P. V. Ramachandran et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6620–6623
6623
b,
c
-diaryl lactones to inhibit NF-
j
B-DNA binding.19 Other assays
MIA PaCa-2
to determine whether the lactones induce apoptosis or affect other
growth/survival signaling pathways are also under way.
100
80
60
40
20
0
0.5µM
2.5µM
5µM
Acknowledgments
Financial support from the Purdue University Herbert C. Brown
Center for Borane Research (P.V.R.), American Cancer Society grant
# RSG-06-267-01-CCE (C.M.S. and M.Y-S.) and The Indiana Genom-
ics Initiative (INGEN) of Indiana University, supported in part by
Lilly Endowment Inc. are gratefully acknowledged.
Supplementary data
12
13
14
17
LC-1
PT
Supplementary data associated with this article can be found, in
Chart 2. Comparison of proliferation assay for Mia PaCa-2 cells with selected
potent AMGBLs.
References and notes
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Melanoma Res. 2010, 20, 21; (b) Steele, A. J.; Jones, D. T.; Ganeshaguru, K.; Duke,
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A. B.; Prentice, A. G.; Hoffbrand, A. V.; Wickremasinghe, R. G. Leukemia 2006,
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200
0.5µM
2.5µM
5µM
160
120
80
40
0
5. Ramachandran, P. V.; Yip-Schneider, M. T.; Schmidt, C. M. Future Med. Chem.
2009, 1, 179.
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A.; Schmidt, C. M. Mol. Cancer Ther. 2005, 587.
12
13
14
17
LC-1
PT
Chart 3. Comparison of proliferation assay for BxPc-3 cells with selected potent
AMGBLs.
9. (a) Yip-Schneider, M. T.; Wu, H.; Njoku, V.; Ralstin, M.; Holcomb, B.; Crooks, P.
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3719.
ing observations were made from the data obtained: (i) substitu-
tions at b, and c-positions of AMGBL are necessary; lack of substi-
tution at either position results in reduced activity, (ii) the
methylene group is critical for anti-proliferative activity; an
a
a
-
-
alkylidene group is not as effective, (iii) aromatic groups at both
b- and -positions reveal increased potency, (iv) the cytotoxicity
increased further with the bulkier aromatic group (naphthyl vs
phenyl) at the -position, (v) electron-donating groups on the aro-
matic moiety at the -position increases the potency, and (vi) the
stereochemistry of the substitutions also affect the cytotoxicity;
b, -trans-disubstituted -methylene- -butyrolactones are more
c
c
c
c
a
c
potent than the corresponding cis-isomers.
Our analysis has identified 12, 13, 14, and 17 to be as potent or
slightly superior inhibitors than parthenolide for all three human
pancreatic cancer cell lines examined. Among the lactones exam-
ined, trans-b,c-diphenyl- and trans-c-2-naphthyl-b-phenyl-a-
16. Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T. Chem. Commun. 1999, 1979.
17. Ramachandran, P. V.; Pratihar, D.; Biswas, D. Org. Lett. 2006, 8, 3877.
18. Percent cell growth is expressed relative to control treated cells (100%). Bars,
mean +/- SEM.
19. (a) Rüngeler, P.; Castro, V.; Mora, G.; Gren, N.; Vichnewski, W.; Pahl, H. L.;
Merfort, I.; Schmidt, T. J. Bioorg. Med. Chem. 1999, 7, 2343; (b) Siedle, B.; Garcia-
Pineres, A. J.; Murillo, R.; Schulte-Monting, J.; Castro, V.; Rungeler, P.; Klaas, C.
A.; Da Costa, F. B.; Kisiel, W.; Merfort, I. J. Med. Chem. 2004, 47, 6042.
methylene- -butyrolactones, 12 and 17, respectively, showed
c
excellent inhibitory activity for all three cell lines.
The possibility of large-scale synthesis of these lactones with
readily available materials makes this study attractive. Further
work to introduce heteroaryl groups as well as chirality in the
lactones is in progress. We are also examining the ability of the