid (74%); Rf (MeOH/CH2Cl2 5:95)=0.60; purification by flash
column chromatography (deactivated silica gel, MeOH/CH2Cl2
1
2.5:97.5); mp: 149–1508C; H NMR (400 MHz, CDCl3, mixture of ro-
tamers): d=7.45–7.28 (m, 5H, both rotamers), 7.04 and 6.97 (m,
1H, both rotamers), 6.76 (s, 1H, major rotamer), 6.65–6.61 (m, 1H,
both rotamers), 6.51–6.50 (m, 1H, both rotamers), 5.39–5.35 and
5.26–5.22 (m, 1H, both rotamers), 5.12–5.11 (m, 2H, both rotam-
ers), 4.33–4.29 (m, 1H, both rotamers), 3.86–3.74 (m, 9H, both ro-
tamers), 3.37–3.18 (m, 2H, both rotamers), 3.05–3.30 and 2.95–2.80
(m, 2H, both rotamers), 2.60–2.51 (m, 1H, both rotamers), 1.37 and
1.17 ppm (m, 7+2=9H, both rotamers); 13C NMR (100 MHz, CDCl3,
major rotamer): d=154.3, 148.6, 148.4, 148.2, 147.2, 137.2, 130.4,
129.5, 128.7, 127.9, 127.4, 126.7, 115.5, 115.0, 114.4, 114.1, 110.8,
79.5, 71.1, 56.5, 56.3, 56.1, 54.5, 42.3, 36.6, 28.5, 28.1 ppm; FTIR
(KBr): n˜max =3418, 2929, 1687, 1512, 1461, 1252, 1163 cmꢁ1; HRMS
(ESI): m/z: calcd for C31H36BrNO6: 599.1726 [M+]+; found: 599.1729.
tert-Butyl
1-(benzyloxy)-2,9,10-trimethoxy-6a,7-dihydro-4H-di-
benzo[de,g]quinoline-6(5H)-carboxylate (25c): White solid (88%);
Rf (EtOAc/hexane 40:60)=0.60; purification by flash column chro-
matography (deactivated silica gel, hexane/EtOAc 7.5:2.5); mp:
150–1528C; 1H NMR (400 MHz, CDCl3): d=8.07 (s, 1H), 7.39–7.29
(m, 5H), 6.76 (s, 1H), 6.66 (s, 1H), 4.92 (d, J=8.0 Hz, 1H), 4.66 (d,
J=12.0 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.41 (d, J=8.0 Hz, 1H),
3.92 (s, 6H), 3.51 (s, 3H), 2.98–2.64 (m, 5H), 1.49 ppm (s, 9H);
13C NMR (100 MHz, CDCl3): d=154.8, 152.2, 148.2, 147.2, 143.6,
137.4, 129.9, 128.8, 128.4, 128.2, 112.1, 110.9, 79.9, 74.7, 56.1, 55.9,
55.5, 51.9, 38.8, 35.2, 30.6, 28.7 ppm; FTIR (KBr): n˜max =3413, 2972,
1686, 1595, 1466, 1391, 1250, 1112 cmꢁ1; HRMS (ESI): m/z: calcd for
C31H35NO6: 518.2537 [M+H]+; found: 518.2533.
tert-Butyl
1-(2-bromo-4,5-dimethoxybenzyl)-7-ethoxy-6-me-
thoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (24 f): White
solid (78%); Rf (MeOH/CH2Cl2 5:95)=0.60; purification by flash
column chromatography (deactivated silica gel, MeOH/CH2Cl2
1
3:97); mp: 110–1128C; H NMR (400 MHz, CDCl3, mixture of rotam-
ers): d=7.03 and 6.96 (m, 1H, both rotamers), 6.77–6.51 (m, 3H,
both rotamers), 5.36–5.21 (m, 1H, both rotamers), 4.36–4.31 and
4.09–4.03 (m, 1H, both rotamers), 3.91–3.79 (m, 11H, both rotam-
ers), 3.28–3.17 (m, 2H, both rotamers), 3.02–2.54 (m, 2H, both ro-
tamers), 1.48–1.32 (m, 6H, both rotamers), 1.24–1.16 ppm (m, 6H,
major rotamer); 13C NMR (100 MHz, CDCl3, major rotamer): d=
154.3, 148.6, 148.4, 148.3, 146.8, 130.5, 128.9, 126.8, 115.5, 115.0,
114.4, 111.7, 111.7, 79.5, 64.7, 56.4, 56.3, 56.1, 54.4, 42.3, 36.6, 28.5,
28.3, 28.1 ppm; FTIR (KBr): n˜max =3419, 1687, 1510, 1417, 1383,
1257, 1162, 1097 cmꢁ1; HRMS (ESI): m/z: calcd for C26H34BrNO6:
537.1570 [M+2]+; found: 537.1578.
tert-Butyl 2-ethoxy-1,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo-
[de,g]quinoline-6(5H)-carboxylate (25d): White solid; 90%); Rf
(EtOAc/hexane 40:60)=0.65; purification by flash column chroma-
tography (deactivated silica gel, hexane/EtOAc 7:3); mp: 101–
1
1038C; H NMR (400 MHz, CDCl3): d=8.17 (s, 1H), 6.76 (s, 1H), 6.62
(s, 1H), 4.68–4.65 (m, 1H), 4.38 (s, 1H), 4.12–4.07 (m, 2H), 3.90 (d,
J=7.2 Hz, 6H), 3.67 (s, 3H), 2.97–2.60 (m, 5H), 1.51–1.46 ppm (m,
12H); 13C NMR (100 MHz, CDCl3): d=154.8, 151.3, 148.3, 147.4,
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144.9, 130.1, 127.8, 125.8, 124.4, 111.8, 111.6, 110.9, 79.9, 64.2, 60.0,
CH2Cl2 1:99, v/v), which furnished 27a–o or 27q–s (69–93%) as a
56.0, 55.9, 51.9, 38.8, 34.9, 30.5, 28.6, 15.5 ppm; FTIR (KBr): n˜max
=
white solid.
