Design, synthesis and evaluation of novel (S)-tryptamine derivatives containing an allyl group and an aryl sulfonamide unit as anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2019.02.023

A series of (S)-tryptamine derivatives containing an allyl group and an aryl sulfonamide unit were designed, synthesized and evaluated for their potential application as anticancer agents. The structures of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against HepG2, HeLa, CNE1 and A549 human cancer cell lines. Some of the synthesized compounds showed moderate to good anticancer activities against four selected cancer cell lines, among of which 6ag was found to be the most active analogue possessing IC₅₀ values 16.5–18.7 μM. Further mechanism studies revealed that compound 6ag could significantly induce HepG2 cell cycle arrest at G1 phase, promote cell apoptosis, and inhibit the colony formation as well.

Full text of DOI:10.1016/j.bmcl.2019.02.023

Accepted Manuscript
Design, Synthesis and Evaluation of Novel (S)-Tryptamine Derivatives Con-
taining an Allyl Group and an Aryl Sulfonamide Unit as Anticancer Agents
Zhenbo Guo, Yiming Xu, Yujie Peng, Haroon-Ur-Rashid, Wei Quan, Peng Xie,
Lichuan Wu, Jun Jiang, Lisheng Wang, Xu Liu
PII:
S0960-894X(19)30108-8
https://doi.org/10.1016/j.bmcl.2019.02.023
BMCL 26303
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 July 2018
13 February 2019
20 February 2019
Please cite this article as: Guo, Z., Xu, Y., Peng, Y., Haroon-Ur-Rashid, Quan, W., Xie, P., Wu, L., Jiang, J., Wang,
L., Liu, X., Design, Synthesis and Evaluation of Novel (S)-Tryptamine Derivatives Containing an Allyl Group and
an Aryl Sulfonamide Unit as Anticancer Agents, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://
doi.org/10.1016/j.bmcl.2019.02.023
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Design, Synthesis and Evaluation of Novel (S)-Tryptamine Derivatives Containing an Allyl
Group and an Aryl Sulfonamide Unit as Anticancer Agents
a,
a,
b
a
a
Zhenbo Guo †, Yiming Xu †, Yujie Peng , Haroon-Ur-Rashid a, c, Wei Quan , Peng Xie ,
Lichuan Wu b, Jun Jiang a, Lisheng Wang b,*, Xu Liu b,*
a School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi 530004,
PR China
b Medical College of Guangxi University, Nanning, Guangxi 530004, PR China
c Department of Chemistry, Sarhad University of Science & Information Technology, Peshawar KP,
Pakistan
† These authors have contributed equally.
A R T I C L E I N F O
Keywords:
A B S T R A C T
A series of (S)-tryptamine derivatives containing allyl group
Tryptamine
and aryl sulfonamide units were designed, synthesized and
evaluated for their potential application as anticancer agents. The
Aryl sulfonamide
Cell cycle arrest
Anticancer
1
structures of the synthesized compounds were characterized by H
NMR, 13C NMR and ESI-MS spectral analyses. The target
compounds were evaluated for their in vitro cytotoxicity against
HepG2, HeLa, CNE1 and A549 human cancer cell lines. Some of
the synthesized compounds showed moderate to good anticancer
activities against four selected cancer cell lines, among of which
6ag was found to be the most active analogue possessing IC50
values 16.5 μM-18.7 μM. Further mechanism studies revealed that
compound 6ag could significantly induce HepG2 cell cycle arrest at
G1 phase, promote cell apoptosis, and inhibit the colony formation
as well.
Cancer has become one of the most serious
threats against human health and life all over
the world, and its mortality rate surpasses heart
diseases.1 Nowadays, the progress of cancer
treatment still relies on chemotherapy in which
antitumor drugs play an important role.2
Although researchers made much efforts to
develop new drugs to cure cancer, still millions
of cancer caused deaths are reported globally.3
Therefore, it remained a tremendous challenge
for scientists to search for effective and
unexplored anticancer agents with valid potency
against tumor cells.
* Corresponding author
E-mail address: lswang@gxu.edu.cn (L. Wang)
E-mail address: wendaoliuxu@163.com (X. Liu)
Tryptamine, a bicyclic heterocycle, is the
most important and best-characterized member
of the indoleamine family. Tryptamine scaffold
is regarded as a privileged structure, due to its
broad applications for designing medicinal
agents. The tryptamine and its analogues have
been
pharmacological activities (Fig.1), such as anti-
migraine4, 5, antibacterial6 and antitumour2, 7
Owning to its multiples pharmacological
reported
to
exhibit
diverse
.

