K. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1455–1465
1465
6. (a) Degterev, A.; Huang, Z.; Boyce, M.; Li, Y.; Jagtap, P.;
Mizushima, N.; Cuny, G. D.; Moskowitz, M.; Yuan, J.
Nat. Chem. Biol. 2005, 2, 112; (b) Teng, X.; Degterev, A.;
Jagtap, P.; Xing, X.; Choi, S.; Denu, R.; Yuan, J.; Cuny,
G. D. Bioorg. Med. Chem. Lett. 2005, 15, 5039.
7. (a) Lo, E. H.; Dalkara, T.; Moskowitz, M. A. Nat. Rev.
Neurosci. 2003, 224, 29; (b) Gwag, B. J.; Lobner, D.; Koh,
J. Y.; Wie, M. B.; Chio, D. W. Neuroscience 1995, 68, 615;
(c) Rosenbaum, D. M.; Gupta, G.; D’Amore, J.; Singh,
M.; Weidenheim, K.; Zhang, H.; Kessler, J. A.
J. Neurosci. Res. 2000, 61, 686; (d) Martin-Villalba, A.;
Herr, I.; Jeremias, J.; Hahne, M.; Brandt, R.; Vogel, J.;
Schenkel, J.; Herdegen, T.; Debatin, K. M. J. Neurosci.
1999, 19, 3809; (e) Martin-Villalba, A.; Hahne, M.;
Kleber, S.; Vogel, J.; Falk, W.; Schenkel, J.; Krammer,
P. H. Cell Death Differ. 2001, 8, 679.
Our preliminary SAR study demonstrated that the EC50
value for inhibition of necroptosis in FADD-deficient
Jurkat T cells treated with TNFa of Nec-5 is closely
related to the chemical structure of the molecule. First
of all, the presence of thioethylcyanide moiety on the
a-position of fused pyrimidone-4 part is essential, substi-
tution of this moiety results in complete loss of activity.
The exceptions are corresponding methylthio ethers as
3a and 7i exhibit same EC50 value as Nec-5, although
it provides significantly lower, max protection value of
71% and 97%. Meanwhile, oxidation of the sulfur atom,
either to sulfoxide 3y or to sulfone 3z completely elimi-
nates the activity. Second, presence of –OMe group in
the para-position of the benzene ring located on pyrim-
idone nitrogen is also important. Compound with para-
bromophenyl group exhibited (4k) loss of the activity
since variation of the electronic effect of the aryl substit-
uents including modification of –OMe group position
gave only less even inactive compound. Compound with
para-fluorophenyl group (4h) displayed significant EC50
value and a slightly decreased max protection of 85.1%,
while larger halides were not tolerated. Furthermore,
ethylene dioxy group is preferable to methoxy with 14c
showing almost twofold increase in activity. Finally,
cyclopentyl (6k), cycloheptyl (6l), and even benzene ring
(6n) exhibit certain degree of activity. It is worthy to
point out that introduction of two methyl groups to
the a and b position of thiophene ring will bring com-
pound with significant activities. Our results suggest that
while Nec-5 displays a stringent SAR, there are also
positions in the molecule especially phenyl ring attached
to the N-pyrimidone, which can be potentially further
optimized to generate more active Nec-5 analogs.
8. Li, M.; Beg, A. A. J. Virol. 2000, 74, 7470.
9. (a) Lin, Y.; Choksi, S.; Shen, H. M.; Yang, Q. F.; Hur, G.
M.; Kim, Y. S.; Tran, J. H.; Nedospasov, S. A.; Liu, Z. G.
J. Biol. Chem. 2004, 279, 10822; (b) Wilson, C. A.;
Browning, J. L. Cell Death Differ. 2002, 9, 1321.
10. Chan, F. K. J. Biol. Chem. 2003, 278, 51613.
11. (a) Gewald, K.; Schinke, E.; Bottcher, H. Chem. Ber 1966,
99, 94; (b) Tranberg, C.; Zickgraf, A.; Giunta, B. N.;
Luetjens, H.; Figler, H.; Murphree, L. J.; Falke, R.;
Fleischer, H.; Linden, J.; Scammells, P. J.; Olsson, R. A.
J. Med. Chem. 2002, 45, 382; (c) Gutschow, M.; Kuerschner,
L.; Neumann, U.; Pietsch, M.; Loser, R.; Koglin, N.;
Eger, K. J. Med. Chem. 1999, 42, 5437; (d) Gewald, K.;
Neumann, G. Chem. Ber. 1968, 101, 1933.