3417, 2930, 1681, 1514, 1412, 1380, 1250, 1105 cmꢁ1; HRMS (ESI):
1-[1,2,9,10-Tetramethoxy-6a,7-dihydro-4H-dibenzo[de,g]quino-
lin-6(5H)-yl]ethanone (27a): White solid (73%); Rf (MeOH/CH2Cl2
5:95)=0.55; purification by flash column chromatography (deacti-
vated silica gel, MeOH/CH2Cl2 3:97); mp: 172–1748C; 1H NMR
(400 MHz, CDCl3, both rotamers): d=8.17–8.14 (m, 1H), 6.78–6.76
(m, 1H), 6.65–6.62 (m, 1H), 5.08–4.94 (m, 1H), 4.00–3.83 (m, 10H),
3.65 (s, 3H), 3.33–3.27 (m, 1H), 3.08–2.63 (m, 5H), 2.21–2.18 ppm
(m, 3H); 13C NMR (100 MHz, CDCl3, major rotamer): d=169.2, 152.1,
148.4, 147.5, 145.0, 130.6, 129.9, 129.2, 128.0, 125.9, 124.0, 111.7,
110.9, 60.1, 56.0, 54.2, 50.8, 42.2, 36.2, 33.6, 30.9, 22.8 ppm; FTIR
(KBr): n˜max =2943, 2847, 1607, 1575, 1418, 1256, 1034 cmꢁ1; HRMS
(ESI): m/z: calcd for C22H25NO5: 384.1805 [M+H]+; found: 384.1801.
m/z: calcd for C26H33NO6: 456.2381 [M+H]+; found: 456.2386.
tert-Butyl
2-(benzyloxy)-1,9,10-trimethoxy-6a,7-dihydro-4H-di-
benzo[de,g]quinoline-6(5H)-carboxylate (25e): White solid (73%);
Rf (EtOAc/hexane 40:60)=0.60; purification by flash column chro-
matography (deactivated silica gel, hexane/EtOAc 7.5:3.5); mp:
143–1458C; 1H NMR (400 MHz, CDCl3): d=8.15 (s, 1H), 7.46–7.37
(m, 5H), 6.75 (s, 1H), 6.68 (s, 1H), 5.13 (q, J=12.0 Hz, 2H), 4.67 (s,
1H), 4.37 (s, 1H), 3.91 (d, J=2.4 Hz, 6H), 3.69 (s, 3H), 2.92–2.74 (m,
4H), 2.59 (d, J=15.2 Hz, 1H), 1.48 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=154.6, 151.0, 148.1, 147.2, 145.0, 136.9, 129.9, 128.5,
127.9, 127.8, 127.2, 126.2, 124.2, 112.2, 111.6, 110.8, 79.8, 70.7, 60.0,
55.9, 55.7, 51.8, 38.4, 34.8, 30.3, 28.5 ppm; FTIR (KBr): n˜max =3416,
2930, 1690, 1513, 1460, 1380, 1252, 1027 cmꢁ1; HRMS (ESI): m/z:
calcd for C31H35NO6: 518.2537 [M+H]+; found: 518.2532.
1,2,9,10-Tetramethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-
4H-dibenzo[de,g]quinoline (27b): White solid (93%); Rf (MeOH/
CH2Cl2 5:95)=0.65; purification by flash column chromatography
(deactivated silica gel, MeOH/CH2Cl2 3:97); mp: 258–2608C;
1H NMR (400 MHz, CDCl3): d=8.13 (s, 1H), 6.78 (s, 1H), 6.63 (s, 1H),
4.49 (t, J=9.6 Hz, 1H), 4.12–4.09 (m, 1H), 3.92–3.89 (m, 9H), 3.65–
3.64 (m, 3H), 3.30–3.23 (m, 1H), 2.99 (d, J=10 Hz, 2H), 2.94–2.86
(m, 4H), 2.69 ppm (d, J=15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=152.5, 148.6, 147.7, 145.1, 129.5, 128.9, 128.2, 124.6, 123.8,
111.7, 111.2, 110.8, 60.1, 56.0, 55.9, 53.4, 40.7, 39.7, 37.0, 29.6 ppm;
FTIR (KBr): n˜max =2964, 2846, 1632, 1595, 1458, 1329, 1254,
1106 cmꢁ1; HRMS (ESI): m/z: calcd for C21H25NO6S: 420.1475 [M+
H]+; found: 420.1479.
tert-Butyl 1-ethoxy-2,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo-
[de,g]quinoline-6(5H)-carboxylate (25 f): White solid (79%); Rf
(EtOAc/hexane 40:60)=0.65; purification by flash column chroma-
tography (deactivated silica gel, hexane/EtOAc 7:3); mp: 113–
1
115 8C; H NMR (400 MHz, CDCl3): d=8.18 (s, 1H), 6.75 (s, 1H), 6.61
(s, 1H), 4.63 (d, J=12.4 Hz 1H), 4.39 (d, J=8.0 Hz, 1H), 3.94–3.91
(m, 6H), 3.87 (s, 3H), 3.68–3.60 (m, 1H), 2.96–2.73 (m, 4H), 2.62 (d,
J=14.8 Hz, 1H), 1.48 (s, 9H), 1.31 ppm (t, J=7.2 Hz 3H); 13C NMR
(100 MHz, CDCl3): d=154.8, 152.1, 148.2, 147.2, 143.8, 130.1, 130.1,
128.1, 125.9, 124.5, 111.9, 110.9, 110.9, 110.5, 79.9, 68.6, 55.9, 55.9,
52.0, 38.7, 35.0, 30.5, 29.8, 28.6, 16.0 ppm; FTIR (KBr): n˜max =3417,
2934, 1685, 1515, 1463, 1391, 1252, 1018 cmꢁ1; HRMS (ESI): m/z:
calcd for C26H33NO6: 456.2308 [M+H]+; found: 456.2303.
