Synthesis and evaluation of C-ring aromatized analogues of phenanthridone alkaloids

Article abstract of DOI:10.1007/s12272-011-0703-1

Phenanthridone alkaloids are envisaged as an attractive lead for the development of anticancer agents. We have prepared a series of aromatized analogues on the basis of the structure of this class of alkaloids with the hope of finding the simplified compounds with comparable activities. The obtained analogues were evaluated for their cytotoxic effect against several cancer cell lines and found to be virtually inactive. These observations together with molecular modeling studies strongly suggest that the stereochemistries of hydroxyl groups in C-ring of phenanthridone alkaloids are crucial to biological effects.

Full text of DOI:10.1007/s12272-011-0703-1

Arch Pharm Res Vol 34, No 7, 1065-1070, 2011
DOI 10.1007/s12272-011-0703-1
Synthesis and Evaluation of C-ring Aromatized Analogues of Phenan-
thridone Alkaloids
Seokwoo Lee, Soonho Hwang, Shuai Yu, Wonyoung Jang, Yun Mi Lee, and Sanghee Kim
College of Pharmacy, Seoul National University, Seoul 151-742, Korea
(Received July 5, 2010/Revised August 20, 2010/Accepted August 23, 2010)
Phenanthridone alkaloids are envisaged as an attractive lead for the development of
anticancer agents. We have prepared a series of aromatized analogues on the basis of the
structure of this class of alkaloids with the hope of finding the simplified compounds with
comparable activities. The obtained analogues were evaluated for their cytotoxic effect against
several cancer cell lines and found to be virtually inactive. These observations together with
molecular modeling studies strongly suggest that the stereochemistries of hydroxyl groups in
C-ring of phenanthridone alkaloids are crucial to biological effects.
Key words: Phenanthridone alkaloids, Anticancer activity, Structure-activity relationship,
Aromatization, Heck coupling
Due to their promising pharmacological profiles and
unique structural features, coupled with low natural
INTRODUCTION
Phenanthridone alkaloids are a small group of alka- abundance, many synthetic methodologies have been
loids isolated mainly from the plants of the Amarylli- developed by medicinal and synthetic chemist for the
daceae family (Kornienko and Evidente, 2008). The synthesis of natural phenanthridone alkaloids and
most representative are pancratistatin (
deoxypancratistatin (Green et al., 1972), narciclasine and Hudlicky, 2005; Chapleur et al., 2006; Shin et al.,
), and lycoricidine ( ). These highly oxygenated tri- 2007). These endeavors have enhanced our under-
1, Fig. 1), 7- their unnatural and truncated derivatives (Rinner
(3
4
cyclic natural products exhibit a variety of biological standing of the structure activity relationship (SAR)
effects such as anticancer (Green et al., 1972), anti- of this class of compounds. Since the synthesis of
viral (Gabrielsen et al., 1992), and growth regulatory phenanthridone alkaloids is still very complex and re-
activities (Pettit et al., 2002). Among these, the most quires many steps that are not amenable to a scalable
intriguing biological property is the profound cancer process, it is highly desirable to find novel analogues
cell growth inhibitory activity. Although the reported that pliable to large-scale preparation.
in vitro potencies vary, many of this class of alkaloids
The obvious synthetic challenge posed by phenan-
were found to have GI50 values in the low nM concen- thridone alkaloids is the highly oxygenated C-ring
tration range (Pettit et al., 2005, 2006). Thus, natural which contains the contiguous stereogenic centers. We
phenanthridone alkaloids and their derivatives have envisioned that the removal of stereogenic centers by
been under preclinical development for nearly two aromatization of C-ring would create analogues with a
decades. However, there are several unfavorable pro- general structure
5 (Fig. 1) that are easily synthesiz-
perties that hinder their clinical application which ed. This assumption prompted us to perform the
include poor aqueous solubility and the low natural synthesis and cytotoxicity evaluation of a series of C-
availability (Fox, 1991).
ring aromatized analogues. Herein we wish to report
our studies on this subject.
