Structure-activity studies of phenanthroindolizidine alkaloids as potential antitumor agents

Article abstract of DOI:10.1016/j.bmcl.2007.05.021

Five phenanthroindolizidine alkaloids (PA) were chemically synthesized and seven were isolated from Tylophora atrofolliculata. To facilitate future drug design of phenanthroindolizidine alkaloids as potential antitumor agents, we have explored the structu

Full text of DOI:10.1016/j.bmcl.2007.05.021

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4338–4342
Structure–activity studies of phenanthroindolizidine alkaloids
as potential antitumor agents
Wenli Gao,a Scott Bussom,a Susan P. Grill,a Elizabeth A. Gullen,a You-Cai Hu,b
Xueshi Huang,b Sanbao Zhong,c Conrad Kaczmarek,c Julio Gutierrez,c Samson Francis,c
b,
a, ,
*
David C. Baker,c,* Shishan Yu and Yung-Chi Cheng
*
aDepartment of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
bInstitute of Materia Medica, Chineses Academy of Medical Sciences & Peking Union Medical College,
No. 1 Xiannongtan Street, Beijing 100050, PR China
cDepartment of Chemistry, The University of Tennessee, Knoxville, TN 37996-1600, USA
Received 26 January 2007; revised 6 May 2007; accepted 9 May 2007
Available online 16 May 2007
Abstract—Five phenanthroindolizidine alkaloids (PA) were chemically synthesized and seven were isolated from Tylophora atrofol-
liculata. To facilitate future drug design of phenanthroindolizidine alkaloids as potential antitumor agents, we have explored the
structure–activity relationships (SAR) of this class of compounds. We demonstrated that DCB-3503 and tylophorinidine (PA-7)
were among the most active compounds against tumor growth both in vitro and in vivo. In the hepatocellular carcinoma cell line
HepG2, the GI50s of DCB-3503 and PA-7 were 35 5 nM and 11 5 nM, respectively. DCB-3503 and PA-7 significantly inhibited
HepG2 tumor growth in nude mice at a dose of 9 mg/kg given by intraperitoneal (ip) injections twice a day every third day for a total
of four cycles (P < 0.05 for DCB-3503 and P < 0.01 for PA-7). Their potent antitumor activities correlated with their potent NF-jB-
inhibitory effects and their cyclin D1 down-regulatory effects.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Phenanthroindolizidine alkaloids (PA) have been a focus
of our research due to their potent antitumor,1–5 anti-
inflammatory,6,7 and anti-autoimmune disease proper-
ties.8 Five tylophorine analogs that belong to the group
of phenanthroindolizidine alkaloids, DCB-3500, DCB-
3501, DCB-3502, DCB-3503, and DCB-3506 are
synthetic compounds (Fig. 1). Among these analogs,
DCB-3503 has been shown to exert potent growth-inhib-
itory effects against HepG2, a human hepatocellular car-
cinoma cell line, both in vitro and in vivo.5 DCB-3503
was also active in vitro against PANC-1, a human pan-
creatic ductal carcinoma cell line.9 In addition, DCB-
3500, DCB-3501, DCB-3502, and DCB-3503 were
equally effective against both parental human nasopha-
ryngeal carcinoma KB cells and KB variants, which are
resistant to etoposide, hydroxyurea or camptothecin.5
During our investigation of the mechanisms of action
of the tylophorine analogs, we discovered that this class
of compounds has potent inhibitory effects against NF-
jB-mediated transcription.5 NF-jB is a family of tran-
scription factors that play critical roles in the process
of inflammation,10 cell survival,11 and chemoresis-
tance.12 Overexpression of NF-jB may contribute to
chemoresistance of cancers,12 making NF-jB an attrac-
tive target for antitumor drug development.13 The potent
inhibitory effects of phenanthroindolizidine alkaloids on
NF-jB-mediated transcription may be one of the mech-
anisms of their antitumor activity. We previously found
that DCB-3503 down-regulated the expression of cyclin
D1.9 Cyclin D1 plays a critical role during cell cycle pro-
gression from G1 to S phase.14 Cyclin D1 transcription
and translation increase through Ras-dependent path-
ways during growth factor signaling.14 Cyclin D1 overex-
pression has been observed in a number of human
tumors15,16 and is associated with poor prognosis and
chemoresistance.17 Therefore, the down-regulatory effect
of cyclin D1 also contributes to the antitumor activity of
these phenanthroindolizidine alkaloids.