activities, tryptamine has been considered as the
common functional group in a set of compounds
termed collectively substituted tryptamines.
D-tryptophan (Fig.2), a non-protein amino
acid derived from Tryptamine, possesses special
physiological properties due to its optical
activity, which can serve as sweetener, feed
additive and plant growth substance etc. in
various fields. Especially in pharmaceuticals, it
is an essential synthetic precursor for anticancer
agents and immunosuppressants8. The above
suggestions urged us to perform modifications
based on D-tryptophan, maintaining the
chirality and tryptamine scaffold. On the other
hand, the S-allylcysteine (Fig.2) is identified as
a potent compound from garlic, and is reported
to have anticancer effect9-10. An obvious
characteristic is the similarity of chiral center
between D-tryptophan and S-allylcysteine. It
was also discovered that the biochemical
transformation of the allyl sulfur compounds in
the cell and their adducts with thiol functional
groups of proteins, could be considered relevant
events to uncover the anticancer properties of
the allyl sulfur compounds11. Moreover, lack of
allyl group can cause the biological activity of
S-allylcysteine lose12. Thus, with the chirality
and tryptamine structure of D-tryptophan
unchanged, allyl group was primarily
introduced into the D-tryptophan, forming
another analogous scaffold of S-allylcysteine,
which was expected to exhibit anticancer
synergies.
chemistry, the degree of selectivity was altered
followed by modification on amino position. On
the other hand, sulfonamide moiety is a core
part of many clinical drugs which have broad
spectrum applications in the fields of medicine,
pharmacology and pharmaceutics such as
antibacterial,
antiviral,
anti-inflammatory,
protease inhibitor, anti-diabetic, anti-cancer,
anti-epileptic and anti-tumor etc13. For example,
indisulam (Fig.2) is an aryl sulfonamide drug
with anticancer activity, which caused cell cycle
arrest in G1 phase, followed by cell death14.
SAR analysis of indisulam indicated that
sulfonamide group is essential for antitumor
properties of indisulam. More importantly, the
aryl group and substituent are particularly
important for the mitotic arrest phenotype15.
Souvik Banerjee’s et al.16 discovered an aryl
sulfonamide drug which significantly reduced
B16 melanoma metastasis in vivo. More
remarkably, Yoshinori et al. synthesized a series
of N-Sulfonyl D-tryptophan derivatives and
revealed that their inhibitory activities were
greatly affected by the introduction of the
sulfonamide moiety into amino group as novel
candidates for the treatment of cancer17.
Herein, aryl sulfonamide was then introduced
into amino group to synthesize a series of (S)-
tryptamine derivatives (Fig.3). Subsequently,
the derivatives were evaluated for their
anticancer activities via in vitro cytotoxicity
assay against cancer cell lines (HepG2, HeLa,
CNE1 and A549). Furthermore, the mechanism
of action of compound 6ag against liver cancer
cell (HepG2) was also investigated.
Further, in considering the significant
biological effect of chirality in medicinal
O
H
OMe
H
NMe2
HN
OMe
NH
NH
O
NH3
Cl
O
MeO
S
MeHN
9
O
N
N
N
H
H
H
OMe
anti-migraine
antibacterial
antitumor
Fig.1. Pharmaceutically important tryptamine analogues

