4102
L. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4100–4102
affected the anti-proliferative activities of compounds 6d–6g. The
methoxyphenyl analog 6i18,19 exhibited the most potent inhibitory
References and notes
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activity (IC50 = 0.5
lg/mL for Hep7402, 0.8
lg/mL for B16-F10,
0.6 g/mL for A549, and 1.2
l
lg/mL for TW03) compared with the
positive control colchicine. The structure–activity relationships of
the target compounds demonstrate that the amido bond is neces-
sary for the anti-tumor activities of matrine. When this bond is
broken, the anti-proliferative activities are lost. For example, com-
pounds 2, 3a, and 3b showed no activities. Compound 6i was sig-
nificantly more active than compounds 6b and 6c, in which the
electron-withdrawing nitro group of the benzene ring changed
the electron cloud density distribution of 6b and 6c, resulting in
a weak interaction with the tumor cells. Compound 6j was less ac-
tive than compound 6i; the only difference between them is the
position of the methoxy group, which is in the m-position for 6j
and in the p-position for 6i.
In conclusion, a series of matrine derivatives has been success-
fully synthesized and characterized via infrared spectroscopy, pro-
ton nuclear magnetic resonance spectroscopy, mass spectrometry,
and elemental analysis. The results of the in vitro antitumor tests
show that 15 of the 19 matrine derivatives exhibited good activi-
ties against cancer cells, suggesting that one of the synthesized ma-
trine derivatives, such as compound 6i, can be used in the
treatment of certain drug-resistant cancers. The results of the pres-
ent study provide useful information for further structural modifi-
cations of these compounds and for the synthesis of new, potent
antitumor agents.
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18. Preparation for compound 6i: Anhydrous tetrahydrofuran (50 mL) was added
into a round-bottomed flask (100 ml) containing matrine (0.005 mol) and
sodium hydride (0.1 mol). The solution was stirred and 4-
methoxybenzaldehyde (0.025 mol) was added at room temperature. The
solution was then refluxed for 8 h. After cooling to room temperature, the
mixture was treated with hydrochloric acid (5%, 20 mL) to hydrolyze the
excess sodium hydride and then extracted with chloroform (20 mL Â 3). The
combined organic layer was concentrated, and the residue was purified in a
reverse-phase silica gel column (petroleum ether/ethyl acetate = 1:5, v/v) to
give the compound.
Acknowledgments
The work was supported by Guangxi Key Laboratory of
Traditional Chinese Medicine Quality Standards (Guangxi Institute
of Traditional Medical and Pharmaceutical Sciences) (guizhongz-
hongkai 0802) and Guangxi Natural Science Foundation (2010GX
NSFD013040).
19. Analytical data for key compound 6i: Yield 27%, yellow liquid, IR(KBr, m
cmÀ1):
3058.16, 2930.25, 2812.32, 2751.42, 1608.61, 1510.66, 1478.00, 1453.13; 1H
NMR (DMSO, d ppm): 7.66 (s, 1H), 7.41 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz,
2H), 4.49 (dd, J = 4.2 Hz, 4.2 Hz, 1H), 3.94 (s,1H), 3.80 (s, 3H), 3.20 (m, 1H), 2.84
(m, 3H), 2.28 (m, 1H), 2.06 (m, 1H), 1.80 (m, 2H), 1.76–1.64 (m, 3H), 1.53–1.20
(m, 9H); MS (EI, m/z): 366(M+), 323, 245, 177, 150, 135, 96, 41. Elemental anal.
Calcd: C, 75.37; H, 8.25; N, 7.64. Found: C, 75.53; H, 8.36; N, 7.83.
Supplementary data
Supplementary data associated with this article can be found, in