1,2,9,10-Tetramethoxy-6-(m-tolylsulfonyl)-5,6,6a,7-tetrahydro-
4H-dibenzo[de,g]quinoline (27c): White solid (90%); Rf (MeOH/
CH2Cl2 5:95)=0.60; purification by flash column chromatography
(deactivated silica gel, MeOH/CH2Cl2 3:97); mp: 207–2098C;
1H NMR (400 MHz, CDCl3): d=8.12 (s, 1H), 7.62–7.59 (m, 2H), 7.31–
7.26 (m, 2H), 6.81 (s, 1H), 6.48 (s, 1H), 4.59–4.55 (m, 1H), 4.10 (d,
J=15.2 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H), 3.62 (s, 3H),
3.29 (t, J=12.0 Hz, 1H), 3.13–3.09 (m, 1H), 3.03–2.96 (m, 1H), 2.46–
2.36 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=152.3, 148.5,
147.7, 144.9, 140.8, 139.5, 133.5, 129.6, 129.2, 128.1, 127.4, 127.4,
124.1, 123.9, 111.7, 111.3, 110.6, 60.1, 56.0, 55.9, 53.5, 41.2, 37.7,
29.8, 28.9, 21.5 ppm; FTIR (KBr): n˜max =2931, 2845, 1602, 1513,
1460, 1317, 1254, 1104 cmꢁ1; HRMS (ESI): m/z: calcd for C27H29NO6S:
496.1788 [M+H]+; found: 496.1783.
General procedure for the synthesis of 1,2,9,10-tetrame-
thoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline ana-
logues 26a–f
Anhydrous ZnBr2 (4.00 mmol, 4 equiv) was added to a solution of
compound 25a–f (1.00 mmol, 1 equiv) in dry CH2Cl2 (10 mL) under
a nitrogen atmosphere, and the mixture was stirred at room tem-
perature for 6 h. The mixture was then quenched with a solution
of saturated NaHCO3 (10 mL) and was extracted with CH2Cl2 (3ꢂ
50 mL). The combined organic layer was dried (anhydrous Na2SO4)
and concentrated under reduced pressure to afford crude amine
26a–f, which was immediately used in the next step without any
further purification. (CAUTION: compound was found to be unstable
for long-term storage).
1-(2-Ethoxy-1,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo[de,g]qui-
nolin-6(5H)-yl)ethanone (27d): White solid (77%); Rf (MeOH/
CH2Cl2 5:95)=0.65; purification by flash column chromatography
(deactivated silica gel, MeOH/CH2Cl2 2:98); mp: 219–2218C;
1H NMR (400 MHz, CDCl3, mixture of rotamers): d=8.18–8.15 (m,
1H), 6.77–6.76 (m, 1H), 6.64–6.61 (m, 1H), 5.08–4.93 (m, 1H), 4.12–
4.08 (m, 2H), 4.00–3.97 (m, 1H), 3.93–3.90 (m, 6H), 3.67–3.66 (m,
3H), 3.33–2.61 (m, 5H), 2.21–2.17 (m, 3H), 1.51–1.47 ppm (m, 3H);
13C NMR (100 MHz, CDCl3, major rotamer): d=169.2, 151.4, 148.3,
147.4, 145.2, 130.5, 129.9, 129.1, 128.0, 127.6, 125.8, 124.1, 111.7,
111.4, 64.2, 60.0, 56.0, 54.2, 50.7, 42.2, 36.6, 33.6, 30.8, 22.8,
15.1 ppm; FTIR (KBr): n˜max =2931, 1639, 1512, 1449, 1353,
1255, 1099 cmꢁ1; HRMS (ESI): m/z: calcd for C23H27NO5: 398.1962
[M+H]+; found: 398.1967.
