Structural simplification of evodiamine: Discovery of novel tetrahydro-β-carboline derivatives as potent antitumor agents

Article abstract of DOI:10.1016/j.bmcl.2021.127954

Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro-β-carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G₂/M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure–activity relationships of evodiamine.

Full text of DOI:10.1016/j.bmcl.2021.127954

Bioorg. Med. Chem. Lett. 40 (2021) 127954
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structural simplification of evodiamine: Discovery of novel
tetrahydro-β-carboline derivatives as potent antitumor agents
,
b
,
,
,
,
,b
Zonglin Maa d, Yahui Huangb d, Kun Wanc d, Fugui Zhua b, Chunquan Shenga
,
,
,
,*
Shuqiang Chenb *, Dan Liua *, Guoqiang Dongb
a Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
b School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
c Medical Supplies Center, Chinese PLA General Hospital, Beijing 100039, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. How-
ever, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor
drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating
nonessential structures. Herein, a series of tetrahydro-β-carboline derivatives were designed by elimination of the
D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which
displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor
activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound
45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G2/M cell cycle
arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug
development, discovered compound 45 as a potent antitumor lead compound and enriched the structure–activity
relationships of evodiamine.
Evodiamine
Structural simplification
Antitumor activity
Structure–activity relationship
Natural products (NPs) have historically played a promising role in
drug discovery and development, especially in the field of antitumor
drugs.1,2 Statistics indicate that nearly four-fifths of small molecule
clinical antitumor drugs were involved in NPs.3 For example, the mar-
keted drugs topotecan (TPT)4 and irinotecan (IRT)5 were modified from
the NP camptothecin (CPT), and docetaxel (DTX)6 was derived from the
NP paclitaxel (PTX). However, the high structural complexity and mo-
lecular weights (MWs) of NPs generally lead to unfavorable physico-
chemical and absorption, distribution, metabolism, excretion and
toxicity (ADMET) profiles along with synthetic difficulty, which has
hampered the further development of NPs.7–9 Hence, few clinical drugs
are derived from unmodified NPs, and it is of great significance to
modify the structures of NPs before they are developed into clinical
drugs.9,10 Generally, the structural optimization strategies of NPs
include the design of NP analogs, the structural simplification of NPs
with complex structures, scaffold hopping, selective modifications of
NPs, and so forth.7 Due to the high efficiency and success rate, structural
simplification of NPs by truncating unnecessary substructures is a
powerful method. Compared with other structural optimization strate-
gies, structural simplification could accelerate the discovery of new and
simpler compounds with improved drug-likeness, and a variety of
marketed drugs or drug candidates have been developed by means of
this strategy.11–14 For example, pethidine (Fig. 1) is a simplified analog
of the NP morphine constructed by the elimination of the B, C and E
rings, which exhibits improved analgesic effects and oral potency.15
Further structural optimization gave rise to the development of a series
of synthetic analgesics, such as fentanyl.16,17 Trichostatin A (TSA, Fig. 1)
was isolated from the actinomycete Streptomyces hygroscopicus and
identified to be a highly potent histone deacetylase (HDAC) inhibitor (Ki
= 3.4 nM).18 Structural simplification of TSA by elimination of the chiral
center and conjugated double bonds afforded the simplified analog
vorinostat,19 which retained excellent HDAC inhibitory activity
(HDAC1, IC50 = 0.04 μM) and was approved by the FDA for the treat-
ment of advanced primary cutaneous T-cell lymphoma.12,20
Evodiamine (1, Fig. 2) is an alkaloid active ingredient originally
isolated from the traditional Chinese herb Evodiae fructus that exhibits
* Corresponding authors.
E-mail addresses: chenshuq1992@163.com (S. Chen), liudan@syphu.edu.cn (D. Liu), dgq-81@163.com (G. Dong).
d
These authors contributed equally to this work.
https://doi.org/10.1016/j.bmcl.2021.127954
Received 19 December 2020; Received in revised form 27 February 2021; Accepted 7 March 2021
Available online 17 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