Correspondence to: Sanghee Kim, College of Pharmacy, Seoul
National University, San 56-1, Shilim, Kwanak, Seoul 151-742,
Korea
MATERIALS AND METHODS
Tel: 82-2-880-2487, Fax: 82-2-888-0649
E-mail: pennkim@snu.ac.kr
All chemicals were reagent grade and used as pur-
1065

1066
S. Lee et al.
washed with 5% citric acid solution, 5% sodium bicar-
bonate solution, and brine. The organic solution was
dried over MgSO4 and concentrated in vacuo. The
residue was dissolved in EtOH (15 mL), and added
KOH (29.91 mmol). The reaction mixture was refluxed
for 18 h, and then the solvent was concentrated in
vacuo. The residue was dissolved in water and ex-
tracted with EtOAc twice. The combined organic layers
were dried over MgSO4, and concentrated in vacuo
Purification of the residue by column chromatography
on silica gel ( -hexane-EtOAc = 3:1 v/v) afforded aniline
in 65-84% yield (The yields of 6a' 6b' 6c', and 6d'
.
n
6
,
,
were 84%, 75%, 66%, and 65%, respectively).
General synthetic procedure for compounds
(10a'-d')
To a solution of 2-iodobenzoic acid
9 (3.42 mmol) in
benzene (3 mL) containing two drops of DMF was
added oxalyl chloride 2.0 M solution in CH2Cl2 (6.84
mmol). The reaction mixture was stirred at room
Fig. 1. Natural phenanthridone alkaloids and C-ring
aromatized analogues
temperature for 5 h, and then concentrated in vacuo
.
chased. All reactions were performed under an inert To this residue was added a solution of (2.85 mmol)
6
atmosphere of dry argon or nitrogen using dry solv- in dry THF (15 mL) and triethylamine (3.42 mmol),
ents. Reactions were monitored by TLC analysis using and stirred at room temperature for 2 h. The reaction
Merck silica gel 60 F-254 thin layer plates. Flash mixture was concentrated in vacuo and diluted with
column chromatography was carried out on Merck CH2Cl2. The solution was washed with 2
silica gel 60 (230-400 mesh). 1H-NMR was recorded in tion, 10% NaOH solution, and brine. The organic layer
units relative to deuterated solvent as internal refer- was dried over MgSO4, and concentrated in vacuo
N HCl solu-
.
ence at 300 MHz.
Purification of the residue by column chromatography
on silica gel ( -hexane-EtOAc = 3:1 v/v) afforded amide
10
n
.
General synthetic procedure for compounds
(8a'-d')
To a solution of benzaldehyde
CH3CN/ -BuOH/H2O (2:2:1 v/v/v, 63 mL) was added dioxole-5-carboxamide (10a')
NaH2PO4
2H2O (62.82 mmol), 2-methyl-2-butene (37.68 Brown solid (2.1 g, 64%); 1H-NMR (300 MHz, CDCl3):
mmol), and NaClO2 (25.12 mmol). The reaction mixture 5.09 (s, 2H), 5.11 (s, 4H), 6.08 (s, 2H), 6.08 (s, -NH),
was stirred at room temperature for 10 min. It was 6.64 (s, 1H), 6.78 (d, = 9.2 Hz, 1H), 7.2-7.48 (m,
diluted with EtOAc (20 mL), acidified with 2 HCl 15H), 7.64 (s, 1H), 8.10 (d, = 9.2 Hz, 1H).
7 (6.28 mmol) in 6-Iodo-N-(2,3,4-tris(benzyloxy)phenyl)benzo[d][1,3]
t
·
δ
J
N
J
solution until pH 2, and then extracted with EtOAc
twice. The combined organic layers were washed with
N
-(2,3-Bis(benzyloxy)phenyl)-6-iodobenzo[
dioxole-5-carboxamide (10b')
The crude mixture was used in the next step without Brown solid (1.1 g, 52%); 1H-NMR (300 MHz, CDCl3):
d][1,3]
brine, dried over MgSO4, and concentrated in vacuo
.
further purification.
δ
5.10 (s, 2H), 5.16 (s, 2H), 6.01 (s, 2H), 6.66 (s, 1H),
6.81 (dd, = 0.9, 8.3 Hz, 1H), 7.07 (t, = 8.3 Hz, 1H),
= 8.3 Hz,
J
J
7.20-7.41 (m, 10H), 7.90 (s, 1H), 8.10 (d,
1H).
