2-carboxylic acid N-(3,5-dichlorophenyl)amide (2h) exhibited
the most potent NF-κB inhibitory activity (75%). 2,3-
Supplementary data
Supplementary data (Methods, materials, and general
preparation procedures and analytical data) associated with this
dihydrobenzofuran-2-carboxylic
N-(3′,4′-
dichlorophenyl)amide (2i) (65% NF-κB inhibition) was 1.5
times more potent (IC50: 23.0 µM) than reference compounds
KL-1156 (IC50: 37.2 µM) and PDTC (IC50: 34.5 µM). Taken
together, the data of the current study identify several
derivatives of 1a–s, 2a–k, 3a–s, 4a–k with more potent NF-κB
inhibitory activities in LPS-stimulated RAW 264.7 cells than
those of the parent lead compound KL-1156 and PDTC.
References and notes
1. Khan, Z.; Bisen, P. S. Biochem. Biophys. Res. Acta 2013, 1836,
123–145
2. Nowell, P.C. Cancer Research 1986, 46, 2203–2207
3. Vogelstein, B.; Kinzler, K.W. Nature Medicine 2004, 10, 789–
799.
4. Ichihashi, M.; Ueda, M..; Budiyanto, A.; Bito, T.; Oka, M.;
Fukunaga, K.; Tsuru, T.; Horikawa, T. Toxicology 2003, 189,
21–39
In relation to the SAR towards NF-κB inhibitory activity,
compounds possessing hydrophobic groups on the N-phenyl
ring were most potent as NF-κB inhibitors. For instance, di-
chloride, dimethyl, dimethoxy, and trifluoromethyl groups (2i,
2h, 3q, 4a, 4b, 4c, 4e, and 4k) exhibited most potent NF-κB
inhibitory activities (Table 3). On the other hand, among the
compounds having hydrophilic 4′-OH group on the N-phenyl
ring, only 3m exhibited promising NF-κB inhibitory activity.
Collectively, the data from the current study indicate that only
benzofuran-2-carboxylic acid N-(4′-hydroxyphenyl)amide
(3m) can be considered as a novel derivative for inhibiting the
transcription factor NF-κB, which also has potent anticancer
activity against all six human cancer cell lines. Interestingly,
several of the synthesized novel benzofuran- and 2,3-
dihydrobenzofuran-2-carboxylic acid N-(substituted)phenyl
amide derivatives exhibited more potent anticancer activities
and inhibition of NF-κB transcriptional activity than the parent
reference compound KL-1156.
5. Clemens, M.R. Klinische Wochenschrift 1991, 69, 1123–1134.
6. Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Nature
2008, 454, 436–444
7. Clayton, P.E.; Banerjee, I.; Murray, P.G.; Renehan, A.G.
Nature Reviews Endocrinology 2011, 7, 11–24
8. Porta, C.; Riboldi, E.; Sica, A. Cancer Lett. 2011, 305, 250–
262.
9. Hayden, M.S.; Ghosh, S. Genes & Development 2004, 18,
2195–2224.
10. Bonizzi G.; Karin M. Trends Immunol. 2004, 25, 280-288.
11. Shinkura, R.;Kitada, K.; Matsuda, F.; Tashiro, K.; Ikuta, K.;
Suzuki, M.; Kogishi, K.; Serikawa, T.; Honjo, T. Nat. Genet.
1999, 22, 74–77.
12. Perkins, N.D.; Gilmore, T.D. Cell Death and Differentiation
2006, 13, 759–772.
13. Greten F. R.; Eckmann L.; Greten T. F.; Park J. M.; Li Z. W.;
Egan L. J.; Kagnoff M. F.; Karin M. Cell 2004, 118, 285–296.
14. Perkins N. D. Trends Cell. Biol. 2004, 14, 64–69.
15. Luo J. L.; Kamata H.; Karin M. J. Clin. Invest. 2005, 115,
2625-2632.
In conclusion, a series of novel benzofuran and 2,3-
dihydrobenzofuran-2-carboxylic acid N-(substituted)phenyl
amide derivatives (1a–s, 2a–k, 3a–s, and 4a–k) was designed
and synthesized from commercially available starting materials
via well-known epoxidative cyclization and amidation
reactions using CDI. We evaluated the in vitro anticancer
activities of these derivatives against six human cancer cell
16. Ryan K. M.; Ernst M. K.; Rice N. R.; Vousden K. H. Nature
2000, 404, 892–897
17. Kim, B. H.; Reddy, A. M.; Lee, K. H.; Chung, E. Y.; Cho, S.
M.; Lee, H.; Min, K. R.; Kim, Y. Biochem. Biophys. Res.