O
S
H2N
NH2
O
H2N
O
C
COOH
S
COOH
NH
H
S
O
H
N
N
H
Cl
S-allylcysteine
D-tryptophan
Indisulam
Fig.2. Chemical structure of S-allylcysteine, Terrequinone A and Indisulam.
R
O S O
NH2
NH2
C
NH
C
C
COOH
H
H
H
N
N
N
H
H
H
D-tryptophan
6a-6al
Fig.3. Target compounds designing
The synthetic route of the new analogs 6a-6al
is illustrated in Scheme 1. The preparation of
intermediate 1 was performed by following the
procedure reported previously18,19. Indole was
allowed to react with oxalyl chloride in dry
diethyl ether followed by the addition of
methanol to yield the methyl 2-(1H-indol-3-yl)-
2-oxoacetate (1). Then, the intermediate 1 was
allowed to react with LiAlH4 in dry
tetrahydrofuran to afford 2-(1H-indol-3-
yl)ethan-1-ol (2)20. Subsequently, 2-(1H-indol-
3-yl)ethan-1-ol (2) was oxidized by 2-
Iodylbenzoic acid in dimethyl sulfoxide to
afford 2-(1H-indol-3-yl)acetaldehyde (3), a
rapidly decomposing aldehyde and was
therefore used for the next step immediately
after workup21.
Attempts were made to synthesize
compound 4 by the José’s method22. However,
the yield was reported to be very low.
Therefore, further optimization of the reaction
conditions was carried out via Maoqun Tian’s
method23. A mixture of compound 4, (SR)-N-
tert-butanesulfinamide, indium powder, and
Ti(OEt)4 was allowed to react in dry
tetrahydrofuran at 23 °C for 3 h, and was then
treated with allylic bromide at 60 °C for 20 h.
Consequently,
a
mixture
of
two
diastereoisomers of 4 (dr = 2:1) was obtained,
which was separated by silica gel flash column
chromatography and a single isomer 4 was
obtained in moderate yield. This key chiral
compound 4 was then treated with anhydrous
HCl in a mixture of solvents consisted of dry
1, 4-dioxane and dry methanol (1:1).
Consequently, tert-butanesulfinyl group of
chiral 4 was eliminated and compound 5 was
afforded in 90% yield.24 Single crystals of
compound 5 were obtained by recrystallization
in chloroform and the absolute structure was
further confirmed to be S by X-ray diffraction
determination (Fig.4). Crystallographic data of
5 have been deposited at the Cambridge
Crystallographic Data Centre (CCDC) with
deposition numbers of 1812759.
In order to testify the rationality of design,
two modification strategies were adopted.
Compound 5 was firstly allowed to react with

arylsulfonyl chloride in CH2Cl2 in the presence
of trimethylamine, yielding the target
compounds 6a-6am. On the other hand,
compound 7 was prepared by reduction of 5
via aqueous hydrazine in the presence of a
catalytic amount of FeCl3·6H2O25. Finally,
target 8a-8b were prepared according to the
synthesized process of compounds 6a-6am.
Based on the X-ray crystallographic structure
analysis of 5, absolute configuration of 6a-
6am and 8a-8b were determined. All the
synthesized compounds were purified by silica
gel flash column chromatography using ethyl
acetate and petroleum ether as gradient eluents
and their structures were characterized by H
NMR, 13C NMR and ESI-MS spectral
analyses.
1
O
OH
CHO
c
O
O
a
b
N
N
H
N
H
N
H
H
3
1
2
R
O
t-Bu
O S O
NH
S
NH
NH2
d
e
f
N
H
N
N
H
H
4
5
6a-6am
g
R
O S O
NH
NH2
f
N
H
N
H
7
8a-8b
6a R=4-FPh
6o R=4-Br-3-FPh
6p R=4-Br-2-FPh
6q R=4-Br-2,5-di-FPh
6r R=4-Br-3-MePh
6s R=4-CF3Ph
6t R=2-Cl-4-CF3Ph
6u R=2-Br-4-CF3Ph
6v R=2-NO2-4-CF3Ph
6w R=3-CF3Ph
6x R=3-Br-5-CF3Ph
6y R=3,5-di-CF3Ph
6z R=4-MePh
6ac R=2,4,6-tri-MePh
6ad R=2,3,5,6-tetra-MePh
6ae R=4-propylPh
6af R=4-isopropylPh
6ag R=2,4,6-tri-isopropylPh
6ah R=4-biphenyl
6ai R=2-naphthyl
6aj R=5-(di-MeN)naphthyl
6ak R=4-OCF3Ph
6al R=2-OCF3Ph
6b R=3-Cl-4-FPh
6c R=5-Cl-2,4-di-FPh
6d R=4-F-3-CF3Ph
6e R=2-ClPh
6f R=2-Cl-4-FPh
6g R=2,4-di-ClPh
6h R=4-Br-2-ClPh
6i R=4-Cl-2-FPh
6j R=4-Cl-2-NO2Ph
6k R=4-Cl-3-NO2Ph
6l R=4-Cl-3-CF3Ph
6am R=Ph
8a R=Ph