J
General synthetic procedure for compounds
(6a'-d')
To a solution of carboxylic acid
dioxane (10 mL) was added diphenylphosphoryl azide
(DPPA, 3.59 mmol) and triethylamine (4.49 mmol). dioxole-5-carboxamide (10c')
After the reaction mixture was stirred for 30 min at Brown solid (1.3 g, 78%); 1H-NMR (300 MHz, CDCl3):
room temperature, EtOH (6 mL) was added. The mix- 5.02 (s, 2H), 5.07 (s, 2H), 5.99 (s, 2H), 6.59-6.64 (m,
ture was refluxed for 2 h. The solvent was removed in 3H), 7.00 (s, 1H), 7.28-7.41 (m, 10H), 7.88 (s, 1H), 8.35
vacuo and redissolved in CH2Cl2. The solution was (d, = 8.6 Hz, 1H).
8 (2.99 mmol) in
N-(2,4-Bis(benzyloxy)phenyl)-6-iodobenzo[d][1,3]
δ
J

Aromatized Phenanthridone Alkaloid Analogues
1067
N
-(2,3-Bis(benzyloxy)phenyl)-6-iodobenzo[
dioxole-5-carboxamide (10d')
Brown solid (314 mg, 92%); 1H-NMR (300 MHz, CDCl3): one (12c')
5.12 (s, 2H), 5.17 (s, 2H), 5.28 (s, 1H), 6.01 (s, 1H), Yellow solid (279 mg, 92%); 1H-NMR (300 MHz, CDCl3):
6.89 (d, = 6.4 Hz, 1H), 6.95 (dd, = 1.4, 6.5 Hz, 1H), δ −0.17-0.14 (m, 9H), 0.74 (t, = 8.0 Hz, 2H), 1.58 (s,
7.00 (s, 1H), 7.25-7.46 (m, 11H). 2H), 3.59 (t, = 8.3 Hz, 2H), 5.13 (s, 2H), 5.15 (s, 2H),
6.07 (s, 1H), 6.12 (s, 2H), 6.80 (d, = 2.7 Hz, 1H), 7.23
(d, = 3.0 Hz, 1H), 7.34-7.52 (m, 10H), 7.87 (s, 1H).
d
][1,3]
2,4-Bis(benzyloxy)-5-((2-(trimethylsilyl)ethoxy)
methyl)-[1,3]dioxolo[4,5-j]phenan thridin-6(5H)-
δ
J
J
J
J
J
J
General synthetic procedure for compounds
(11a'-d')
To a solution of amide 10 (0.57 mmol) and NaH (60% 2,3-Bis(benzyloxy)-5-((2-(trimethylsilyl)ethoxy)
dispersion in mineral oil, 1.71 mmol) in dry DMF (6 methyl)-[1,3]dioxolo[4,5- ]phenan thridin-6(5 )-
mL) were added dropwise 2-(Trimethylsilyl)ethoxy- one (12d')
methyl chloride (SEMCl, 0.86 mmol) at 0oC. After stir- Yellow solid (104 mg, 44%); 1H-NMR (300 MHz, CDCl3):
ring at room temperature for 1 h, the reaction mixture δ −0.01-0.01 (m, 9H), 0.94 (dt, = 2.8, 8.1 Hz, 2H),
was diluted with Et2O and washed with brine. The 1.73 (s, 2H), 3.71 (t, = 8.1 Hz, 2H), 5.25 (s, 2H), 5.28
j
H
J
J
organic layers were dried over MgSO4, and concen- (s, 2H), 5.74 (s, 1H), 6.09 (s, 2H), 7.26-7.43 (m, 8H),
trated in vacuo. Purification of the residue by column 7.50-7.53 (m, 4H), 7.83 (s, 1H).
chromatography on silica gel (
v) afforded SEM protected amide 11 in 53-94% yield
(The yields of 11a' 11b' 11c', and 11d' were 77%,
n-hexane-EtOAc = 5:1 v/
General synthetic procedure for compounds
(5a-d)
,
,
53%, 91%, and 94%, respectively).
To a solution of 12 (0.13 mmol) in EtOAc (7 mL) was
charged with palladium hydroxide (50% w/w). The
reaction mixture was stirred for 1 h under a balloon
filled with hydrogen gas at room temperature. It was
General synthetic procedure for compounds
(12a'-d')
To a solution of protected amide 11 (0.57 mmol) in diluted with EtOAc and filtered through a pad of
dry DMF (6 mL) was added Pd(OAc)2 (0.10 mmol), Celite. The solvent was removed in vacuo. Purification
P(o-Tol)3 (0.21 mmol), and Ag2CO3 (1.04 mmol) at room of the residue by column chromatography on silica gel
temperature. After the reaction mixture was refluxed with
n-hexane-EtOAc (1:1 v/v). The above pure debenzy-
for 1 h and then cooled to room temperature. The lated compounds were dissolved in CH2Cl2 (2 mL),
resulting solution was diluted with Et2O-EtOAc (1:1 v/ and added trifluoroacetic acid (TFA, 0.2 mL) at 0oC.