Keywords: Phenanthroindolizidine alkaloids; Structure–activity rela-
tionships; Antitumor activity.
*
Corresponding authors. Tel.: +1 203 785 7118; fax: +1 203 785 7129
(Y.C.C.); Tel.: +86 10 6316 5324; fax: +86 10 6301 7757 (S.Y.); Tel.:
+1 865 974 1066; fax: +1 865 974 1536 (D.C.B.); e-mail addresses:
dcbaker@utk.edu; yushishan@imm.ac.cn; yccheng@yale.edu
Fellow of the National Foundation for Cancer Research.
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.021

W. Gao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4338–4342
4339
R1
2
R2
3
R4
14
1
R5
14b
4
13a
14a
13
11
4a
4b
12
N
8b
5
6
10
8a
8
9
R3
7
OMe
R1
Compounds
DCB-3500
DCB-3501
DCB-3503
R2
R3
R4
R5
N10
OMe OMe OMe
OMe OMe OMe OH (R) H (S)
OMe OMe OMe OH (S) H (S)
H
H (S)
–
–
–
–
–
DCB-3506
OMe OH
OMe OH (S) H (S)
OMe OH (S) H (S)
PA-2 (Tylophoridicine E)
PA-3 (Tylophoridicine C)
PA-4 (Tylophoridicine F)
PA-5
H
H
H
H
OH
OMe OH
OH (S) H (S) N+–O–
OMe OMe OH (R) H (S) N+–O–
OMe OH
H
H (R)
–
[(R)-(+)-Deoxytylophorinidine]a
PA-6 (Tylophorinine)b
H
H
OMe OMe OH (R) H (S)
OMe OH OH (S) H (S)
–
–
PA-7 (Tylophorinidine)
a Compound 5 in ref. 18.
b Compound 6 in ref. 18.
OMe
MeO
MeO
H
N
OMe
DCB-3502
Figure 1. Chemical structures of phenanthroindolizidine alkaloids.
Seven phenanthroindolizidine alkaloids, tylophoridicine
D (PA-1), tylophoridicine E (PA-2), tylophoridicine C
(PA-3), tylophoridicine F (PA-4), R-(+)-deoxytylophor-
inidine (PA-5), tylophorinine (PA-6), and tylophorini-
dine (PA-7) (Fig. 1), were isolated from the roots of
Tylophora atrofolliculata (a medicinal plant widely dis-
tributed in Southwestern China) and found to have dif-
ferent degrees of growth-inhibitory activities in cell
culture.18 In this study, we explored the structure–activ-
ity relationships of these phenanthroindolizidine alka-
loids through comparison of their cytotoxicities,
antitumor activities in vivo, inhibitory effects against
NF-jB, cAMP response element (CRE), and activator
protein-1 (AP-1) mediated transcription, and their
down-regulatory effects on the key cell-cycle control
protein, cyclin D1. The main objectives were to study
the structure–activity relationships that will aid in the
future design of anti-cancer drugs from phenanthroind-
olizidine alkaloids and to obtain candidate compounds
for clinical trials in cancer patients, especially for those
who are failing current chemotherapy protocols.
tested using the previously described cytotoxicity assay.5
As shown in Table 1, PA-2 and DCB-3506 were the least
active among the compounds tested, with GI50’s (con-
centration of drug that inhibits cell growth by 50% after
continuous drug exposure for three doubling times)
against HepG2 > 5000 nM and >600 nM, respectively.
PA-2 and DCB-3506 differ structurally from the rest
of the PA analogs by the presence of an OH group at
the R2 position (OH replaces OMe). Interestingly,
DCB-3503 with an OMe group at R2 is more active than
DCB-3506 with an OH group at R2. This suggests that
the OMe group at R2 is required for the cytotoxic po-
tency of a PA analog. Therefore, substituting an O-alkyl
or an O-aryl group at the R2 position may be a future
direction for synthesis in this class of compounds. The
major structural differences between DCB-3501 and -
3503 and tylophorinine (PA-6) is at the R1 position
where DCB-3501 and -3503 have an OMe group and
PA-6 has a hydrogen atom. These also differ in the con-
figuration of the 14-OH group. The GI50 value for PA-6
was 20 6 nM and 11 4 nM in HepG2 cells and
PANC-1 cells, respectively. These values were less than
the GI50 values of DCB-3501, suggesting that the addi-
tion of the OMe group at R1 decreases cytotoxicity.