Z. Ma et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127954
Fig. 1. Successful cases of marketed drugs based on a structural simplification strategy.
Fig. 2. The chemical structures of highly active derivatives derived from evodiamine.
various biological activities.21 For the past few years, the antitumor
activity of evodiamine and its derivatives has aroused substantial in-
terest among medicinal chemistry researchers. However, the unclear
molecular mechanisms and unfavorable physicochemical properties
have hindered the further development of evodiamine. Previously, the
systematic structural optimization of evodiamine in our lab led to the
discovery of a series of novel derivatives (compounds 2–4, Fig. 2) with
excellent antitumor activity.22,23 Moreover, diverse evodiamine-
inspired scaffolds were generated that showed good to excellent anti-
neoplastic potency against various human cancer cell lines. In partic-
ular, thio-evodiamine 5 was discovered by replacing the D ring N-methyl
with a sulfur and reversing the connectivity of the B/C rings afforded
indolopyrazinoquinazolinone derivative 6 (Fig. 2). Both compounds 5
and 6 showed excellent in vivo antitumor potency in a HCT116 xenograft
model with low toxicity.24,25 In addition, antitumor mechanistic studies
demonstrated that evodiamine derivatives such as 10-hydroxyevodi-
amine (2) acted by apoptosis induction and autophagy.26 Considering
that the chemical structure of evodiamine features a rigid five-ring
system, structural simplification of evodiamine might generate potent
evodiamine derivatives with improved physicochemical properties and
potent antitumor activities. Inspired by these results, a structural
simplification strategy was adopted by unfolding the D ring of evodi-
amine to give a tetrahydro-β-carboline scaffold (11, Fig. 3). Further
structure–activity relationship (SAR) studies revealed that compound 45
not only showed excellent antitumor potency in vitro but also strongly
suppressed the growth of colon cancer in the HCT116 xenograft model
with low toxicity.
Herein, a structural simplification study of evodiamine was carried
out, and a series of simplified derivatives were designed (Fig. 3). First,
the D ring of evodiamine was removed to reduce the number of rings and
synthetic difficulty, which afforded tetrahydro-β-carboline derivative
11. Then, isopropyl groups and different substituted phenyl groups were
introduced onto the C ring at the C1 position. In our previous study, the
10-methoxyl and 10-hydroxyl evodiamine derivatives strongly sup-
pressed tumor growth in vitro and in vivo. Therefore, a methoxyl or hy-
droxyl group was introduced into a similar position onto the A ring of
the new scaffold. In addition, various E ring-substituted derivatives were
synthesized to explore further the SAR of the tetrahydro-β-carboline
derivatives.
The synthetic routes of the target compounds are depicted in
Schemes 1 and 2. Starting from commercially available tryptamine (7),
intermediate 9 were prepared via two steps according to the literature.22
Then, the reduction reaction of 9 in the presence of sodium borohydride
(NaBH4) and methanol at 0 ◦C gave compound 10. Finally, target
compound 11 was prepared by reacting intermediate 10 with benzoyl
chloride in the presence of triethylamine (TEA) in tetrahydrofuran
(THF).
The synthetic method for diverse tetrahydro-β-carboline derivatives
is outlined in Scheme 2.27 The Pictet-Spengler reaction of tryptamine or
5-methoxytryptamine with diverse substituted aldehydes and tri-
fluoroacetic acid (TFA) in dichloromethane (DCM) yielded in-
termediates 12, 13, 18–24. Then, target compounds 14–16, 25–45 were
2