v), and filtered through a pad of Celite. The solvent After the reaction mixture was stirred at 0oC for 30
was removed in vacuo. Purification of the residue by min, the solution was diluted with toluene. The result-
column chromatography on silica gel (
EtOAc = 3:1 v/v) afforded protected penanthridone 12
n
-hexane- ing suspension was centrifugated at 1000 rpm twice
for 10 min, and removed supernatant. The residual
solid was triturated 3 times with -hexane-EtOAc (1:1
v/v) to give the final penanthridone
.
n
2,3,4-Tris(benzyloxy)-5-((2-(trimethylsilyl)eth-
oxy)methyl)-[1,3]dioxolo[4,5- ]phenanthridin-6
(5 )-one (12a')
Yellow solid (286 mg, 95%); 1H-NMR (300 MHz, CDCl3): 6(5
δ −0.06-0.01 (m, 9H), 0.92 (dt,
= 2.7, 8.3 Hz, 2H), Gray solid (2.0 mg, 18%); 1H-NMR (300 MHz, C5D5N):
1.77 (s, 2H), 3.59 (dt, = 2.7, 9.7 Hz, 2H), 5.28 (s, 2H), 5.99 (s, 2H), 7.71 (s, 1H), 7.76 (s, 1H), 8.32 (s, 1H).
5.
j
H
2,3,4-Trihydroxy-[1,3]dioxolo[4,5-j]phenanthridin-
H)-one (5a)
J
J
δ
5.30 (s, 2H), 5.34 (s, 4H), 6.20 (s, 2H), 6.24 (s, 2H),
7.63-7.97 (m, 15H), 8.00 (s, 1H).
3,4-Dihydroxy-[1,3]dioxolo[4,5-
(5 )-one (5b)
3,4-Bis(benzyloxy)-5-((2-(trimethylsilyl)ethoxy) Gray solid (8.0 mg, 62%); 1H-NMR (300 MHz, C5D5N):
j]phenanthridin-6
H
methyl)-[1,3]dioxolo[4,5-
j
]phenan thridin-6(5
H
)-
δ
6.04 (s, 2H), 7.74 (d,
8.29 (s, 1H).
J = 8.8 Hz, 1H), 7.84 (s, 1H),
one (12b')
Yellow solid (248 mg, 84%); 1H-NMR (300 MHz, CDCl3):
δ
0.00 (s, 9H), 0.95 (t,
3.63 (t, = 8.4 Hz, 2H), 5.23 (s, 2H), 5.33 (s, 2H), 6.17- (5
6.23 (m, 3H), 7.14 (d,
= 9.0 Hz, 1H), 7.39-7.60 (m, Yellow solid (4.5 mg, 48%); 1H-NMR (300 MHz, C5D5N):
10H), 7.89 (d, = 9.0 Hz, 1H) 7.97 (s, 1H). 6.05 (s, 2H), 7.10 (s, 1H), 7.67 (s, 1H), 7.93 (s, 1H),
8.34 (s, 1H).
J
= 8.3 Hz, 2H), 1.74 (s, 2H), 2,4-Dihydroxy-[1,3]dioxolo[4,5-
j]phenanthridin-6
J
H)-one (5c)
J
J
δ

1068
S. Lee et al.
2,3-Dihydroxy-[1,3]dioxolo[4,5-j]phenanthridin-6
(5
Gray solid (6.3 mg, 34%); 1H-NMR (300 MHz, C5D5N):
6.03 (s, 2H), 7.35 (s, 1H), 7.87 (s, 1H), 8.14 (s, 1H),
H)-one (5d)
δ
8.29 (s, 1H).
Sulforhodamine B assay
The cytotoxicity of individual compounds screened
was determined by the sulforhodamine B (SRB) assay.
