L.-M. Yang et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1013–1015
1015
benzaldehydes by reaction with benzyl bromide in eth-
anol) in the presence of potassium tert-butoxide at room
temperature gave the trans-stilbene benzenesulfonamide
derivatives 9, 10, 12 and 15. The benzyl-protected stil-
benes were subsequently O-debenzylated by boron tri-
bromide-mediated to provide the target compounds 11,
and 12 displayed significantly selective cytotoxicity
against BT-549 (GI50 0.205 mM/mL) and HT-29 (GI50
0.554 mM/mL), respectively. Thus, structure–activity
investigations revealed that replacing the hydroxyl
group in ring A of resveratrol with a sulfonamide moi-
ety led to trans-stilbene benzenesulfonamide derivatives
with enhanced cytotoxicity and selectivity. Compounds
9 and 12 deserve further development as potential clinical
trials candidates. Further SAR studies will be under-
taken to elucidate the antitumor mechanism of action
involved.
1
3 and 14. The structures and stereochemistry of the
new derivatives 9–15 were determined from spectro-
scopic data, which showed the (E)-isomers. This config-
uration was supported by the coupling constants of the
1
olefinic protons, J=16–17 Hz, in each H NMR spec-
trum. The proposed structural assignments were con-
1
13
firmed by detailed H, C NMR (HMQC, HMBC,
1
1
COSY) and HR-EIMS analyses.
Acknowledgements
These derivatives were screened by the National Cancer
Institute. All compounds were evaluated in vitro against
a total of 60human tumor cell lines derived from eight
cancer types (leukemia, non-small cell lung cancer, colon
cancer, CNS-cancer, melanoma, ovarian cancer, renal
cancer and breast cancer) according to the standard
This study was supported by grant NSC-89-2114-B-077-
013 from the National Science Council of Republic of
China. Thanks are due to the National Cancer Institute,
Bethesda, MD, USA, for performing the antitumor
screening of the synthesized compounds.
1
2
protocol. The dose–response curves for each cell line
were measured with five different drug concentrations,
and the molar concentration causing 50% cell growth
inhibition (GI ) was calculated. The results are shown
References and Notes
5
0
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Various substituents were introduced into the B ring of
the trans-stilbene benzenesulfonamide (9–15). These
substituents included electron-donating groups, such as
2
C. F.; Beecher, C. W. W.; Fong, H. H. S.; Famsworth, N. R.;
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NMe , OH, and OMe, and electron-withdrawing
2
groups, such as F. As seen in Table 1, compounds 9–13
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was active against non-small cell lung cancer (NCI-
H522), renal cancer (ACHN), and breast cancer (BT-
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49); compound 10 against ovarian cancer (OVCAR-4,
OVCAR-8), and breast cancer (HS-578T, BT-549);
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SR), melanoma (UACC-62), ovarian cancer (OVCAR-
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8
), and renal cancer (ACHN); compound 12 against
leukemia (RPMI8226, SR), non-small cell lung cancer
HOP-92, NCI-H226), colon cancer (HCT-15, HT-29),
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(
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1
1
1
993, 36, 3010.
1. All new compounds in this report gave satisfactory analy-
tical and spectroscopic data in full accordance with the
assigned structures. More complete synthetic details will be
described elsewhere.
In conclusion, we have discovered a new series of trans-
stilbene benzenesulfonamide derivatives as a novel class
of antitumor agents. Among these compounds, only 9
12. Boyd, M. R.; Paull, K. D. Drug Dev. Res. 1995, 34, 91.