Z. Ma et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127954
Fig. 3. Design of tetrahydro-β-carboline derivatives as simplified analogs of evodiamine.
Scheme 1. Reagents and conditions: (a) ethyl formate, reflux, 6 h, yield 100%; (b) POCl3, CH2Cl2, 0 ◦C, 6 h, yield 85%; (c) NaBH4, methanol, 0 ◦C, 3 h, yield 90%; (d)
Benzoyl chloride, TEA, THF, 0 ◦C, 12 h, yield 80%.
prepared by reacting intermediates with substituted benzoyl chlorides in
the presence of triethylamine (TEA) in tetrahydrofuran (THF). Finally,
hydroxyl-substituted derivative 46 was obtained by demethylation of
compound 28 in the presence of BBr3 and DCM at ꢀ 78 ◦C.
activity compared with evodiamine. However, further optimization led
to compounds 14, 15 and 16, which were found to be much less potent
with IC50 values greater than 30
μM. Then, methoxyl and hydroxyl
groups were introduced at the C6 position to give compounds 25 and 46,
respectively. Although hydroxyl derivative 46 displayed very weak
antitumor potency, methoxyl derivative 25 showed a significant boost in
The in vitro antiproliferative efficacy of the target compounds was
determined against the human cancer cell lines A549 (lung cancer),
MDA-MB-231 (breast cancer), and HCT116 (colon cancer) using a cell
counting kit-8 (CCK8) assay. Evodiamine and CPT were used as refer-
ence drugs. The growth inhibitory activities of the target compounds
against the three cancer cell lines are summarized in Table 1. Initially,
tetrahydro-β-carboline derivative 11 was obtained by the elimination of
the D ring of evodiamine, which remained comparable antitumor
antiproliferative activity, with IC50 values ranging from 1.48 to 5.29 μM
against all three cell lines. As a consequence, further optimization efforts
focused on varying the substituents on the C and D rings while retaining
the methoxyl group. As shown in Table 1, most of the 6-methoxyl tet-
rahydro-β-carboline derivatives exhibited better activities against the
HCT116 cell line than the other two cancer cell lines. The introduction of
3

Z. Ma et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127954
Scheme 2. Reagents and conditions: (a) diverse substituted aldehyde, TFA, DCM, rt, 24 h, yield 25–53%; (b) substituted benzoyl chlorides, TEA, THF, 0 ◦C, 13 h,
yield 30–81%; (c) BBr3, DCM, ꢀ 78 ◦C, 4.5 h, yield 67%.
4