General procedure for the synthesis of N-acetyl/benzoyl/
methylsulfonyl/m-tolylsulfonyl-protected 1,2,9,10-tetrame-
thoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline ana-
logues 27a–o and 27q–s
Triethylamine (0.50 mmol, 2.5 equiv) was added to a solution of
crude amine 26a–f (0.20 mmol, 1 equiv) in anhydrous CH2Cl2
(20 mL), followed by acetyl chloride (0.24 mmol, 1.2 equiv), metha-
nesulfonyl chloride (0.24 mmol, 1.2 equiv), p-toluenesulfonyl chlo-
ride (0.22 mmol, 1.1 equiv), or benzoyl chloride (0.22 mmol,
1.1 equiv) at room temperature, and the mixture was stirred for 8 h
under a N2 atmosphere. The mixture was quenched with NaHCO3
(5% aqueous solution, 10 mL) and extracted with CH2Cl2 (3ꢂ
50 mL). The combined organic phase was dried (anhydrous
Na2SO4) and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (MeOH/
[2-Ethoxy-1,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo[de,g]qui-
nolin-6(5H)-yl](phenyl)methanone (27e): White solid (69%); Rf
(MeOH/CH2Cl2 5:95)=0.65; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 1:99); mp: 218–
1
2208C; H NMR (400 MHz, CDCl3): d=8.17 (s, 1H), 7.43 (S, 5H), 6.79
(s, 1H), 6.62 (s, 1H), 4.13–4.07 (m, 3H), 3.91 (s, 6H), 3.69 (s, 3H),
&
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Full Papers
3.27–3.21 (m, 3H), 2.89 (q, J=13.2 Hz„ 2H), 2.63–2.59 (m, 1H), 2,9,10-Trimethoxy-6-(methylsulfonyl)-1-propoxy-5,6,6a,7-tetra-
1.49 ppm (t, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=170.9, hydro-4H-dibenzo[de,g]quinoline (27j): White solid (83%); Rf
151.5, 148.3, 147.5, 145.2, 136.9, 129.7, 129.3, 128.7, 128.0, 126.7,
125.4, 124.2, 111.8, 111.5, 111.3, 64.3, 60.0, 56.0, 55.9, 34.8, 29.8,
15.1 ppm; FTIR (KBr): n˜max =3292, 3053, 2921, 2852, 1713, 1604,
(MeOH/CH2Cl2 5:95)=0.60; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 2:98); mp: 185–
1
1868C; H NMR (400 MHz, CDCl3): d=8.14 (s, 1H), 6.78 (s, 1H), 6.62
1428, 1151 cmꢁ1; HRMS (ESI): m/z: calcd for C28H29NO5: 460.2118 (s, 1H), 4.45 (t, J=9.2 Hz, 1H), 4.12–4.08 (m, 1H), 3.92–3.88 (m,
[M+H]+; found: 460.2113.
9H), 3.78 (q, J=8.4 Hz, 1H), 3.55 (q, J=8.0 Hz, 1H), 3.26 (t, J=
12.0 Hz, 1H), 2.99–2.97 (m, 2H), 2.89–2.87 (m, 4H), 2.71–2.67 (m,
1H), 1.77–1.68 (m, 2H), 0.92 ppm (t, J=8.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=152.5, 148.5, 147.5, 144.5, 129.4, 128.6, 128.5,
124.6, 124.1, 112.1, 111.1, 110.8, 74.9, 56.0, 55.9, 53.4, 40.7, 39.6,
37.2, 29.8, 29.8, 29.6, 23.8 ppm; FTIR (KBr): n˜max =2925, 2849, 1631,
1514, 1462, 1386, 1254, 1077 cmꢁ1; HRMS (ESI): m/z: calcd for
C23H29NO6S: 448.1788 [M+H]+; found: 448.1783.
2-Ethoxy-1,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahy-
dro-4H-dibenzo[de,g]quinoline (27 f): White solid (91%); Rf
(MeOH/CH2Cl2 5:95)=0.60; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 2:98); mp: 241–
1
2428C; H NMR (400 MHz, CDCl3): d=8.14 (s, 1H), 6.78 (s, 1H), 6.62
(s, 1H), 4.49 (t, J=9.2 Hz, 1H), 4.12–4.07 (m, 2H), 3.92–3.90 (m,
6H), 3.67 (s, 3H), 3.30–3.23 (m, 1H), 2.99 (d, J=9.2 Hz, 2H), 2.89–
2.87 (m, 3H), 2.67 (d, J=15.6 Hz, 1H), 1.50 ppm (t, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=151.8, 148.5, 147.7, 145.3, 129.4, hydro-4H-dibenzo[de,g]quinoline (27k): White solid (87%); Rf
128.8, 128.2, 124.4, 123.9, 111.8, 111.7, 111.2, 64.3, 60.1, 56.1, 55.9, (MeOH/CH2Cl2 5:95)=0.65; purification by flash column chroma-
2,9,10-Trimethoxy-1-propoxy-6-(m-tolylsulfonyl)-5,6,6a,7-tetra-
53.4, 40.7, 39.7, 37.1, 29.6, 15.1 ppm; FTIR (KBr): n˜max =2929, 2851,
tography (deactivated silica gel, MeOH/CH2Cl2 2.5:97.5); mp: 265–
1631, 1514, 1419, 1355, 1256, 1102 cmꢁ1; HRMS (ESI): m/z: calcd for 2678C; 1H NMR (400 MHz, CDCl3): d=8.12 (s, 1H), 7.62–7.59 (m,
C22H27NO6S: 434.1632 [M+H]+; found: 433.1638.
2H), 7.34–7.31 (m, 2H), 6.81 (s, 1H), 6.47 (s, 1H), 4.54 (dd, J=
4.8,13.6 Hz 1H), 4.11–4.06 (m, 1H), 3.94–3.88 (m, 6H), 3.82 (s, 3H),
3.78–3.72 (m, 1H), 3.10 (dd, J=3.6, 14.0 1H), 2.99 (t, J=13.2 Hz,
1H), 2.36–2.34 (m, 5H), 1.77–1.65 (m, 2H), 0.90 ppm (t, J=7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=152.3, 148.4, 147.4, 144.2,
140.8, 139.5, 133.5, 129.5, 129.2, 128.9, 128.4, 127.4, 124.8, 124.2,
124.1, 112.0, 111.1, 110.6, 75.0, 55.9, 55.9, 55.6, 41.2, 37.8, 29.8, 28.8,
23.7, 21.5, 10.5 ppm; FTIR (KBr): n˜max =2931, 1632, 1513, 1461,
1339, 1254, 1012 cmꢁ1; HRMS (ESI): m/z: calcd for C29H33NO6S:
524.2101 [M+H]+; found: 524.2106.