Commun. 2004, 325, 223–228.
18. Kwak, J.H.; Kim, B.H.; Jung, J.K.; Kim, Y.; Cho, J.; Lee, H.
Arch. Pharm. Res. 2007, 30, 210–1215
19. Kwak, J. H.; Won, S. W.; Kim, T. J.; Roh, E.; Kang, H. Y.;
Lee, H. W.; Jung, J. K.; Hwang, B. Y.; Kim, Y.; Cho, J.; Lee,
H. Arch. Pharm. Res. 2008, 31, 133–141.
lines.
Benzofuran-2-carboxylic
acid
N-(4′-
hydroxyphenyl)amide (3m) exhibited the most potent
anticancer activity against all tested cell lines. 2,3-
dihydrobenzofuran-2-carboxylic acid N-(3′-hydroxyphenyl)-
amide (1l) exhibited promising growth inhibitory activities
against MM231, NCI-H23, and PC-3 cell lines. 2,3-
dihydrobenzofuran-2-carboxylic acid N-(4′-nitrophenyl)-amide
(1d) showed potent growth inhibitory activity against PC-3 cell
line. 2,3-dihydrobenzofuran derivatives (1a–s and 2a–k) had
higher cytotoxicity against PC-3 than against other tested
cancer cell lines. SAR studies revealed that substitutions at the
planar N-phenyl ring of compounds 1l, 1p, 2f, 3k, 3m, and 3o
(which have +M effect groups) exhibited more potent
anticancer activities than all other derivatives. However,
cytotoxicity of these derivatives was not directly related to
their NF-κB inhibitory activities. Only benzofuran-2-
carboxylic acid N-(4′-hydroxy)phenylamide (3m) exhibited
both outstanding anticancer and NF-κB inhibitory activities.
Our SAR studies have encouraged us to investigate more novel
lead scaffolds exhibiting most potent anticancer activity
through inactivation of NF-κB; this work is in progress.
20. Kwak, J. H.; Won, S. W.; Kim, T. J.; Yi, W.; Choi, E. H.; Kim,
S. C.; Park, H.; Roh, E.; Jung, J. K.; Hwang, B. Y.; Hong, J. T.;
Kim, Y.; Cho, J.; Lee, H. Arch. Pharm. Res. 2009, 32, 167–
175.
21. Kwak, J. H.; Kim, Y.; Park, H.; Jang, J. Y.; Lee, K.K.; Yi, W.;
Kwak, J. A.; Park, S.G.; Kim, H.; Lee, K.; Kang, J. S.; Han,
S.B.; Hwang, B.Y.; Hong, J.T.; Jung, J.K.; Kim, Y.; Cho, J.;
Lee, H. Bioorg. Med. Chem. Lett. 2010, 20, 4620–4623.
22. Singh P.; Rathinasamy K.; Mohan R.; Panda D. IUBMB Life
2008, 60, 368-375.
23. Use of Griseofulvin for Inhibiting the Growth of Cancers. The
Proctor & Gamble Company. Patent WO9705870A2, (1997).
24. Ho, Y. S.; Duh, J. S.; Jeng, J. H.; Wang, Y. J.; Liang, Y.;
Lin, C. H.; Tseng, C. J.; Yu, C. F.; Chen, R. J.; Lin, J. K. Int.
J. Cancer 2001, 91, 393.
25. Ohse T.; Ohba S.; Yamamoto T.; Koyano T.; Umezawa K.; J.
Nat. Prod. 1996, 59, 650–652.
26. Cencic, R.; Carrier, M.; Galicia-Vázquez, G.; Bordeleau, M. E.;
Sukarieh, R.; Bourdeau, A.; Brem, B.; Teodoro, J. G.; Greger,
H.; Tremblay, M. L.; Porco, J. A., Jr.; Pelletier, J. PLoS One
2009, 4, e5223
27. Kim S.; Hwang B. Y.; Su B. N.; Chai H.; Mi Q.; Kinghorn A.
D.; Wild R.; Swanson S. M. Anticancer Res. 2007, 27, 2175-
2183.
Acknowledgments
28. Ramadas, S.; Krupadanam, G. L. D. Tetrahedron: Asymmetry
2000, 11, 3375–3393.
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (NRF-2013R1A1A2009381), and by Medical
Research Center Program (2008-0062275).
29. Montalbetti, C.A.G.N.; Falque, V. Tetrahedron 2005, 61,
10827–10852.
30. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon,
J.; Vistica, D.;. Warren, J.T.; Bokesch, H.; Kenny, S.; Boyd,
M.R. Journal of the National Cancer Institute 1990, 82, 1107–
1112.