Z. Ma et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127954
(ꢀ )-isomer was almost inactive.
Table 1
In vitro antitumor activities of simplified evodiamine derivatives.
Previously, Top1 and Top2 were identified as the targets of evodi-
amine and its derivatives.22–25 These compounds could inhibit the
growth of tumor cells by stabilizing the cleavable complex composed of
Top1-DNA and inhibiting Top2 catalytic activity. Herein, the inhibitory
activity of representative compounds 33, 34, 41, 44 and 45 was inves-
tigated by Top1/2-mediated DNA cleavage assays. CPT, etoposide (Eto)
and evodiamine were used as positive controls. As demonstrated in
Fig. 4A, all tested compounds were found to be active against Top1-
Compds
IC50 (μM)
HCT116
A549
MDA-MB-231
11
14
15
16
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
1
21.45 ± 5.26
>100
>100
45.38 ± 0.28
>100
>100
57.87 ± 1.10
32.47 ± 1.40
2.53 ± 0.06
1.73 ± 0.40
6.18 ± 0.74
4.80 ± 0.09
58.09 ± 8.93
5.56 ± 0.13
6.14 ± 0.22
5.13 ± 0.12
0.36 ± 0.04
0.72 ± 0.02
7.76 ± 0.24
6.45 ± 0.4
>100
51.23 ± 1.07
57.56 ± 1.23
1.48 ± 0.42
1.24 ± 0.23
62.38 ± 4.62
3.28 ± 0.13
6.18 ± 0.04
1.11 ± 0.09
2.81 ± 0.13
3.01 ± 0.11
0.57 ± 0.06
0.34 ± 0.03
0.27 ± 0.01
22.15 ± 1.74
30.97 ± 0.22
40.8 ± 1.61
18.82 ± 0.82
>100
>100
5.29 ± 1.10
12.71 ± 0.59
18.71 ± 3.98
9.27 ± 0.98
25.49 ± 2.15
2.15 ± 0.65
11.76 ± 0.67
12 ± 1.6
mediated relaxation of supercoiled DNA at a concentration of 500
At the lower concentration of 100 M, most of the target compounds
retained their inhibitory activity except for compound 34.
μM.
μ
Moreover, the Top2 inhibitory potency of representative compounds
33, 34, 41, 44 and 45 was detected by incubation with purified Top2
and monitoring the appearance of fractured DNA fragments. As shown
in Fig. 4B, all tested compounds exhibited potent Top2 inhibitory ac-
7.91 ± 0.58
3.80 ± 0.31
2.45 ± 0.18
17.41 ± 1.98
30.25 ± 0.99
11.86 ± 1.01
2.09 ± 0.13
27.18 ± 2.59
1.66 ± 0.02
44.63 ± 1.27
13.57 ± 0.81
14.07 ± 0.51
0.76 ± 0.04
19.30 ± 0.27
>100
tivity at the concentrations of 250
μM and 100 μM. However, they
exhibited only moderate Top2 inhibitory activity at a concentration of
2.65 ± 0.86
3.24 ± 0.04
3.62 ± 0.01
6.73 ± 0.64
0.54 ± 0.10
4.28 ± 0.01
1.97 ± 0.06
0.49 ± 0.05
0.16 ± 0.01
20.95 ± 1.18
19.55 ± 1.78
0.010 ± 0.01
50 μM. To further understand the interactions of compound 45 with
Top1 and Top2, molecular docking was performed. As shown in Fig. 4E,
compound 45 became embedded in the site of DNA cleavage of Top1-
DNA complex (PDB: 1T8I)28 to form a sandwich-like interaction
0.59 ± 0.05
1.08 ± 0.07
0.68 ± 0.01
0.29 ± 0.01
0.16 ± 0.03
>100
network, and face-to-face
π-π interactions were also observed. The
carbonyl group of compound 45 formed a hydrogen bond with Asn722.
The methoxyl group was found to form a hydrogen bond with Arg364.
The binding mode of compound 45 with Top2α was shown in Fig. 4F.
48.98 ± 5.03
0.075 ± 0.01
Compound 45 fit well into the unwinding domain of Top2 (PDB:
5GWK),29 and
π–π stacking interactions were observed between the
CPT
0.045 ± 0.02
indole ring of compound 45 and DNA. Besides, the 6-methoxyl group
was found to form a hydrogen bond with Arg487. Collectively, the above
results indicated that the simplified evodiamine derivatives might act as
dual Top1/2 inhibitors.
Table 2
In vitro antitumor activities of the isomers of compound 45 (IC50, μM).
To further elucidate the molecular mechanism of the simplified
evodiamine derivatives, compound 45 was selected to evaluate cell
apoptosis by flow cytometry based on the in vitro antitumor activity. As
shown in Fig. 5A, after treatment with different concentrations (0.03,
Isomers
HCT116
A549
MDA-MB-231
(ꢀ )-45
(+)-45
17.7 ± 3.18
0.13 ± 0.01
16.13 ± 2.61
0.65 ± 0.02
>50
0.042 ± 0.01
0.15, 0.75 and 1.5 μM) of compound 45 for 48 h, the percentage of
substituents at the para-position of the E ring retained antitumor activity
(compounds 26, 30 and 31) compared with compound 25. However,
nitro-substituted compound 29 showed significantly reduced potency.
In addition, the meta-position substituted derivatives exhibited a slight
effect on the antitumor activity (compounds 28 and 32), while the
introduction of fluorine at the ortho-position (compound 27) led to a loss
in the antitumor activity against A549 and MDA-MB-231 cells. Inter-
estingly, the length of the linker between the C and E rings showed an
important influence on antitumor activity, as compound 33 was
approximately 15 times more potent than compound 25 in the HCT116
cell line. Similar to compound 25, ortho-position substituted derivative
35 also exhibited reduced antitumor potency.
apoptotic cells increased from 10.11% to 30.98%, which was signifi-
cantly higher than that in control (6.77%). These results indicated that
compound 45 could kill cancer cells by inducing cell apoptosis. In
addition, western blotting analysis was conducted to further illustrate
the molecular mechanism of apoptosis induced by compound 45. As
shown in Fig. 5B, after incubation with various concentrations of com-
pound 45 for 24 h, the expression level of Bax increased, while the Bcl-2
protein was downregulated with increasing concentration of 45. In
addition, the expression levels of caspase-3 and caspase-9 increased
dose-dependently after incubation with compound 45, indicating that
compound 45 might induce caspase-dependent apoptosis in HCT116
cells. Cytochrome C has been reported to play an important role in the
mitochondrial apoptosis pathway.30 Therefore, the expression of cyto-
chrome C was determined. The results showed that compound 45
upregulated the expression of cytochrome C in a dose-dependent
manner, indicating that mitochondrial apoptosis was involved in the
inhibition of cell proliferation by compound 45.
Further SAR studies of the C ring revealed that monosubstituted
derivatives led to a decrease in antitumor activity. In addition, 3,4-
difluoro-substituted derivative 37 displayed decreased antitumor ac-
tivity, whereas improved antitumor activity against HCT116 and MDA-
MB-231 cells was observed by the introduction of 3,4-dichlorophenyl
substitution (compounds 41, 43 and 44). Inspired by these encour-
aging results, a derivative simultaneously containing the 3,4-dichloro-
phenyl substitution and a phenethyl group was designed (compound
45). To our delight, compound 45 showed excellent antitumor activity
Previously, evodiamine derivatives were reported to arrest cancer
cells at the G2/M phase.31 Therefore, the effects of compound 45 on cell
cycle progression in HCT116 cells was estimated by the flow cytometric
method (Fig. 6). After 24 h of exposure to compound 45 at the con-
with IC50 values of 0.16, 0.76 and 0.16 μM against HCT116, A549 and
centrations of 0.03, 0.15, 0.75 μM, the ratios of cells in the G2/M fraction
MDA-MB-231 cells, respectively. In order to investigate the influence of
C1 chirality on the antitumor activity, compound 45 was isolated by
chiral chromatography and their values of optical rotation were deter-
mined (Supplementary Material, Table S1). As shown in Table 2, (+)-45
was more active than the (ꢀ )-isomer against all these three cell lines. In
particular, the (+)-45 demonstrated excellent antitumor activity with
were 32.12%, 78.12%, and 88.37%, respectively. Moreover, the ratios of
cells in the G2/M fraction were 67.92% at the concentrations of 0.03
μM
when the incubation time was prolonged to 48 h, indicating a better
time-dependent trend. With the increased concentration of compound
45, nearly all the tumor cells were blocked at G2/M phase. In contrast,
the ratio of untreated cells in the G2/M phase of the cell cycle was
27.78% and 25.01%. Therefore, compound 45 could arrest the HCT116
IC50 value of 0.042
μM against MDA-MB-231 cell. In contrast, the
5