2-Ethoxy-1,9,10-trimethoxy-6-(m-tolylsulfonyl)-5,6,6a,7-tetrahy-
dro-4H-dibenzo[de,g]quinoline (27g): White solid (86%); Rf
(MeOH/CH2Cl2 5:95)=0.55; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 3:97); mp: 196–
1978C; 1H NMR (400 MHz, CDCl3): d=8.13 (s, 1H), 7.62–7.60 (m,
2H), 7.32–7.31 (m, 2H), 6.81 (s, 1H), 6.47 (s, 1H), 4.59–4.55 (m, 1H),
4.11–4.00 (m, 3H), 3.94 (s, 3H), 3.90 (s, 1H), 3.64 (s, 3H), 3.29 (t, J=
11.6 Hz, 1H), 3.13–2.96 (m, 2H), 2.45–2.33 (m, 5H), 1.46 ppm (t, J=
7.2, 3H); 13C NMR (100 MHz, CDCl3): d=151.6, 148.5, 147.6, 145.1,
140.8, 139.6, 133.5, 129.5, 129.3, 129.2, 128.1, 127.4, 124.5, 124.1,
1-[1-(Benzyloxy)-2,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo-
124.0, 111.7, 111.5, 111.2, 64.2, 60.1, 56.1, 55.9. 53.5, 41.2, 37.7, 28.9, [de,g]quinolin-6(5H)-yl]ethanone (27l): White solid (67%); Rf
21.5, 15.1 ppm; FTIR (KBr): n˜max =2927, 2849, 1735, 1632, 1515, (MeOH/CH2Cl2 5:95)=0.55; purification by flash column chroma-
1467, 1336, 1252, 1099 cmꢁ1
; HRMS (ESI): m/z: calcd for tography (deactivated silica gel, MeOH/CH2Cl2 3:97); mp: 165–
C28H31NO6S: 510.1945 [M+H]+; found: 510.1949.
1678C; 1H NMR (400 MHz, CDCl3, mixture of rotamers): d=8.09–
8.06 (m, 1H), 7.37–7.29 (m, 5H), 6.78–6.76 (m, 1H), 6.69–6.65 (m,
1H), 5.08–5.05 (m, 1H), 4.98–3.93 (m, 1H), 4.02–3.90 (m, 6H), 3.49
(s, 3H), 3.32 (t, J=12.4, 1H), 3.08–2.68 (m, 4H), 2.22–2.18 ppm (m,
3H); 13C NMR (100 MHz, CDCl3, major rotamer): d=169.2, 152.2,
148.2, 147.2, 143.8, 137.4, 130.7, 129.7, 129.4, 128.9, 128.7, 128.4,
128.2, 126.0, 124.9, 124.1, 112.1, 111.3, 110.6, 74.6, 56.1, 55.8, 55.5,
54.2, 50.8, 42.2, 36.2, 34.7, 33.6, 31.7, 30.9, 30.9, 30.0, 29.8, 26.9,
25.4, 22.8, 21.8, 20.8 ppm. FTIR (KBr): n˜max =2929, 2840, 1737, 2852,
1621, 1510, 1432, 1392, 1221, 1027 cmꢁ1; HRMS (ESI): m/z: calcd for
C28H29NO5: 460.2118 [M+H]+; found: 460.2112.
1-Ethoxy-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahy-
dro-4H-dibenzo[de,g]quinoline (27h): White solid (92%); Rf
(MeOH/CH2Cl2 5:95)=0.60; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 2:98); mp: 190–
1
1938C; H NMR (400 MHz, CDCl3): d=8.15 (s, 1H), 6.76 (s, 1H), 6.61
(s, 1H), 4.47–4.42 (m, 1H), 4.09–4.06 (m, 1H), 3.90–3.86 (m, 9H),
3.64–3.61 (m, 1H), 3.45–3.44 (m, 3H), 3.28–3.22 (m, 1H), 2.97–2.85
(m, 4H), 2.69–2.66 (m, 1H) 1.34–1.23 ppm (m, 3H); 13C NMR
(100 MHz, CDCl3): d=152.6, 148.4, 147.4, 144.1, 129.4, 128.7, 128.5,
124.6, 111.9, 111.1, 110.7, 68.7, 55.9, 55.9, 55.9, 53.4, 50.8, 40.7, 39.6,
37.1, 29.8, 15.9 ppm; FTIR (KBr): n˜max =2930, 2842, 1730, 1632,
[1-(Benzyloxy)-2,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo[de,g]-
1513, 1464, 1384, 1254, 1104 cmꢁ1; HRMS (ESI): m/z: calcd for quinolin-6(5H)-yl](phenyl)methanone (27m): White solid (71%);
C22H27NO6S: 434.1632 [M+H]+; found: 433.1638.
Rf (MeOH/CH2Cl2 5:95)=0.60; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 1.5:98.5); mp: 165–
1668C; 1H NMR (400 MHz, CDCl3): d=8.08 (s, 1H), 7.44–7.38 (m,
7H), 7.35–7.28 (m, 3H), 6.79(s, 1H), 6.66 (s, 1H), 4.92 (d, J=10.4 Hz,
1H), 4.55 (d, J=10.8 Hz, 1H), 4.12–4.02 (m, 1H), 3.92–3.91 (m, 6H),
3.50 (s, 3H), 3.25–3.12 (m, 2H), 2.97–2.80 (m, 3H), 2.67–2.60 ppm
(m, 1H); 13C NMR (100 MHz, CDCl3): d=170.9, 152.4, 148.3, 147.3,
143.8, 137.4, 136.9, 129.7, 129.7, 128.8, 128.7, 128.6, 128., 128.2,
126.8, 125.7, 124.1, 112.1, 112.2, 110.7, 74.6, 56.1, 55.7, 55.6, 51.4,
34.03, 43.5, 30.9, 29.8 ppm; FTIR (KBr): n˜max =2926, 2856, 1738,
1625, 1508, 1421, 1217, 1024 cmꢁ1; HRMS (ESI): m/z: calcd for
C33H31NO5: 522.2275 [M+H]+; found: 522.2272.
