Antitumor agents. Part 202: Novel 2'-amino chalcones: Design, synthesis and biological evaluation

Article abstract of DOI:10.1016/S0960-894X(00)00072-X

New 4',5',2,3,4-substituted 2'-amino chalcones were synthesized and evaluated for cytotoxicity against a panel of human tumor cell lines. Several compounds displayed significant cytotoxicity. The most promising lead molecule (10) also had high activity to

Full text of DOI:10.1016/S0960-894X(00)00072-X

Bioorganic & Medicinal Chemistry Letters 10 (2000) 699±701
Antitumor Agents. Part 202: Novel 20-Amino Chalcones:
Design, Synthesis and Biological Evaluationy
Yi Xia, Zheng-Yu Yang, Peng Xia, Kenneth F. Bastow, Yuka Nakanishi
and Kuo-Hsiung Lee*
Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
Received 6 December 1999; accepted 20 January 2000
AbstractÐNew 40,50,2,3,4-substituted 20-amino chalcones were synthesized and evaluated for cytotoxicity against a panel of human
tumor cell lines. Several compounds displayed signi®cant cytotoxicity. The most promising lead molecule (10) also had high activity
toward multi-drug resistant KB-VIN, and ovarian 1A9 cell lines. 20-Amino chalcones demonstrated signi®cantly increased anti-
tumor activity compared with the corresponding chalcones, while, the epoxide derivatives generally showed greatly reduced activity.
# 2000 Elsevier Science Ltd. All rights reserved.
Chalcones (1,3-diaryl-2-propen-1-ones, 1) display inter-
esting biological activities, including antimalarial,1 anti-
in¯ammatory,2 cytotoxic,3±5 and anticancer proper-
ties.6,7 A number of chalcones have been reported to be
active antimitotic agents inhibiting tubulin polymeriza-
tion.8 In our continuing study of antimitotic antitumor
agents, we discovered that 2-phenyl-4-quinolones (3)
and 2-phenyl-2,3-dihydro-4-quinolones (4) displayed
potent cytotoxicity against a panel of human tumor cell
lines.9±11 Furthermore, some quinolones showed in vivo
anticancer activity; in the xenograft ovarian OVCAR-3
model, treated mice demonstrated a 130% increase in
life span. Structurally, 20-amino-chalcones (2) are the
fragmented analogues of 2-phenyl-4-quinolones and
have an uncyclized B ring. However, the synthesis of
20-amino chalcones for cytotoxic and anticancer prop-
erties appears to be an unexplored ®eld. In addition, a
number of a,b-unsaturated ketones have demonstrated
preferential reactivity toward thiols.12,13 Alkylation with
a cellular thiol such as glutathione (GSH) may also
occur with chalcones, leading to adducts at the b-posi-
tion. Hence, these a,b-unsaturated ketones may be free
from the problems of mutagenicity and carcinogenicity
that are associated with many alkylating agents used in
cancer chemotherapy.14,15 The aim of the present inves-
tigation therefore was to prepare a number of such
prototypic molecules and related analogues in order to
evaluate their cytotoxic activity (Fig. 1).
As shown in Scheme 1, 20-amino chalcones (7±11) were
synthesized by a base-catalyzed condensation of appro-
priately substituted 2-amino acetophenone
5 and
aldehyde 6.16 Reacting compounds 7, 9 and 10 with
hydrogen peroxide a€orded the corresponding a,b-
epoxide derivatives 12±14.17
The substituted 20-amino chalcones and derivatives 7±14
were assayed for cytotoxicity in vitro against nine
human tumor cell lines, including epidermoid carci-
noma of the nasopharynx (KB), P-gp-expressing epi-
dermoid carcinoma of the masopharynx (KB-VIN),
ostcosarcoma (Hos), melanoma (SKMEL-2), ileocecal
carcinoma (HCT-8), breast cancer (MCF-7), lung car-
cinoma (A-549), glioblastoma (U87-MG), and ovarian
cancer (1A9) cell lines.
From the ED50 values summarized in Table 1, com-
pounds 7±11 showed signi®cant (ED50 ꢀ4.0 mg/mL)
cytotoxic activity, especially selectivity against KB, KB-
VIN and 1A9 cell lines. Compound 10, which contained
a methylenedioxy moiety at the 40, 50 positions and a
methoxy group at the 3 position, was the most active
compound in this study.
*Corresponding author. Tel.: +1-919-962-0066; fax: +1-919-966-
3893; e-mail: khlee@unc.edu
yFor part 201 see Ishida, J.; Wang, H. K.; Bastow, K. F.; Hu, C. Q.;
Lee, K. H. Bioorg. Med. Chem. Lett. 1999, 9, 3319.
By comparing the cytoxic activities of compounds with
di€erent substitutions as well as at di€erent positions,
the following conclusions were reached: (a) Introducing
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00072-X

