1.
2.
Smith, C. C.; Yellon, D. M. J. Cell Mol. Med. 2011, 15, 1797.
Hitomi, J.; Christofferson, D. E.; Ng, A.; Yao, J.; Degterev, A.; Xavier,
R. J.; Yuan, J. Cell 2008, 135, 1311.
Degterev, A.; Huang, Z.; Boyce, M.; Li, Y.; Jagtap, P.; Mizushima, N.;
Cuny, G. D.; Mitchison, T.; Moskowitz, M.; Yuan, J. Nat. Chem. Biol.
2005, 1, 112.
the biphenyl and phenylpyridine scaffold are different, resulting
in different substituted demands. By incorporation of morpholino
(8g) group to the scaffold, other attempt to improve compound’s
solubility was failed.
3.
4.
5.
Cuny, G. D.; Degterev, A.; Yuan, J. Drugs Fut. 2008, 33, 225.
Vandenabeele, P.; Galluzzi, L.; Vanden, B. T.; Kroemer, G. Nat. Rev.
Mol. Cell Biol. 2010, 11, 700.
Table 6. Structures and activities of compounds 8
6.
7.
Teng, X.; Degterev, A.; Jagtap, P.; Xing, X.; Choi, S.; Denu, R.; Yuan, J.;
Cuny, G. D. Bioorg. Med. Chem. Lett. 2005, 15, 5039.
Degterev, A.; Hitomi, J.; Germscheid, M.; Ch’en, I. L.; Korkina, O.;
Teng, X.; Abbott, D.; Cuny, G. D.; Yuan, C.; Wagner, G.; Hedrick, S. M.;
Gerber, S. A.; Lugovskoy, A.; Yuan, J. Nat. Chem. Biol. 2008, 4, 313.
(a) Jagtap, P. G.; Degterev, A.; Choi, S.; Keys, H.; Yuan, J.; Cuny, G. D.
J. Med. Chem. 2007, 50, 1886; (b) Wang, K.; Li, J.; Degterev, A.; Hsu,
E.; Yuan, J.; Yuan, C. Bioorg. Med. Chem. Lett. 2007, 17, 1455; (c) Teng,
X.; Keys, H.; Jeevanandam, A.; Porco, J. A.; Degterev, A.; Yuan, J.;
Cuny, G. D. Bioorg. Med. Chem. Lett. 2007, 17, 6836; (d) Zheng W.;
Degterev, A.; Hsu, E.; Yuan, J.; Yuan, C. Bioorg. Med. Chem. Lett. 2008,
18, 4932; (e) Zheng, W.; Yuan, J.; Yuan, C. CN Patent 101,367,761,
2009; (f) Wu, Z.; Li, Y.; Cai, Y.; Yuan, J.; Yuan, C. Bioorg. Med. Chem.
Lett. 2013, 23, 4903.
Compd.
7f
R
EC50 (µM)
0.84
8.
H
8a
4-F
2.59
8b
4-Cl
Inactive
Inactive
4.76
8c
4-CH3
4-OMe
4-OEt
4-SEt
4-morpholino
8d
8e
Inactive
1.92
9.
Han, W.; Li, L.; Qiu, S.; Lu, Q.; Pan, Q.; Gu, Y.; Luo, J.; Hu, X. Mol.
Cancer Ther. 2007, 6, 1641.
8f
10. For EC50 value determinations, FADD-deficient variant of human Jurkat
T cells (15000 cells/well in a 384-well plate) were treated with
increasing concentrations (0.1, 0.5, 1.0, 5.0, 10 and 20 µM) of test
compounds for 24 h at 37 oC in a humidified incubator with 5% CO2
followed by ATP-based viability assessment. The final DMSO
concentration was 0.1%. Each concentration was done in triplicate. Nec-
8 (10 µM) was used as a positive control to ensure the specificity of E6
and its analogs, all the cell death induced by E6 or its analogs had to be
protected by Nec-8. Cell viability assessments were performed using a
commercial luminescent ATP-based assay kit (CellTiter-Glo, Promega)
according to the manufacturer’s instructions. EC50 was calculated by
non-linear fit of cell viability versus log C. Cell viability = determined
well/DMSO*100.
8g
Inactive
In conclusion, this preliminary report demonstrates for the
first time that functionalized biphenyl compounds exhibit note-
worthy necroptosis inducer activity in a cell-based system. By
systematic synthesis and structure modification of E6, we found
the biphenyl derivative 4p showed increased activities. Taking
this as a new lead compound, we were fortunate to find two
compounds (5h, 5j), which are 17 times more potent than E6.
The two biphenyl derivatives could potentially serve as a starting
point for further optimization studies in conjunction with mecha-
nism of action studies aimed at identifying the molecular target(s)
with which these compounds interact. Taken together, these
results hold significant promise for the development of inducers
directed against drug-resistant cancer.
11. More details about the chemical experiments could be found in
supporting information.
12. We also modified the linkers, such as extending or reducing the length
of the linker, changing the linker from benzylamine to amide or imine
and incorporating methyl group to the benzylic position, but all these
trials failed. For the compounds we synthesized, see the supporting
information.
13. (a) Akselsen, Ø. W.; Skattebølb, L.; Hansen, T. V. Tetrahedron Lett.
2009, 50, 6339; (b) Aldred, R.; Johnston, R.; Levin, D.; Neilan, J. J.
Chem. Soc. Perkin Trans. 1 1994, 1823.
Acknowledgments
14. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
15. Butini, S.; Gemma, S.; Brindisi, M.; Maramai, S.; Minetti, P.; Celona,
D.; Napolitano, R.; Borsini, F.; Cabri, W.; Fezza, F.; Merlini, L.;
Dallavalle, S.; Campiani, G.; Maccarrone, M. Bioorg. Med. Chem. Lett.
2013, 23, 492.
The authors thank Prof. Dawei Ma for helpful discussions.
This work was supported in part by Grants from the National
Natural Science Foundation of China (No. 21072212 to C.Y.)
and the National Institute of Health of US (R37 AG012859 to
J.Y.).
16. Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol.
2010, 14, 347.
References and notes
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