1-Ethoxy-2,9,10-trimethoxy-6-(m-tolylsulfonyl)-5,6,6a,7-tetrahy-
dro-4H-dibenzo[de,g]quinoline (27i): White solid (88%); Rf
(MeOH/CH2Cl2 5:95)=0.65; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 2:98); mp: 230–
2318C; 1H NMR (400 MHz, CDCl3): d=8.15 (s, 1H), 7.62–7.59 (m,
2H), 7.31 (s, 2H), 6.81 (s, 1H), 6.47 (s, 1H), 4.55–4.52 (m, 1H), 4.10–
4.07 (m, 1H), 3.94- 3.91(m, 10H), 3.64–3.60 (m, 1H), 3.32–2.95 (m,
3H), 2.46–2.36 (m, 5H), 1.31–1.27 ppm (m, 3H); 13C NMR (100 MHz,
CDCl3): d=152.4, 148.4, 147.4, 143.9, 140.8, 139.5, 133.5, 129.5,
129.2, 129.1, 128.5, 127.4, 124.7, 124.2, 124.1, 111.9, 111.2, 110.5,
68.7, 55.9, 55.9, 53.6, 41.2, 37.8, 28.9, 21.5, 15.9 ppm; FTIR (KBr):
n˜max =2924, 2830, 1631, 1513, 1464, 1340, 1254, 1105 cmꢁ1; HRMS 1-(Benzyloxy)-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tet-
(ESI): m/z: calcd for C28H31NO6S: 510.1945 [M+H]+; found: rahydro-4H-dibenzo[de,g]quinoline (27n): White solid (88%); Rf
510.1940.
(MeOH/CH2Cl2 5:95)=0.60; purification by flash column chroma-
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Full Papers
tography (deactivated silica gel, MeOH/CH2Cl2 2:98); mp: 178–
1798C; 1H NMR (400 MHz, CDCl3): d=8.04 (s, 1H), 7.37–7.28 (m,
5H), 6.78 (s, 1H), 6.66 (s, 1H), 4.91 (d, J=10.0 Hz, 1H), 4.52–4.46
(m, 2H), 4.14–4.10 (m, 1H), 3.92 (s, 6H), 3.50 (s, 3H), 3.32–3.24 (m,
1H), 3.15–3.13 (m, 1H), 3.02–2.87 (m, 5H), 2.79–2.70 ppm (m, 1H);
13C NMR (100 MHz, CDCl3): d=152.6, 148.4, 147.4, 143.9, 137.2,
129.3, 129.1, 128.8, 128.7, 128.4, 128.3, 124.6, 123.9, 112.1, 111.1,
110.9, 74.7, 56.1, 55.9, 55.6, 53.4, 46.1, 39.6, 37.1, 29.6 ppm; FTIR
(MeOH/CH2Cl2 5:95)=0.65; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 2:98); mp: 175–
1768C; 1H NMR (400 MHz, CDCl3): d=8.14 (s, 1H), 7.48–7.34 (m,
5H), 6.78 (s, 1H), 6.69 (s, 1H), 5.14(q, J=12, 2H), 4.50 (t, J=8.8,
1H), 4.12–4.07(m, 1H), 3.92–3.91(m, 6H), 3.71(s, 3H), 3.28–3.22 (m,
1H), 2.99 (d, J=9.2, 2H), 2.90–2.83 (m, 4H), 2.67–2.63 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d=151.7, 148.6, 147.7, 145.6,
136.9, 129.5, 128.9, 128.8, 128.4, 128.2, 127.4, 124.9, 123.9, 112.5,
111.7, 111.2, 70.9, 60.2, 56.1, 55.9, 53.3, 40.6, 39.7, 36.9, 29.6 ppm;
FTIR (KBr): n˜max =2998, 2844, 1738, 1592, 1459, 1322, 1250,
1018 cmꢁ1; HRMS (ESI): m/z: calcd for C27H29NO6S: 496.1788 [M+
H]+; found: 496.1783.
(KBr): n˜max =2932, 2838, 1738, 1581, 1510, 1448, 1383, 1011 cmꢁ1
;
HRMS (ESI): m/z: calcd for C27H29NO6S: 496.1788 [M+H]+; found:
496.1782.