6m R=3-BrPh
6n R=4-BrPh
6aa R=3-F-4-MePh
6ab R=2,5-di-MePh
8b R=2,4,6-tri-isopropylPh
Scheme 1. Synthetic route for (S)-tryptamine derivatives. Reaction conditions: (a) dry diethyl ether,
oxalyl chloride, 0 °C→rt, 6 h, methanol, 0 °C, 30 min; (b) LiAlH4, dry THF, N2, 0 °C, 1 h and then
70 °C, 4 h; (c) DMSO, IBX, N2, rt, 90 min; (d) dry THF, Indium powder; (SR)-N-tert-
butanesulfinamide, Ti(OEt)4, N2, 23 °C, 3 h; allylic bromide; 60 °C, 20 h; (e) dry 1,4-dioxane/dry
methanol=1:1, anhydrous HCl in dioxane, rt, 1 h; (f) TEA, DCM, rt, overnight; (g) ethanol,
FeCl3·6H2O, aqueous hydrazine, rt, 4 h.
H2N
C10
HN
C
H
5
Fig.4. Perspective drawing of the X-ray crystal structure of 5.
Table 1. Cytotoxic activities assays of compounds 6a-6al against HepG2, HeLa, CNE1 and A549
cell lines.
IC50 (μM) a
Compound
Clog Pc
HepG2b
>100
38.2 ± 4.3
33.2 ± 4.3
36.3 ± 5.1
>100
71.7 ± 7.5
55.4 ± 2.3
54.3 ± 5.2
78.4 ± 9.2
71.3 ± 9.8
89.7 ± 9.1
24.4 ± 2.7
58.9 ± 8.4
39.6 ± 3.9
58.1 ± 6.8
58.7 ± 6.7
35.3 ± 4.3
52.2 ± 4.1
51.8 ± 5.1
33.1 ± 2.0
HeLab
>100
CNE1b
NTd
A549b
NT
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
4.336
5.155
5.335
5.552
4.606
4.855
5.425
5.575
5.155
4.921
4.921
5.922
5.056
5.056
5.305
5.305
5.485
5.555
5.303
5.822
33.8 ± 2.6
46.9 ± 5.3
32.0 ± 1.9
>100
34.2 ± 3.1
34.2 ± 3.9
27.0 ± 3.2
NT
41.6 ± 4.1
50.7 ± 4.9
38.5 ± 4.2
NT
61.7 ± 6.5
41.1 ± 4.8
53.5 ± 3.8
74.4 ± 6.2
67.9 ± 7.8
53.2 ± 4.2
42.8 ± 4.4
40.5 ± 2.1
61.0 ± 6.8
54.5 ± 3.3
58.5 ± 6.2
58.9 ± 5.6
46.7 ± 4.2
41.7 ± 5.3
44.8 ± 3.8
NT
NT
42.7 ± 4.6
38.5 ± 4.0
NT
55.7 ± 5.2
48.8 ± 4.4
NT
NT
NT
34.3 ± 4.1
52.1 ± 6.3
58.6 ± 5.9
NT
NT
NT
28.8 ± 2.6
48.0 ± 2.4
41.2 ± 4.3
NT
NT
NT
43.4 ± 2.4
38.6 ± 4.1
38.1 ± 2.9
36.1 ± 3.2
65.0 ± 9.1
54.1 ± 4.5
49.9 ± 4.9
53.0 ± 6.0
6t

