C. Mu et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127997
H
N
R
H
N
n
N
Cl
Cl
Cl
a
b
Cl
Cl
Cl
5a-5p
H2N
sertraline
c
inactive
Cl
Cl
7
H
N
n
H
N
R2
R1
N
H
Cl
Cl
O
Cl
Cl
8a/8b
6a-6d
inactive
Fig. 1. The design concept of sertraline derivatives.
cell lung cancer, via inducing autophagy and apoptosis.29 These results
have demonstrated the potential of SSRIs to be repurposed as versatile
chemosensitizers. However, it’s noticeable that the experimental con-
centrations of the chemicals are high, thus respective doses in clinical
treatment would probably raise some safety issues.
activity of diastereomers were almost identical, thus screening of the
obtained derivatives was mainly performed using the trans-products as
representative (Fig. 2). Firstly, several alkyl groups were introduced as
the N-substituents, only the butyl substituted 5b turned out to exert
obvious sensitizing effect, other alkyl groups were futile on synergizing
with DDP, especially the branched alkyls. Next, benzyl and substituted
benzyl groups were introduced to obtain 5h–5p. Except for benzyl/4-
OMe-benzyl substituted derivatives 5h/5k which demonstrated slight
sensitizing effects, other electron-donating or -withdrawing benzyls all
failed to improve the activities of the derivatives, and some products
even seemed to further withdraw the antiproliferative effect of DDP.
Disappointingly, all products of the abovementioned structural modifi-
cation exerted inferior effects compared with sertraline (Ser) at 20 µM
(Fig. 2). Moreover, changing the amine type of sertraline to primary
amine or amide groups (7 and 8) also resulted in reduced activities
(Fig. 1, b).
In this work, we proved that sertraline exhibited moderate sensi-
tizing effects on drug resistant gastric cancer cells, via inducing
apoptosis. As a classic antidepressant drug, sertraline has been widely
prescribed and causes only slight and tolerable adverse effects in most
patients,30 thus is promising to be repurposed as a supportive therapy in
gastric cancer treatment, to defeat or prevent the drug resistance raised
in chemotherapies. Moreover, to further improve its efficacy and safety,
structural modification of sertraline to upgrade the activity and lower
the therapeutic dose is necessary. Our work has established a concise de
novo synthetic route to access several sertraline-derived compounds. The
sensitizing effects of the obtained compounds were evaluated over SGC-
7901/DDP, a gastric cancer cell line resistant to cisplatin (DDP), and
several compounds with obviously improved activity were obtained
through the screening. We further evaluated the apoptosis inducing ef-
fects of the compounds and explored the underlying mechanism, in
which we found the classic PI3K/Akt/mTOR pathway31,32 was respon-
sible in regulating the effects inspired by sertraline and its derivatives.
The preliminary studies to modify sertraline by methylation of its
secondary amine moiety (Fig. 1, a) ended up with completely loss of
antiproliferative effects (data not shown), indicating the necessity of the
Considering the positive effects of the presumed hydrogen bonds,
substituents containing extra active hydrogens were introduced,
including 5u and 6a–6d, via deprotection of N-Boc after the reductive
amination step. Fortunately, derivatives with primary amine groups
(6a–6c) or N-unprotected piperazine (6d) exerted excellent activities as
designed, which might generate the expected extra hydrogen bonds
(Fig. 1, c).
Next, products which were more effective than sertraline at 20 µM,
including 6a–6c (both isomers), 5t and its deprotected product 6d, were
further evaluated in a dose-dependent manner (C = 1.0, 2.0, 4.0, 8.0, 12,
16, 20, 24 µM), with IC50 values calculated (Table 1). Comparing with
sertraline (IC50 = 18.73 ± 0.46 µM), these derivatives were significantly
improved in their sensitizing activity, which showed generally lower
IC50. Among them, H-bonds modified trans-6b and trans-6d demon-
strated the best activities, with IC50 values of 6.28 ± 0.50 µM and 5.20 ±
0.36 µM, therefore they were selected as representatives for further
investigation. We also evaluated their cytotoxicity towards GES-01, an
immortalized gastric epithelial cell line, and found 6d showed moderate
selectivity between cancer cell line and normal cell line. Moreover, the
predicted pharmacokinetic parameters also suggested 6d might be a
good lead.
–
active N H to antitumor activity, which might generate a vital
hydrogen bond. Therefore, modification of sertraline was focused on
altering the other substituent on the nitrogen, retaining the active
hydrogen. Attempts of direct demethylation from sertraline to obtain the
primary amine for modification turned out difficult, therefore we
established a de novo synthetic route from commercially available
α
-naphthol 1 and 1,2-dichlorobenzene 2 (Scheme 1). Intermediate
naphthalenone derivative 3 could be smoothly obtained in a high yield
(80%). Then the different substituted amines 4 were reacted with 3 to
afford derivatives 5 via a reductive amination process. Except for a series
–
of secondary amines (5), other amine/amide types retaining N H were
also synthesized, including primary amine 7 and its acylation products
8. All these structures were characterized with 1H NMR, 13C NMR and
HRMS. Relative configuration of 8a/8a’ was assigned according to
Reactivating the apoptosis process to induce drug-resistant cell death
is the main mechanism of action for most chemosensitizers. To prelim-
inarily explore the mechanism of sertraline-induced sensitizing effect,
we first tested whether sertraline and the derivatives could induce
literature33 and conformed by H–1H NOESY analysis. Other products
1
were assigned by analogy.
Subsequently, the antiproliferative effects of the derivatives were
tested over cisplatin-resistant gastric cancer cell line SGC-7901/DDP
together with cisplatin, to evaluate their sensitizing activities. Initial
evaluation was performed in a single concentration, 20 µM, with 15 µM
DDP.34,35 Since two diastereomers were obtained in the reductive ami-
nation step, trans and cis-products 5b/5b’, 6a/6a’ꢀ 6c/6c’ and 7/7′
were comparatively evaluated. The inhibition rate indicated that the
apoptosis in SGC-7901/DDP cells. DDP (15 μM) exhibited identical
apoptotic rate with the control group, while co-administration with
sertraline (C = 8 M) exhibited moderate apoptosis inducing activity,
with 20.9% apoptotic rate. The derivatives 6b and 6d exhibited
μ
improved activity at 3 μM concentration (Fig. 3A and 3B). Meanwhile,
the caspase protein family, which is closely relevant to programmed cell
death, was also analyzed to indicate the apoptosis level. The ‘initiator
2
Mu, Chao