1-(Benzyloxy)-2,9,10-trimethoxy-6-(m-tolylsulfonyl)-5,6,6a,7-tet-
rahydro-4H-dibenzo[de,g]quinoline (27o): White solid (90%); Rf
(MeOH/CH2Cl2 5:95)=0.65; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 1.5:98.5); mp: 119–
1208C; 1H NMR (400 MHz, CDCl3): d=8.04 (s, 1H), 7.63–7.60 (m,
2H), 7.33–7.29 (m, 7H), 6.81 (s, 1H), 6.51 (s, 1H), 5.28 (s, 2H), 4.89
(t, J=5.2 Hz, 1H), 4.58–4.45 (m, 2H), 4.10 (d, J=14.0 Hz, 1H), 3.94–
3.86 (m, 6H), 3.51 (s, 3H), 3.33–3.26 (m, 1H), 3.14–3.95 (m, 1H),
2.51–2.28 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=152.4, 148.4,
147.4, 143.7, 140.7, 139.5, 137.2, 133.5, 129.4, 128.8, 128.4, 128.3,
127.3, 124.1, 112.0, 111.1, 110.7, 74.7, 55.9, 55.9, 55.6, 53.5, 41.2,
32.0, 28.8, 26.9, 14.2 ppm. FTIR (KBr): n˜max =2929, 2856, 1737, 1591,
2-(Benzyloxy)-1,9,10-trimethoxy-6-(m-tolylsulfonyl)-5,6,6a,7-tet-
rahydro-4H-dibenzo[de,g]quinoline (27s): White solid (88%); Rf
(MeOH/CH2Cl2 5:95)=0.60; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 2:98); mp: 125–
1268C; 1H NMR (400 MHz, CDCl3): d=8.14 (s, 1H), 7.62–7.60 (m,
2H), 7.45–7.31 (m, 7H), 6.81 (s 1H), 6.54 (s, 1H), 5.11–5.04 (m, 2H),
4.61–4.56 (m, 1H), 4.10–4.06 (m, 1H), 3.94–3.91 (m, 6H), 3.72–3.68
(m, 3H), 3.31–3.24 (m, 1H), 3.13–2.96 (m, 2H), 2.43–2.36 ppm (m,
5H); 13C NMR (100 MHz, CDCl3): d=151.5, 148.5, 147.6, 145.4,
140.8, 139.5, 136.9, 133.5, 129.6, 129.2, 129.2, 128.7, 128.1, 127.4,
125.1, 124.1, 123.9, 112.2, 111.7, 111.2, 70.8, 60.2, 56.1, 55.9, 53.5,
41.1, 37.6, 28.8, 21.5 ppm; FTIR (KBr): n˜max =2929, 2840, 1735, 1587,
1449, 1339, 1249, 1001 cmꢁ1
; HRMS (ESI): m/z: calcd for
C33H33NO6S: 572.2101 [M+H]+; found: 572.2106.
1457, 1333, 1250, 1017 cmꢁ1
; HRMS (ESI): m/z: calcd for
C33H33NO6S: 572.2101 [M+H]+; found: 572.2106.
1-(Benzyloxy)-2,9,10-trimethoxy-6-methyl-5,6,6a,7-tetrahydro-
4H-dibenzo[de,g]quinoline (27p): Crude amine 26c (0.90 mmol,
1 equiv) and formaldehyde (30% aqueous solution, 1.84 mmol,
2 equiv) were dissolved in CH2Cl2 (15 mL), and the mixture was
stirred at room temperature for 10 min. Sodium triacetoxyborohy-
dride (4.61 mmol, 5.0 equiv) was added, and the mixture was
stirred at room temperature overnight. The mixture was quenched
with NaHCO3 (5% aqueous solution, 10 mL) and extracted with
CH2Cl2 (3ꢂ50 mL). The combined organic phase was dried (anhy-
drous Na2SO4) and concentrated under reduced pressure. The
crude product was purified by flash column chromatography
(MeOH/CH2Cl2 1:99, v/v), which furnished 27p as a solid (67%): Rf
(MeOH/CH2Cl2 5:95)=0.50; 1H NMR (400 MHz, CDCl3): d=7.99 (s,
1H), 7.33–7.23 (m, 5H), 6.75 (s, 1H), 6.59 (s, 1H), 4.88 (d, J=
14.4 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.54 (s, 3H), 3.20–2.97 (m,
4H), 2.70–2.65 (m, 1H), 2.60–2.48 ppm (m, 5H), 13C NMR (100 MHz,
CDCl3): d=152.2, 147.9, 147.3, 142.9, 137.3, 129.2, 129.1, 128.9,
128.3, 128.1, 127.7, 127.2, 124.6, 112.1, 110.7, 110.5, 74.9, 62.7, 55.9,
55.9, 55.7, 53.4, 44.1, 34.6, 29.3 ppm; FTIR (KBr): n˜max =2938, 2843,
1736, 1591, 1453, 1371, 1223, 1151 cmꢁ1; HRMS (ESI): m/z: calcd for
C27H29NO4: 432.2169 [M+H]+; found: 432.2163.
Biological methods
Platelet aggregation inhibitory activity evaluation:[11a–c] Synthe-
sized novel aporphine analogues 34a–s were dissolved in DMSO
before testing. To eliminate the effects of the solvent on aggrega-
tion, the final concentration of DMSO was fixed at 0.5%. Arachi-
donic acid (AA), disodium ethylenediaminetetraacetate (Na2EDTA),
bovine serum albumin, and dimethyl sulfoxide (DMSO) were pur-
chased from Sigma Chemical Co.
Platelet aggregation inhibitory bioassay: Blood was collected
from the rabbit marginal ear vein (several studies established that
rabbit platelets were surrogate to human platelets both in vitro
and in vivo)[11d] and was mixed with Na2EDTA to a final concentra-
tion of 6 mm. It was centrifuged for 10 min at 90 g at room tem-
perature, and the supernatant was obtained as platelet-rich
plasma. The latter was further centrifuged at 500 g for 10 min. The
platelet pellets were washed with Tyrode’s solution (Ca+2-free) con-
taining 2 mm Na2EDTA (0.1 mgmLꢁ1) and bovine serum albumin
(3.5 mgmLꢁ1) and was centrifuged at 500 g for 10 min. Then, the
pellets were washed with Tyrode’s solution without Na2EDTA. After
centrifugation under the same conditions, the platelet pellets were
finally suspended in Tyrode’s solution of the following composi-
tion: NaCl (136.8 mm), KCl (2.8 mm), NaHCO3 (11.9 mm), MgCl2
(2.1 mm), NaH2PO4 (0.33 mm), CaCl2 (1.0 mm), and glucose
(11.2 mm) containing bovine serum albumin (0.35%).