12. (a) Sabnis, R. W. Sulfur Rep. 1994, 16, 1; (a) Sabnis, R.
W.; Rangnekar, D. W. J. Heterocycl. Chem. 1999, 36, 333.
13. (a) Vishnu, J. R.; Hrishi, K. P.; Arnold, J. V.
J. Heterocycl. Chem. 1981, 18, 1277; (b) Devani, M. B.;
Shishoo, C. J.; Pathak, U. S.; Parikh, S. H.; Saha, G. F.;
Padhya, A. C. J. Pharm. Sci. 1976, 65, 660; (c) Leistner, S.;
Gutschow, M.; Wagner, G. Synthesis 1987, 466; (d)
Modica, M.; Santagati, M.; Santagati, A.; Russo, F.;
Cagnotto, A.; Goegan, M.; Mennini, T. Bioorg. Med.
Chem. Lett. 2000, 10, 1089; (e) Duval, E.; Case, A.; Stein,
R. L.; Cuny, G. D. Bioorg. Med. Chem. Lett. 2005, 15,
1885.
Acknowledgments
This Project was supported in part by the Chinese Acad-
emy of Sciences, National Institute of General Medical
Sciences (USA), and National Institute of Neurological
Disorders and Stroke (USA) (to J.Y.) and the National
Natural Science Foundation of China (Nos. 20272075,
20372076 to C.Y.)
14. Nec-5: mp 212–214 °C. 1H NMR(CDCl3) (d): 1.82–1.90
(m, 4H, CH2), 2.77–2.97 (m, 4H, CH2), 3.89 (s, 5H,
OCH3 + CH2CN), 7.18 (d, J = 8.7 Hz, 2H, OCH3–PhH),
7.36 (d, J = 8.7 Hz, 2H, OCH3–PhH). IR (KBr, cmꢁ1):
2939, 2848, 2249(C„N), 1630(s, C@O), 1444, 1321, 1262,
872. MS m/z (rel intensity): 383 (M+) (31.21), 311 (27.60),
146(base). Anal. Calcd for C19H17N3O2S2: C, 59.51; H,
4.47; N, 10.96. Found: C, 59.13; H, 4.48; N, 10.80.
15. Oxidation of compound 3 was carried out as follows: a
mixture of 3a (1 mmol) and m-chloroperoxybenzoic acid
(m-CPBA) (2.2 mmol) in CH2Cl2 (20 ml) was stirred for
48 h. The reaction was completed as monitored by TLC.
The product was separated by silica gel column chroma-
tography using chloroform as eluent. The product 3z was
crystallized from chloroform–ethanol as colorless crystal,
yield 87%, mp 230 °C. 1H NMR(d): 1.86–1.92 (m, 4H,
CH2), 2.47 (s, S(O)2CH3), 2.73–2.78 (m, 2H, CH2), 2.91–
2.97 (m, 2H, CH2), 3.87 (s, 3H, OCH3), 7.02 (d,
J = 9.0 Hz, 2H, ArH), 7.19 (d, J = 9.0 Hz, 2H, ArH).
IR(KBr)cmax: 3199, 2938, 2837, 1712, 1655 (s, C@O),
1510, 1246, 829. MS m/z (rel intensity): 390 (M+), 359, 311
(base), 199, 159. Anal. Calcd for C18H18N2O4S2: C, 55.37;
H, 4.65; N, 7.17. Found: C, 55.98; H, 4.79; N, 6.84.
References and notes
1. (a) Degterev, A.; Boyce, M.; Yuan, J. Oncogene 2003, 22,
8543; (b) Yuan, J.; Lipinski, M.; Degterev, A. Neuron
2003, 40, 401.
2. Vercammen, D.; Brouckaert, G.; Denecker, G.; Van de
Craen, M.; Declercq, W.; Fiers, W.; Vandenabeele, P.
J. Exp. Med. 1998, 188, 919.
3. Matsumura, H.; Shimizu, Y.; Ohsawa, Y.; Kawahara, A.;
Uchiyama, Y.; Nagata, S. J. Cell Biol. 2000, 151, 1247.
4. Holler, N.; Zaru, R.; Micheau, O.; Thome, M.; Attinger,
A.; Valitutti, S.; Bodmer, J.; Schneider, P.; Seed, B.;
Tschopp, J. Nat. Immunol. 2000, 1, 489.
5. Kawahara, A.; Ohsawa, Y.; Matsumura, H.; Uchiyama,
Y.; Nagata, S. J. Cell Biol. 1998, 143, 1353.