Briefly, cells were plated in 96-well plates at the
density of 5×104 cells/well (HCT 116 and PC-3) or
2.5×104 cells/well (A549) and incubated for 24 h. Test
compounds (dissolved in pure DMSO) were diluted in
the medium and treated to cells for 48 h. The cells
were fixed with 10% trichloroacetic acid for 30 min at
4oC. The fixed cells were stained with 0.4% SRB for 30
min at room temperature. The stained cells were
dissolved in 10 mM Tris buffer (pH 10.0). The absor-
bance was measured at 515 nm. The cell survival (%)
of each tested group was determined by comparison
with solvent-treated control cells. The IC50 value, the
concentration of 50% cell survival, was estimated by
non-linear regression analysis.
Electrostatic potential calculation using DMol3
program
Electrostatic potential calculations of lycoricidine (4)
and aromatization of C-ring analogue 5a were per-
formed by DMol3 program in the Material Studio
5.0TM. The two molecules were optimized by the dens-
ity functional theory at DND level. A generalized gra-
dient approximation (GAA) for the exchange correla-
tion function of Perdew, Burke, and Ernzerhof (PBE)
was used with the double-numerical plus d-functions
(DND) as implemented in DMol3.
Scheme 1. Reagents and conditions: (a) K2CO3, BnBr, KI,
DMF; (b) NaClO2, NaH2PO4·2H2O, 2-methyl-2-butene, CH3CN-
t-BuOH-H2O = 2:2:1; (c) 1. DPPA, Et3N, dioxane, EtOH, reflux,
2. KOH, EtOH, reflux; (d) 2-iodobenzoic acid, oxalyl chloride
2.0 M solution in CH2Cl2, benzene, cat. DMF; (e) Et3N, THF;
(f) SEMCl, NaH, DMF; (g) Pd(OAC)2, P(o-tol)3, Ag2CO3, DMF;
(h) Pd(OH)2, H2, EtOAc; (i) TFA, CH2Cl2. DMF = N,N-di-
methylformamide, DPPA = diphenylphosphoryl azide. SEMCl
= 2-(trimethylsilyl)-ethoxymethyl chloride, TFA = trifluoro-
acetic acid.
RESULTS AND DISCUSSION
Among the members of phenanthridone alkaloids,
we chose 7-deoxypancratistatin (
2
) and lycoricidine (
4)
followed by NaClO2-mediated oxidation of aldehyde
as a template for designing the aromatized analogues. function provided carboxylic acids
Although they are approximately 10-fold less active yield. The obtained acids were subjected to a modi-
than the corresponding 7-hydroxylated congeners fied Curtius rearrangement using DPPA in the pre-
and , they are sufficiently active to make a compari- sence of ethanol to afford ethyl carbamate, which was
son with respect to their SAR. Furthermore, the pre- then converted to anilines by refluxing with KOH in
paration of their A-ring precursor is easier than that ethanol (Alonso-Alija et al., 2004).
8 in high overall
8
1
3
6
of 7-hydroxylated compounds.
For the formation of B-ring of designed analogues,
For the synthesis of the designed compounds, we aromatic amines
chose to employ an intramolecular Heck coupling known 2-iodobenzoic acid
6
were first condensed with the
(Takeda et al., 2007) to
strategy. Our synthesis is shown in Scheme 1. The bis give 10 in high yield (Scheme 1). Our initial attempts
or tri-benzyloxy substituted anilines were prepared of the intramolecular Heck coupling reaction with 10
from the corresponding hydroxylated benzaldehydes were unsuccessful, presumably due to the unfavorable
. Benzyl protection of phenolic hydroxyl groups of -trans conformation of 10. Thus, we decided to con-
9
6
7
7,
s

Aromatized Phenanthridone Alkaloid Analogues
1069
vert the secondary amide of 10 to the tertiary amide
by adding protecting group to induce the conforma-
tional changes. The 2-(trimethylsilyl)ethoxymethyl
(SEM) group was chosen for this purpose. Alkylation
of amide 10 with SEMCl in the presence of NaH gave
the protected amide 11 in high yield. The Heck
coupling reaction of amide 11 with Pd(OAc)2, P(o-Tol)3
as a phosphine ligand, and Ag2CO3 as a base in DMF
under reflux afforded the desired cyclized products 12
in good to excellent yield (Harayama et al., 2001). The
global deprotection of benzyl protecting groups in 12
followed by removal of SEM protecting group by TFA
furnished the final target compounds
overall yield.
5 in modest
As a preliminary evaluation of the aromatized ana-
logues , the cytotoxic activity in various cancer cells
5
Fig. 2.