1-[2-(Benzyloxy)-1,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo-
[de,g]quinolin-6(5H)-yl]ethanone (27q): White solid (70%); Rf
(MeOH/CH2Cl2 5:95)=0.60; purification by flash column chroma-
tography (deactivated silica gel, MeOH/CH2Cl2 2:98); mp: 165–
1668C; 1H NMR (400 MHz, CDCl3, mixture of rotamers): d=8.19–
8.16 (m, 1H), 7.49–7.32 (m, 5H), 6.78–6.67 (m, 2H), 5.17–4.93 (m,
3H), 3.99–3.9 (m, 7H), 3.71 (s, 3H), 3.32–2.65 (m, 5H), 2.21–
2.18 ppm (m, 3H); 13C NMR (100 MHz, CDCl3, major rotamer): d=
169.3, 151.3, 148.4, 147.4, 145.5, 137.1, 129.9, 129.1, 128.7, 128.0,
127.4, 126.4, 125.3, 124.1, 112.3, 111.8, 111.4, 70.9, 60.2, 56.1, 50.8,
42.1, 31.7, 29.7, 22.8, 14.3 ppm; FTIR (KBr): n˜max =2927, 2852, 1737,
1636, 1509, 1422, 1249, 1025 cmꢁ1; HRMS (ESI): m/z: calcd for
C28H29NO5: 460.2118 [M+H]+; found: 460.2114.
Aggregation was measured by a turbidimetric method by using a
Lumi-aggregometer (Chrono-Log Corp., Havertown, PA, USA). All
glassware was siliconized. Three minutes before the addition of
the aggregation inducer, the platelet suspension was stirred at
1200 rpm. The percentage of aggregation was calculated as follows
[Eq. (1)]:
2-(Benzyloxy)-1,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tet-
rahydro-4H-dibenzo[de,g]quinoline (27r): White solid (91%); Rf
ꢀ
ꢁ
Aplatelet suspensionꢁAfinal post-aggregation
Aplatelet suspensionꢁATyrode solution
Aggregation ½%ꢂ ¼
ꢃ 100
ð1Þ
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Full Papers
Percent aggregation was expressed assuming the absorbance of
platelet suspension (Aplatelet suspension) as 0% aggregation and the ab-
sorbance of platelet-free Tyrode’s solution (ATyrode solution) as 100%
aggregation. For each compound, IC50 values were calculated by
SigmaPlot.
ship, respectively. Materials Research Centre, MNIT, Jaipur, is
gratefully acknowledged for providing analytical facilities.
Conflict of interest
In vitro antioxidant DPPH radical scavenging activity:[12a–e] In the
DPPH radical-scavenging method, the sample at different concen-
trations ranging from 10 to 100 mgmLꢁ1 was mixed with a metha-
nol solution of DPPH (20 mgLꢁ1, 1.5 mL). Pure methanol was taken
as control and ascorbic acid (vitamin C) was used as a reference
compound. The percent of DPPH decoloration of the sample was
calculated according to Equation (2):
The authors declare no conflict of interest.
Keywords: alkaloids
·
antioxidant activity
·
antiplatelet
activity · radicals · structure–activity relationships
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ꢀ
ꢁ
Asample
Acontrol
Decoloration ½%ꢂ ¼ 1ꢁ
ꢃ 100
ð2Þ
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1000
IC50
ð3Þ
AE ¼
In silico molecular docking simulation studies
The molecular docking studies were performed by using SYBYL-X
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IM8) and dithiothreitol (ligand ID: DID), respectively, were used for
the molecular docking studies. Prior to molecular docking, the pro-
tein structures were prepared by using a standard protocol for the
structure preparation tool of the SYBYL-X suite that included addi-
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minimization. The Surflex-Dock (SFCX) search algorithm2 was used
to dock the co-crystallized ligand (ID: IM8, DID) and synthesized
compounds. The ligands were prepared by the ligand preparation
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program parameters, each co-crystallized ligand was extracted
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as the ligand was treated as fully flexible. A protomol-based
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in Surflex-Dock was used to calculate the interaction of the ligands
and proteins. The scoring functions included hydrophobic, polar,
repulsive, entropic, solvation, and crash terms. The Surflex-Dock
scores are expressed in ꢁlog10 (Kd) units to represent binding af-
finities.
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Acknowledgements
S.C. acknowledges MNIT Jaipur for SERB fast track scheme for
young scientist, New Delhi (CS-037/2013); DST, New Delhi for
DST-RFBR Indo-Russian Joint Research Project (INT/RUS/RFBR/P-
169); and CSIR-New Delhi Grant [02 (0189)/14/EMR-II]. P.K.J. and
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Manuscript received: May 9, 2018
Revised manuscript received: July 6, 2018
[13] a) D. K. Yadav, S. Kumar, Saloni, S. Misra, L. Yadav, M. Teli, P. Sharma, S.
Chaudhary, N. Kumar, E. H. Choi, H. S. Kim, M. H. Kim, Sci. Rep. 2018, 8,
Accepted manuscript online: && &&, 0000
Version of record online: && &&, 0000
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A familiar ring: Functionalized apor-
phine analogues with alkoxy functional
groups at C1/C2 of ring A and an acyl
or phenylsulfonyl functionality at the N6
position of ring B of the aporphine scaf-
fold were synthesized and evaluated for
their arachidonic acid induced antiplate-
let aggregation inhibitory activity and
free-radical-scavenging antioxidant ac-
tivity. In silico molecular docking simula-
tion studies of the active analogues
were also performed.
V. Sharma, P. K. Jaiswal, S. Kumar,
M. Mathur, A. K. Swami, D. K. Yadav,
S. Chaudhary*
&& – &&
Discovery of Aporphine Analogues as
Potential Antiplatelet and Antioxidant
Agents: Design, Synthesis, Structure–
Activity Relationships, Biological
Evaluations, and in silico Molecular
Docking Studies
ChemMedChem 2018, 13, 1 – 17
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