Also, PA-7 with an OH substitution at the R3 position
The growth-inhibitory effect of the PA analogs (PA-1
was not included in this study because of the shortage
of this compound) on HepG2 and PANC-1 cells were

4340
W. Gao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4338–4342
Table 1. Cytotoxicity of PA analogs in HepG2 and PANC-1 cells
800
700
600
500
400
300
200
100
0
a
HepG2 GI50 (nM)
a
PANC-1 GI50 (nM)
control
DCB-3503
PA-5
Compound
DCB-3500
DCB-3501
DCB-3502
DCB-3503
DCB-3506
PA-2
11 4b
110 45b
264 115b
35 5b
>600
nd
nd
PA-7
nd
51 3b
nd
>5000
>5000
98 38
PA-3
PA-4
67
63
11
11
7
9
7
3
4
71
13
20
11
9
3
6
5
PA-5
PA-6
PA-7
0
0
1
2
3
4
5
6
7
8
9
10 11
a Values are means SD of three experiments, with each data point
done in triplicate (nd, not determined).
b Published.5,7
Time (days)
treatment
125
100
75
50
25
0
had similar potency to PA-6 with an OMe group at the
R3 position (Table 1). This suggests that the substitution
of an OH group for an OMe group at R3 is not critical
for maintaining potent cytotoxicity.
DCB-3501 and DCB-3503 are modified from DCB-3500
by addition of an (R)-OH and an (S)-OH group at the
R4 position, respectively. In HepG2 cells, the GI50s of
DCB-3500, DCB-3501, and DCB-3503 were determined
to be 11 4 nM, 110 45 nM, and 35 5 nM, respec-
tively. The addition of either an OH group at R4 did
not increase the cytotoxicity in cell culture, although
the addition of an (S)-OH group at R4 affected the cyto-
toxic activity less than the addition of an (R)-OH group
at R4; thus a 14-(S)-OH group seems to favor activity
over an epimeric 14-(R)-OH group. We previously ob-
served that DCB-3503 was more potent against tumor
growth in vivo than DCB-3500.5 The antitumor activity
of DCB-3503 was confirmed in this study (as shown in
Fig. 2) using nude mice bearing HepG2 tumor xeno-
grafts by ip injections at 9 mg/kg twice per day every
third day for four cycles (DCB-3503 vs control:
P < 0.05). While PA-5 did not show activity against tu-
mor growth in vivo (Fig. 2a), PA-7 treatment at 9 mg/kg
twice per day every third day for four cycles showed a
significant tumor-suppressive effect (PA-7 vs control:
P < 0.01), as shown in Fig. 2a. The lack of an in vivo ef-
fect for PA-5 could be due to its structural differences
from PA-7. The stereocenter at C-13 is of the (R)-config-
uration in PA-5, while it is of the (S)-configuration in
PA-7. Moreover, there is an addition of an (S)-OH
group at R4 in PA-7. DCB-3503 is more active against
tumor growth than DCB-3500, and PA-7 is more active
than PA-5 in vivo. Interestingly, both DCB-3503 and
PA-7 have (S)-OH groups at position R4. It is our
hypothesis that the addition of an OH group at R4
may favor the pharmacokinetics of these compounds
in vivo. This point requires further investigation. There
was no significant difference in body weight loss com-
paring the groups treated with PA-7 and PA-5 to that
of the vehicle control group (Fig. 2b). With the group
treated with DCB-3503, there was a 15% body weight
loss by the end of treatment days 9 and 10. We previ-
ously observed that on discontinuation of treatment
there was recovery of the loss in body weight.5
0
1
2
3
4
5
6
7
8
9
10 11
Time (days)
treatment
Figure 2. Antitumor activity of phenanthroindolizidine alkaloids.
Four-week-old male NCr-nude mice were injected subcutaneously
with 8 · 106 HepG2 cells. Treatment was initiated when the tumors
were 200–300 mm3, which is around 8 days after injection of HepG2
cells. DCB-3503, PA-5, and PA-7 were dissolved in 0.5% Tween 80 in
PBS, and solvent alone served as control. Drugs were administered by
ip injections. DCB-3503, PA-5, and PA-7 were administered at 9 mg/
kg, every 12 h on days 0, 3, 6, and 9. HepG2 tumors were measured
daily using a caliper, and the body weights of the mice were monitored
for toxicity. Tumor volume was estimated by using the formula
length · width2 · p/6. (a) Effect of DCB-3503, PA-5, and PA-7 on
HepG2 tumor growth in nude mice. (b) Effect of DCB-3503, PA-5, and
PA-7 on the body weight of nude mice. There were five mice in each
group. Data points represent means of the groups SD. Statistical
analysis was performed using one-way ANOVA (Dunnett’s) to
compare the treatment groups and the vehicle control.