Z. Ma et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127954
Fig. 4. (A) Inhibition of Top1 relaxation activity by the test compounds at 500, 250, and 100
μ
M. Lane 1, supercoiled plasmid DNA; lane 2, DNA + Top1; lane 3,
DNA + Top1 + CPT; lanes 4–8, DNA + Top1 + test compounds (33, 34, 41, 44 and 45, respectively) at 500, 250, and 100 μM. (B) Inhibition of Top2 relaxation
activity by the test compounds at 250, 100, and 50
test compounds (33, 34, 41, 44 and 45, respectively) at 250, 100, 50
1, supercoiled plasmid DNA; lane 2, DNA + Top1; lane 3, DNA + Top1 + CPT; lanes 4–6, DNA + Top1 + 1 (500, 250 and 100
Top2 relaxation activity by compound 1 at different concentrations. Lane 1, supercoiled plasmid DNA; lane 2, DNA + Top2; lane 3, DNA + Top2 + Eto (100
lanes 4–6, DNA + Top2 + 1 (250, 100 and 50 M, respectively). (E) Binding mode of compound 45 with the Top1-DNA complex (PDB code: 1T8I). (F) Binding mode
of compound 45 with the unwinding domain of Top2 (PDB code: 5GWK).
μ
M. Lane 1, supercoiled plasmid DNA; lane 2, DNA + Top2; lane 3, DNA + Top2 + Eto; lanes 4–8, DNA + Top2 +
M. (C) Inhibition of Top1 relaxation activity by compound 1 at different concentrations. Lane
M, respectively). (D) Inhibition of
M);
μ
μ
μ
μ
α
6