6u
6v
6w
6x
6y
42.1 ± 3.3
40.4 ± 1.3
46.9 ± 3.9
25.3 ± 2.1
21.9 ± 2.0
>100
39.1 ± 3.5
44.6 ± 8.4
37.2 ± 4.2
24.7 ± 2.3
58.4 ± 5.6
46.4 ± 4.2
16.5 ± 1.2
43.0 ± 3.6
44.89 ± 4.8
52 ± 5.3
39.3 ± 4.5
35.7 ± 2.6
45.1 ± 3.5
31.9 ± 2.1
30.2 ± 3.1
>100
34.4 ± 2.1
39.3 ± 4.6
40.7 ± 4.4
22.9 ± 2.5
24.1 ± 2.1
NT
39.8 ± 4.3
42.0 ± 2.0
31.5 ± 3.2
26.3 ± 3.2
NT
43.6 ± 3.0
18.3 ± 1.6
34.5 ± 3.0
45.2 ± 5.1
36.0 ± 3.5
39.9 ± 2.5
66.9 ± 7.2
40.8 ± 3.7
47.1 ± 3.5
17.8 ± 1.0
>100
43.9 ± 3.6
74.2 ± 6.2
52.1 ± 5.1
29.3 ± 1.9
35.6 ± 4.4
NT
70.2 ± 8.9
48.3 ± 5.5
40.4 ± 2.8
29.9 ± 3.1
NT
53.0 ± 5.2
18.7 ± 1.5
33.6 ± 2.9
55.5 ± 6.1
52.4 ± 5.4
57.8 ± 5.7
65.9 ± 4.8
77.1 ± 6.2
91.5 ± 7.8
39.8 ± 3.3
>100
5.772
5.170
5.303
6.272
6.371
4.390
4.835
4.889
5.388
5.787
5.448
5.318
8.172
5.779
5.065
5.390
5.278
4.798
3.891
4.375
8.656
2.306
2.79
6z
6aa
6ab
6ac
6ad
6ae
6af
6ag
6ah
6ai
6aj
6ak
6al
6am
8a
43.6 ± 4.7
45.6 ± 3.0
35.3 ± 5.1
26.1 ± 3.5
67.1 ± 7.3
43.5 ± 2.4
16.5 ± 1.1
34.5 ± 2.1
52.7 ± 5.9
34.5 ± 3.6
57.3 ± 6.2
68.2 ± 5.6
69.5 ± 5.3
78.9 ± 4.8
16.4 ± 0.9
>100
36.0 ± 4.1
39.5 ± 4.2
58.4 ± 4.8
68.7 ± 5.5
30.8 ± 2.4
>100
8b
5
7
>100
>100
>100
>100
Cisplatin
4.9 ± 0.2
10.0 ± 1.1
2.5 ± 0.3
16.3 ± 2.1
a IC50 values are indicated as the mean ± SD of three independent experiments. The cells were continuously treated
with compounds for 48 h.
b
Cells lines include human liver cancer cell line (HepG2), cervix cancer cell line (HeLa), nasopharyngeal cancer
cell line (CNE2), lung cancer cell line (A549).
c ClogP values produced by Chemdraw software.
d NT means not tested.
After synthesis and characterization of the
target compounds, their cytotoxic activities
were determined against four different cancer
cell lines viz. HepG2, HeLa, CNE1 and A549.
The viability of the cell was assessed by the
MTT assay in vitro.26 Cisplatin was used as a
positive control which showed IC50 values of
4.9 ± 0.2 μM for HepG2, 10.0 ± 1.1 μM for
Hela, 2.5 ± 0.3 μM for CNE1 and 16.3 ± 2.1
μM for A549 cancer cell lines. The anticancer
potency of these compounds as half maximal
Table 1.
The cytotoxic activity results indicated that
most of the synthesized compounds exhibited
anticancer activity with IC50 below 100 μM,
while some showed potent activity with IC50
below 50 μM against four selected cancer cell
lines, respectively. Among the synthesized
compounds, compound 6ag was found to be the
most potent derivative against HepG2, HeLa,
CNE1 and A549 with IC50 values of 16.5 ± 1.2
μM, 16.5 ± 1.1 μM, 18.3 ± 1.6 μM, 18.7 ± 1.5
μM respectively, which showed equivalent
efficacy with Cisplatin in regard to HeLa and
A549 cells.
inhibitory
concentration
(IC50)
values
represented the compound concentration which
causes a 50% reduction of cell growth. The IC50
values of target compound are summarized in
As expected, most compounds of 6a-6am