In comparing the cytotoxicity of PA-4 and PA-6 (Table
1), we observed that PA-6 is ꢀ3- to 5-fold more potent
than PA-4. The structural difference between PA-4 and
PA-6 is the presence of an N-oxide in PA-4 (Fig. 1), indi-
cating that the addition of an N-oxide leads to a de-
crease in cytotoxicity. This is further confirmed by PA-
3’s decreased cytotoxicity as compared with that of
PA-7. The presence of the N-oxide in PA-3 is the only
structural difference that appears to contribute to its de-
crease of cytotoxicity, as the loss of R1 or the substitu-
tion of an OH group at R3 in PA-3 did not lead to a
decrease in cytotoxicity as indicated above. The struc-
tural difference between DCB-3500 and DCB-3502 is
the double bond at position 14–14a, and there was
about a 20-fold difference in cytotoxicity. The GI50 for

W. Gao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4338–4342
4341
Table 2. IC50’s of the inhibitory effect of PA analogs against NF-jB-,
CRE-, and AP-1-mediated transcription in HepG2 cells
DCB-3502 and DCB-3500 was 264 115 nM and
11 4 nM, respectively. We predict, based on the cyto-
toxicity and the antitumor activity in vivo, that the ideal
compound would be a compound modified using the
DCB-3503 or PA-7 scaffold. The removal of R1 (replace
R1 = OMe with R1 = H) in DCB-3503 could be benefi-
cial to activity.
a
a
a
Compound
NF-jB IC50
(nM)
CRE IC50
(nM)
AP-1 IC50
(nM)
DCB-3500
DCB-3501
DCB-3502
DCB-3503
DCB-3506
PA-2
41 20c
315 64
>300
>300b,c
>300
>300
>300b,c
>300b
>300b
87 6c
1067 231
>300
>1000
1067 116
>1000
>3000
322 19
>1000
We then analyzed the effects of the different phenanthro-
indolizidine alkaloids on NF-jB-, CRE-, and AP-1-
mediated transcription. HepG2 cells stably transfected
with firefly luciferase reporter vector pBIIX-luc (con-
taining two tandemly repeated NF-jB binding sites)
were generated as previously described and referred to
as HepG2-NF-jB-luc.5 Similarly, HepG2-CRE-luc and
HepG2-AP-1-luc stable cell lines were generated by
transfection of HepG2 cells with pCRE-luc and pAP-
1-luc (Clontech), respectively. Tumor necrosis factor a
(TNFa), forskolin and 12-O-tetradecanoylphorbol 13-
acetate (TPA) were used to activate NF-jB-, CRE-,
and AP-1-mediated transcription, respectively, as previ-
ously described.5 Stable cell lines were pretreated with 3-
fold serial dilutions of PA analogs for 1 h, then the cells
were stimulated with their corresponding activators for
4 h. The luciferase activities were measured using Pro-
mega’s luciferase assay kit. The IC50 was determined
as the concentration of the compound at which the lucif-
erase activity is inhibited by 50%. In Table 2, the inhib-
itory effects of PA analogs against NF-jB-, CRE-, and
AP-1-mediated transcription are shown. The results
indicate that this class of compounds preferentially
inhibits NF-jB-mediated transcription, as the IC50 val-
ues in terms of NF-jB inhibition are significantly lower
than those of CRE- and AP-1-mediated transcription.
For example, the IC50 of DCB-3503 with regards to
NF-jB-, CRE-, and AP-1-inhibition was 87 6 nM,
1067 231 nM, and 1067 116 nM, respectively. Con-
sistent with the cytotoxicity data, DCB-3502, DCB-
3506, and PA-2 are the least active compounds, whereas
PA-5, PA-6, and PA-7 are the most active compounds in
terms of their NF-jB inhibition. Thus, the potency of
NF-jB inhibition corresponds directly with the degree
of cytotoxicity.