Z. Ma et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127954
Fig. 5. The induction of apoptosis by compound 45 in HCT116 cells. HCT116 cells were incubated with various concentrations of compound 45 for 48 h and then
analyzed by flow cytometry. (A) Apoptosis was examined with Annexin V/PI staining, and representative data are displayed. (B) Effects of compound 45 on the
expression of the apoptosis-related proteins caspase-9, caspase-3, Bcl-2, Bax and cytochrome C at the indicated concentrations after 24 h of treatment in
HCT116 cells.
Fig. 6. Cell cycle arrest by compound 45 in HCT116 cells. HCT116 cells were incubated with various concentrations of compound 45 for 24 h (A) and 48 h (C)
respectively, and then analyzed by flow cytometry. The cell cycle was assayed with PI staining, and representative data are displayed in (B) and (D).
cell cycle at the G2/M phase.
investigation.
In summary, a structural simplification strategy was employed to
To further evaluate the in vivo effects of these simplified evodiamine
derivatives, a xenograft model was prepared by inoculating HCT116
cells into nude mice. Compound 45 was administered intraperitoneally
(ip) at a dose of 50 mg/kg/day for 21 consecutive days, and evodiamine
was administered at the same dosage to serve as a control. As depicted in
Fig. 7A, compound 45 showed significant in vivo antitumor potency with
a tumor growth inhibition (TGI) value of 50.7%, which was significantly
improved compared with evodiamine (TGI = 22.5%). Notably, com-
pound 45 was well tolerated, as no significant loss of body weight was
observed during the test (p > 0.05, Fig. 7B), indicating that compound
45 showed low toxicity. Therefore, compound 45 is an effective anti-
tumor lead compound that exhibits low toxicity and is worthy of further
reduce the molecular complexity of evodiamine, and a series of tetra-
hydro-β-carboline derivatives were designed and synthesized. SAR
studies and antitumor activity screening led to the discovery of com-
pound 45 as a potent antitumor lead compound with improved in vivo
antitumor activity compared with evodiamine. Further mechanistic
research suggested that compound 45 acted by dual Top1/2 inhibition,
and apoptosis induction and G2/M cell cycle arrest were also involved in
its antitumor mechanism. On the other hand, besides Top1/2, other
targets might also contribute to the antitumor activity of the synthesized
compounds, which remained to be further identified. Further structural
optimization investigations and multitargeted antitumor mechanisms of
7

Z. Ma et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127954
Fig. 7. In vivo antitumor activity of compound 45 in the HCT116 tumor xenograft model. (A) Tumor growth inhibition from compound 45 and evodiamine in the
HCT116 xenograft model at a dose of 50 mg/kg. (B) Changes in the body weights of the mice after tumor implantation. Data are presented as the mean ± SEM; n = 5
nude mice per group. (*) p < 0.05 vs control group determined with Student’s t-test.
3 Newman DJ, Cragg GM. J Nat Prod. 2016;79:629.
evodiamine derivatives are currently ongoing.
4 Kingsbury WD, Boehm JC, Jakas DR, et al. J Med Chem. 1991;34:98.
5 Garcia-Carbonero R, Supko JG. Clin Cancer Res. 2002;8:641.
Declaration of Competing Interest
6 Meng Z, Lv Q, Lu J, et al. Int J Mol Sci. 2016;17:796.
7 Wang S, Dong G, Sheng C. Chem Rev. 2019;119:4180.
8 Rodrigues T, Reker D, Schneider P, Schneider G. Nat Chem. 2016;8:531.
9 Yao H, Liu J, Xu S, Zhu Z, Xu J. Expert Opin Drug Discov. 2017;12:121.
10 Chen J, Li W, Yao H, Xu J. Fitoterapia. 2015;103:231.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
11 Evdokimov NM, Van Slambrouck S, Heffeter P, et al. J Med Chem. 2012;2011:54.
12 Huang Y, Dong G, Li H, Liu N, Zhang W, Sheng C. J Med Chem. 2018;61:6056.
13 Lee J, Hahm ER, Singh SV. Carcinogenesis. 2010;31:1991.
Acknowledgements
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15 Woolfe G, Macdonald AD. J Pharmacol Exp Ther. 1944;80:300.
16 Ziering A, Lee J. J Org Chem. 1947;12:911.
This work was supported by the National Natural Science Foundation
of China (Grants 81872742 to G. D., and 22007099 to S. C.), Shanghai
Rising-Star Program (20QA1411700 to G. D.).
17 Van Bever WFM, Niemegeers CJE, Janssen PAJ. J Med Chem. 1974;17:1047.
18 Yoshida M, Horinouchi S, Beppu T. BioEssays. 1995;17:423.
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Appendix A. Supplementary data
24 Wang S, Fang K, Dong G, et al. J Med Chem. 2015;58:6678.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127954.
25 Wang L, Fang K, Cheng J, et al. J Med Chem. 2020;63:696.
26 Chen S, Dong G, Wu S, Liu N, Zhang W, Sheng C. Acta Pharm. Sin. B. 2019;9:144.
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