700
Y. Xia et al. / Bioorg. Med. Chem. Lett. 10 (2000) 699±701
Figure 1.
Scheme 1. General synthetic routes to 20-amino chalcones.
Table 1. In vitro cytotoxic activities of 40, 50, 2,3,4-substituted 20-amino chalcones18
ED50 (mg/mL)a
KBb
KB-VINb
HOSb
SKMEL-2b
HCT-8b
MCF-7b
A-549b
U87-MG
1A9b
7
8
9
10
11
12
13
14
15
1.35
0.65
1.50
0.52
1.25
0.30
0.95
0.30
2.20
11.50
2.30
1.30
14.00
4.00
2.00
4.00
2.40
5.10
3.50
6.50
2.30
9.80
4.50
3.00
1.50
6.10
1.30
2.60
0.48
5.10
19.50
2.30
1.10
19.00
3.50
1.20
2.00
0.45
4.20
17.00
3.50
2.00
18.50
>10(34)
5.10
7.00
1.20
0.80
1.50
0.35
3.50
12.50
1.85
1.20
15.00
8.00
3.10
6.00
9.00
6.50
>10(49)
>20(28)
9.00
5.00
>20(20)
15.50
15.40
2.00
>20(47)c
4.00
4.50
>20(45)
9.50
9.80
>20(41)
4.80
2.10
18.70
>20(42)
>20(42)
>20(28)
aED50 was the concentration of compound which a€ords 50% reduction in cell number after 3 days incubation.
bHuman epidermoid carcinoma of the nasopharynx (KB), pgP-expressing human epidermoid carcinoma of the nasopharynx (KB-VIN), ostco-
sarcoma (Hos), human melanoma cancer (SKMEL-2), human ileocecal carcinoma (HCT-8), human breast cancer (MCF-7), human lung carcinoma
(A-549), and human ovarian cancer (1A9).
cInhibition <50% at the highest test concentration (percentage observed is given in brackets).
the methylenedioxy moiety at the 40, 50 position (10) led
to enhanced cytotoxic activity compared with the A-
ring unsubstituted compound 8. (b) The methoxy group
at the 3-position was greatly bene®cial for increased
cytotoxicity. Compound 10 was about 3- and 6-times as
active as 9 and 11, respectively, and 8 with a 3-methoxy
was also more active than 7. Compounds 8 and 10 dis-
played signi®cant cytotoxic e€ects with ED50 values less
than 1 mg/mL against KB and 1A9 cell lines. (c) Con-
verting the a/b unsaturated ketones (7, 9 and 11) to the
corresponding epoxides (12, 13 and 14) dramatically
reduced the cytotoxicity. Thus, although the epoxy
group might also act as a second alkylating moiety,15
the a,b-unsaturated ketone moiety of 20-amino chal-
cones appears to play an important role in thiol/
enzyme-alkylation, preferentially via Michael addi-
tion.15 This result demonstrated that the double bond is
the essential moiety for chalcones as antitumor agents.

Y. Xia et al. / Bioorg. Med. Chem. Lett. 10 (2000) 699±701
701
In addition, all 20-amino chalcones showed fairly good
activity against nasopharynx (KB), breast (MCF-7),
and lung (A549) cell lines as well as increased activity
against ovarian cancer (1A9). In comparing chalcones
with and without the amino group at the 20-position 9
was about 40-fold more active than the corresponding
3-methoxy-40,50-methylenedioxy chalcone (15), which
does not contain the 20-amino group. In addition, 20-
amino chalcones showed better tumor selectivity than
the corresponding 2-phenyl-4-quinolones,10,11 which are
cyclic a,b-unsaturated ketones. Additional mechanism
studies are ongoing to better understand the results.
3. Dimmock, J. R.; Kandepu, N. M.; Hetherington, M.; Quail,
J. W.; Pugazhenthi, U.; Sudom, A. M.; Chamankhah, M.;
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10. Li, L.; Wang, H. K.; Kuo, S. C.; Wu, T. S.; Lednicer, D.;
Lin, C.; Hamel, E.; Lee, K. H. J. Med. Chem. 1994, 37, 1126.
11. Xia, Y.; Yang, Z. Y.; Xia, P.; Bastow, K.; Tachibana, Y.;
Kuo, S. C.; Hamel, E.; Hackl, T.; Lee, K. H. J. Med. Chem.
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In summary, we have discovered a novel class of 20-
amino chalcones as potential antitumor agents. The
position and the size of the substituents seem to be
important for antitumor activity in the 20-amino chal-
cones. Compound 10 with a methylenedioxy moiety at
the 40, 50 positions and methoxy group at the 3-position
is the lead compound with potent cytotoxic activity.
Evaluation against multi-drug resistance cells, as well as
further SAR studies, are continuing.
14. Benvenuto, J. A.; Connor, T. H.; Monteith, D. K.; Laid-
law, J. L.; Adams, S. C.; Matney, T. S.; Theiss, J. C. J. Pharm.
Sci. 1993, 82, 988.
15. Lee, K. H.; Hall, I. H.; Starness, C. D.; Elgebaly, S. A.;
Waddell, T. G.; Hadgraft, R. T.; Ru€ner, C. G.; Weidner, I.
Science 1977, 196, 533.
16. Dhar, D. N. The Chemistry of Chalcones and Related
Compounds; John Wiley and Sons: New York, 1981.
17. All new compounds gave satisfactory analytical and spec-
troscopic data. Selected spectroscopic data for 2-20-Amino-3-
methoxy-40,50-methylenedioxy-chalcone (10): 1H NMR (300
MHz, CDCl3) d: 3.87 (s, 3H, OCH3), 5.95 (s, 2H, OCH2O),
6.20 (s, 1H, 30-H), 6.65 (br, 2H, NH2), 6.94 (m, 1H, 4-H),
7.14±7.36 (m, 4H, H-60, H-2, H-5, H-6), 7.48 (d, J=15.5 Hz,
1H, H-a), 7.68 (d, J=15.5 Hz, 1H, H-b); MS (M+) 297.10.
18. The cytotoxic assay was performed previously as described
in ref 11.
Acknowledgements
This investigation was supported by grant CA-17625
from the National Cancer Institute awarded to K. H.
Lee.
References and Notes
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