series showed better anticancer activity than 5,
which indicated aryl sulfonamide group played
an important role in enhancing activity.
interactions with receptors and the toxicity
resulting from molecular metabolism etc. This
may be the reason for better antiproliferative
activities of compounds 6d, 6l, 6t, 6u, 6x, 6y
6ad and 6ag.
Finally, SAR analysis was focused on allyl
group. In order to understand whether allyl
group could take effect on activity, compounds
8a and 8b were synthesized and tested for
cytotoxic activity. With 6am, 6ag as a
reference, 8a and 8b showed lower activity than
6am and 6ag, respectively, which revealed the
allyl group was beneficial for anticancer
activity.
In general, the aryl sulfonamide and allyl
moieties were necessary in the tryptamine
derivatives for anticancer activity and the
lipotropy caused by the substituents on aryl
sulfonamide have a vital role in anticancer
improvement. Since compound 6ag afforded a
potent anticancer activity, it was chosen as a
representative to further carry out its
mechanism of action of cytotoxic activities
study.
Thus, the SAR studies were first focused on
the substituents on the phenyl group of R.
Through comparing the anticancer results of 6a-
6al with 6am, it can be observed that presence
of electron-withdrawing or electron-donating
substituent groups on aryl could not promote
activity to produce a single effect. In other
words, electronic effect may not be the
determinant for activity. Moreover, among 6a-
6y with electrondrawing group, the compounds
possessed -CF3 group generally exhibited potent
anticancer activity, such as 6d, 6l, 6t, 6u 6x and
6y. On the other hand, compounds 6ad and 6ag
showed the most potent activity among 6aa-6al.
An
obvious
characteristic
is
that
trifluoromethyl, 2, 3,5,6-tetra-methyl (6ad) and
2,4,6-tri-isopropyl
significantly improve
(6ag)
groups
lipotropy.
could
The
aforementioned results lead us to the following
assumptions that lipophilic effect may be due to
the substituent group which in turn is
responsible for enhancement of cytotoxic
activity. It can be observed that, the Clop values
of compounds 6d, 6l, 6t, 6u, 6x, 6y, 6ad and
6ag are larger than other compounds, indicating
that compounds 6d, 6l, 6t, 6u, 6x, 6y, 6ad and
6ag are comparatively more lipophilic.
Hydrophobicity, known as a fundamental
pharmacological parameter, could influence the
absorption of medicine, biological activities,
We selected colony assay to investigate
whether compound 6ag could inhibit the
proliferation of HepG2 cells (Fig.5 A and B).
Compared to the control, HepG2 cells treated
with the compound 6ag exhibited fewer
colonies with 95% inhibitions at 7.5 μM,
indicating that compound 6ag could inhibit the
proliferation of cancer cells in a dose dependent
manner.