PA-3
PA-4
600 173
367 116
>1000
>1000
>3000
>3000
PA-5
PA-6
PA-7
11
12
10
6
9
4
135 21
80 28
95 92
68 46
110 14
65 35
a Values are means SD of three experiments, with each data point
done in triplicate.
b Data generated from transient transfections.
c Graphical version was published.5
DCB-3503
PA-6
PA-5
PA-7
nM:
-
30 100 10 30
10 30
10 30
1
2
3
4
5
6
7
8
9
Cyclin D1
β-actin
120
100
80
60
40
20
0
1
2
3
4
5
6
7
8
9
Figure 3. Effects of phenanthroindolizidine alkaloids on cyclin D1
expression. HepG2 cells were treated with DCB-3503, PA-5, PA-6, and
PA-7 as indicated for 2 h. (a) cyclin D1 expressions were analyzed by
Western blot using a specific monoclonal antibody; b-actin was used as
the internal control. (b) Quantitation of cyclin D1 protein levels
normalized with b-actin expression by densitometer scanning.
Previously we observed that cyclin D1 could be down-
regulated by DCB-3503.9 We then analyzed whether
other PA analogs could also down-regulate this critical
cell-cycle control protein. As shown in Figure 3, all the
PA analogs studied show a dose-dependent down-regu-
lation of cyclin D1. The cyclin D1 protein level with
10 nM PA-5 treatment is similar to that for the 100 nM
DCB-3503 treatment. Similar down-regulatory effects
against cyclin D1 were observed with PA-6 and PA-7
treatment. Their potency, in terms of cyclin D1 down-
regulation, correlates with the degree of their cytotoxic-
ity, as PA-5, PA-6, and PA-7 are the most active against
both tumor cell growth and cyclin D1 down-regulation.
and lack of the indolizidine ring led to the loss of cyto-
toxicity.19 Lee et al. synthesized a novel class of phenan-
threne-based tylophorine analogs with greatly enhanced
yield and polarity by opening the indolizidine ring.
However, the GI50s of the most potent compounds syn-
thesized were found to be in the sub-micromolar
range.20 We evaluated some compounds from Dr. Lee
in our laboratory. Their mechanism of action appears
to be different from the phenanthroindolizidine alka-
loids we studied (our unpublished results). Although
these compounds were derived from phenanthrene-
based tylophorine, they may constitute a different class
of cytotoxic compounds that are different from the tyl-
ophorine analogs we studied. In addition, Kim et al.
reported that a rigid phenanthrene structure is required
to maintain potent cytotoxicity. The unshared electron
pair on nitrogen is important for a high activity, and
cytotoxicity is dependent on the type and pattern of sub-
The structure–activity relationships of phenanthroindo-
lizidine alkaloids have been studied by other investiga-
tors. Wu et al. observed that the introduction of a
methoxyl functionality on the phenanthrene ring at
positions-2, -3, -6, and -7 increased the cytotoxicity,

4342
W. Gao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4338–4342
stitution on the phenanthrene ring.21 The SAR and
mechanisms of action of phenanthroindolizidine alka-
loids have been studied by various investigators; how-
ever, their molecular targets are still unknown. The
tylophorine analogs we studied have an impact on both
NF-jB-mediated transcription and cyclin D1 expres-
sion, which is due to a decrease in its synthesis. The
underlying mechanisms could be the same, a point that
is currently being investigated. Based on our studies, the
molecular target of tylophorine analogs may be novel
and different from the targets of known anti-cancer
drugs. Given the novel mechanism of action and activity
against cancer and autoimmune diseases in vivo, the
molecular mechanisms of this class of compounds must
be further explored.
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Chemical synthesis of DCB-3500 was carried out by the
procedure reported by Nylander and Njoroge.22 Both
DCB-3501 and -3503 were synthesized by a procedure
modified from that reported by Buckley and Rapo-
port.23 DCB-3502 and -3506 are new compounds, and
details of their syntheses and characterization are pro-
vided in Supplementary data to this paper.
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Acknowledgments
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The authors acknowledge Ginger Dutschman and Dr.
Elijah Paintsil for critical reading of the manuscript.
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Thakur, A.; Bollig, A.; Sarkar, F. H.; Liao, J. D. Clin.
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Supplementary data
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Supplementary data associated with this article (details
of the syntheses and characterization of DCB-3502
and -3506) can be found, in the online version, at
doi:10.1016/j.bmcl.2007.05.021.
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