(A) Comparison of the electrostatic potential energy
was determined by SRB assay as described previously
(Lee et al., 1998, 2003a, 2003b). As shown in Table I,
surface of minimum energy conformations of lycoricidine (
and C-ring aromatized analogue 5a. ( ) Superimposition of
energy-minimized conformers of C-ring aromatized ana-
logue 5a (green) and of lycoricidine ( , grey).
4)
B
the designed analogues
cytotoxicities against the cancer cells tested up to 50
M. Only tri-hydroxylated analogue 5a exhibited
modest activity against colon carcinoma HCT116 cells.
5 did not show any significant
4
µ
These observations strongly suggest that the stereo-
To understand the dramatic activity differences, we chemistries of hydroxyl groups in C-ring of phenan-
performed the molecular modeling studies (Rinner et thridone alkaloids are crucial to exhibit biological
al., 2004). The energy-minimized conformations were effects. The previous SAR studies were mostly focused
optimized by the density functional theory method on the absence or presence of hydroxyl groups, not on
(PBE) at the DND level (DMol3) (Kim et al., 2008). As their stereochemistries. Thus, our study not only adds
shown in Fig. 2, molecular models of 5a and its cor- to our understanding of structural and functional
responding natural product lycoricidine (4) show aspects of stereochemistry of phenanthridone alkaloids,
interesting electron-density similarities (Fig. 2A). but also provides a basis for the design of new phen-
However, comparison of the superimposed structures anthridone-type anticancer agents.
of lycoricidine (
ments of the hydroxyl groups in C-ring of two com- anthridone alkaloids, we have prepared a series of C-
pounds and 5a are somewhat different (Fig. 2B). ring aromatized analogues. We have established the
While the C-4 hydroxyl group of lycoricidine ( ) and preliminary strereochemistry-activity relationships,
4) and 5a reveals the spatial arrange-
In conclusion, based on the naturally occurring phen-
4
4
the corresponding phenolic hydroxyl group of 5a are and deduced the critical structural requirements for
nearly overlapped each other, the C-2 and C-3 two potency, through the modifications. These results will
pseudo-axial hydroxyl groups of lycoricidine are ori- help us in the design of potent anticancer agents.
ented differently to the corresponding hydroxyl groups Further medicinal chemical studies on this interesting
of 5a
.
class of natural products are ongoing, and will be
Table I. Cytotoxic activity and IC50 of aromatized analogues
a
IC50
(µM)
Compound
R1
R2
R3
HCT116b
A549c
PC-3d
e)
lycoricidine (
4)
-
-
-
0.2
29.9
>50
>50
>50
-
0.1
49.0
>50
>50
>50
5a
5b
5c
5d
-OH
-H
-OH
-OH
-OH
-H
-OH
-OH
-OH
>50
>50
>50
-OH
-OH
-H
>50
b
c
aAll values are the means of a minimum of three experiments; Human colon carcinoma; Human lung carcinoma;
dHuman prostate adenocarcinoma; The data were obtained from the National Cancer Institute’s (NCI) Developmental
e
Therapeutics Program (DTP) website (Human Tumor Cell Line Screen: http://dtp.nci.nih.gov/docs/cancer/cancer_data.
html)

1070
S. Lee et al.
Chem. Soc., 130, 16807-16811 (2008)
.
reported in due course.
Kornienko, A. and Evidente, A., Chemistry, biology, and
medicinal potential of narciclasine and its congeners.
Chem. Rev., 108, 1982-2014 (2008).
ACKNOWLEDGEMENTS
Lee, S. K., Cui, B., Mehta, R. R., Kinghorn, A. D., and Pezzuto,
J. M., Cytostatic mechanism and antitumor potential of
This work was supported by the SRC/ERC program
(R11-2007-107-02001-0) and the WCU progrm (R32-
2008-000-10098-0) through KOSEF funded by MEST.
We are grateful to the Research Institute of Pharma-
ceutical Sciences at Seoul National University for pro-
viding some experimental equipment.
novel 1H-cyclopenta[b]benzofuran lignans isolated from
Aglaia elliptica Chem. Biol. Interact., 115, 215-228 (1998).
.
Lee, S. K., Nam, K. A., and Heo, Y. H., Cytotoxic activity and
G2/M cell cycle arrest mediated by antofine, a phenan-
throindolizidine alkaloid isolated from Cynanchum pani-
culatum. Planta Med., 69, 21-25 (2003a).
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