Fig.5. (A) Images of HepG2 cells colonies after treatment with compound 6ag at 0, 2.5, 5 and 7.5 μM for 2
weeks. (B) The rate of inhibition induced by compound 6ag was expressed as the mean ± SD. The clonogenicity
assay was quantified using Image J software (*P<0.05, **P<0.01).
To explore the detail cytotoxic effect of 6ag
on HepG2 cells, we determined the effect of
6ag on cell apoptosis27. HepG2 cells treated
with 0 μM, 10 μM, 20 μM and 30 μM of 6ag,
were subjected to AnnexinV-FITC/PI double
staining and were then quantified by flow
cytometry analysis (Fig 6. A and B). The results
showed that, the percentage of HepG2 apopotic
cells (Lower right quadrant, AV+/PI and Upper
growth by interrupting the cell cycle progress,
cellular DNA was analyzed and stained with
propidium iodide (PI). Flow cytometry was then
applied to analyze the cells. The profiles are
shown in Fig.7 (A and B). Obviously, compared
to the control group, an increase in the G1
population of HepG2 cells was observed after
treatment with 6ag at a dose of 0, 15, 25 and 35
μM for 24 h. The percentage of HepG2 cells at
G1 phase gradually increased from 39.79% (0
μM) to 44.89% (15 μM), 48.82% (25 μM) and
53.35% (35 μM). These results confirmed that
compound 6ag could induce cell cycle arrest of
HepG2 cells at G1 phase.
right
quadrant,
AV+/PI+)
significantly
increased from 4.91% to 9.61%, 26.14%,
73.71% at 0 μM, 10 μM, 20 μM, 30 μM of 6ag
concentrations treatment, respectively after 48h
incubation.
To establish whether 6ag inhibited cell

Fig.6. Compound 6ag induced apoptosis in HepG2 cells. (A) HepG2 was treated with compound 6ag at 0, 10, 20
and 30 μM for 48h. (B) HepG2 apoptosis rates were quantified by flow cytometry. Three individual experiments
were performed for each group. The data were expressed as the Mean ± SD. **p < 0.01, ***p < 0.001 compared to
the control. Concentration of compound 6ag.
Fig.7. Compound 6ag could induce G1 cell cycle arrest in HepG2 cancer cells. (A) 6ag induces G1 cell cycle arrest
in HepG2 cells in a dose-dependent manner. (B) Distributions of G1, S and G2 in HepG2 cells under 6ag treatment.
In summary, a series of new (S)-tryptamine
derivatives containing allyl groups and aryl
sulfonamide units were synthesized. Based on
X-ray crystallographic structure analysis of 5,
absolute configurations of the synthesized
compounds were determined. All the
synthesized compounds were subjected to in
vitro cytotoxicity against four human cancer
cell lines viz. HepG2, HeLa, CNE1 and A549.
The results revealed that compound 6ag
exhibited strong cytotoxicity, which could
induce cell cycle arrest at the G1 stage and
promote
apoptosis.
Further
biological
assessment of 6ag indicated that it possessed
potent anti-growth ability against cancer cell.
Meanwhile, the structure-activity relationship
studies showed that, aryl sulfonamide and allyl
moieties were necessary in the tryptamine
derivatives for anticancer activity and the
lipotropy caused by the substituents on aryl
sulfonamide have a vital role in anticancer
improvement. Collectively, our findings suggest
that tryptamine derivatives can serve as
promising lead compounds for the development

of novel anticancer agents.
Chem B 2011, 115, 13408.
Acknowledgments
13. Irfan, A.; Batool, F.; Irum, S.; Ullah, S.; Umer, M.;
Shaheen, R.; Chand, A. J. World Journal of
Pharmaceutical Research 2018, 7, 257.
This work was supported by the high-level
innovation team and outstanding scholar project
of Guangxi institutions of higher education
(guijiaoren (2014) 49 hao).
14. Owa, T.; Yoshino, H.; Tatsuo Okauchi; Yoshimatsu,
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Highlights
 38 novel (S)-tryptamine derivatives containing allyl group and aryl sulfonamide
units were synthesized as anticancer agents.
 Anticancer activities of these compounds were evaluated in four cancer cell lines.
 Most of these compounds exhibited moderate to good activity.

Compound 6ag induce apoptosis and arrest HepG2 cell at G1 phase.