408
S. Denoyelle et al. / Bioorg. Med. Chem. Lett. 22 (2012) 402–409
Osterling, D. J.; Pease, L. J.; Soni, N. B.; Stewart, K. D.; Stoll, V. S.; Tapang, P.;
Supplementary data
Reuter, D. R.; Davidsen, S. K.; Michaelides, M. R. J. Med. Chem. 2007, 50, 1584.
31. Miyazaki, Y.; Tang, J.; Maeda, Y.; Nakano, M.; Wang, L.; Nolte, R. T.; Sato, H.;
Sugai, M.; Okamoto, Y.; Truesdale, A. T.; Hassler, D. F.; Nartey, E. N.; Patrick, D.
R.; Ho, M. L.; Ozawa, K. Bioorg. Med. Chem. Lett. 2007, 17, 1773.
32. Sun, M.; Chen, J.; Wei, H.; Yin, S.; Yang, Y.; Ji, M. Chem. Biol. Drug Des. 2009, 73,
644.
33. Arrington, K. L.; Dudkin, V. Y. Chem. Med. Chem. 2007, 2, 1571.
34. Tao, Z. F.; Wang, L.; Stewart, K. D.; Chen, Z.; Gu, W.; Bui, M. H.; Merta, P.; Zhang,
H.; Kovar, P.; Johnson, E.; Park, C.; Judge, R.; Rosenberg, S.; Sowin, T.; Lin, N. H. J.
Med. Chem. 2007, 50, 1514.
Supplementary data associated (calculated physicochemical
properties of the reported N,N0-diarylureas, TC assays on KLN cell
line, HPLC and HR mass spectral data of the N,N0-diarylureas, syn-
thetic procedures, 1H NMR and HPLC analyses of the four selected
N,N0-diarylureas (3, 7, 9, and 27)) with this article can be found, in
35. Boyle, R. G.; Imogai, H. J.; Cherry, M. PCT Int. Appl. WO 2003101444 A1
20031211, 2003; Chem. Abstr. 2003, 140, 16750.
36. Anderson, M. O.; Yu, H.; Penaranda, C.; Maddux, B. A.; Goldfine, I. D.; Youngren,
J. F.; Guy, R. K. J. Comb. Chem. 2006, 8, 784.
37. Gable, K. L.; Maddux, B. A.; Penaranda, C.; Zavodovskaya, M.; Campbell, M. J.;
Lobo, M.; Robinson, L.; Schow, S.; Kerner, J. A.; Goldfine, I. D.; Youngren, J. F.
Mol. Cancer Ther. 2006, 5, 1079.
38. Khire, U. R.; Bankston, D.; Barbosa, J.; Brittelli, D. R.; Caringal, Y.; Carlson, R.;
Dumas, J.; Gane, T.; Heald, S. L.; Hibner, B.; Johnson, J. S.; Katz, M. E.; Kennure,
N.; Kingery-Wood, J.; Lee, W.; Liu, X. G.; Lowinger, T. B.; McAlexander, I.;
Monahan, M. K.; Natero, R.; Renick, J.; Riedl, B.; Rong, H.; Sibley, R. N.; Smith, R.
A.; Wolanin, D. Bioorg. Med. Chem. Lett. 2004, 14, 783.
39. Wilhelm, S. M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.;
Zhang, X.; Vincent, P.; McHugh, M.; Cao, Y.; Shujath, J.; Gawlak, S.; Eveleigh, D.;
Rowley, B.; Liu, L.; Adnane, L.; Lynch, M.; Auclair, D.; Taylor, I.; Gedrich, R.;
Voznesensky, A.; Riedl, B.; Post, L. E.; Bollag, G.; Trail, P. A. Cancer Res. 2004, 64,
7099.
References and notes
1. De Benedetti, A.; Harris, A. L. Int. J. Biochem. Cell Biol. 1999, 31, 59.
2. Graff, J. R.; Boghaert, E. R.; De Benedetti, A.; Tudor, D. L.; Zimmer, C. C.; Chan, S.
K.; Zimmer, S. G. Int. J. Cancer 1995, 60, 255.
3. Cohen, N.; Sharma, M.; Kentsis, A.; Perez, J. M.; Strudwick, S.; Borden, K. L.
EMBO J. 2001, 20, 4547.
4. Kentsis, A.; Dwyer, E. C.; Perez, J. M.; Sharma, M.; Chen, A.; Pan, Z. Q.; Borden, K.
L. J. Mol. Biol. 2001, 312, 609.
5. Rousseau, D.; Gingras, A. C.; Pause, A.; Sonenberg, N. Oncogene 1996, 13, 2415.
6. Chen, T.; Ozel, D.; Qiao, Y.; Harbinski, F.; Chen, L.; Denoyelle, S.; He, X.; Zvereva,
N.; Supko, J. G.; Chorev, M.; Halperin, J. A.; Aktas, B. H. Nat. Chem. Biol. 2011, 7,
610.
7. Berns, A. Cell 2008, 133, 29.
8. Marshall, R. A.; Dorywalska, M.; Puglisi, J. D. Proc. Natl. Acad. Sci. U.S.A. 2008,
105, 15364.
40. Penning, T. D.; Chandrakumar, N. S.; Chen, B. B.; Chen, H. Y.; Desai, B. N.; Djuric,
S. W.; Docter, S. H.; Gasiecki, A. F.; Haack, R. A.; Miyashiro, J. M.; Russell, M. A.;
Yu, S. S.; Corley, D. G.; Durley, R. C.; Kilpatrick, B. F.; Parnas, B. L.; Askonas, L. J.;
Gierse, J. K.; Harding, E. I.; Highkin, M. K.; Kachur, J. F.; Kim, S. H.; Krivi, G. G.;
Villani-Price, D.; Pyla, E. Y.; Smith, W. G. J. Med. Chem. 2000, 43, 721.
41. Zhu, G. D.; Gandhi, V. B.; Gong, J.; Thomas, S.; Woods, K. W.; Song, X.; Li, T.;
Diebold, R. B.; Luo, Y.; Liu, X.; Guan, R.; Klinghofer, V.; Johnson, E. F.; Bouska, J.;
Olson, A.; Marsh, K. C.; Stoll, V. S.; Mamo, M.; Polakowski, J.; Campbell, T. J.;
Martin, R. L.; Gintant, G. A.; Penning, T. D.; Li, Q.; Rosenberg, S. H.; Giranda, V. L.
J. Med. Chem. 2007, 50, 2990.
9. Dever, T. E.; Yang, W.; Astrom, S.; Bystrom, A. S.; Hinnebusch, A. G. Mol. Cell Biol.
1995, 15, 6351.
10. Aktas, H.; Fluckiger, R.; Acosta, J. A.; Savage, J. M.; Palakurthi, S. S.; Halperin, J.
A. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 8280.
11. Palakurthi, S. S.; Fluckiger, R.; Aktas, H.; Changolkar, A. K.; Shahsafaei, A.;
Harneit, S.; Kilic, E.; Halperin, J. A. Cancer Res. 2000, 60, 2919.
12. Palakurthi, S. S.; Aktas, H.; Grubissich, L. M.; Mortensen, R. M.; Halperin, J. A.
Cancer Res. 2001, 61, 6213.
13. Kozak, M. J. Cell Biol. 1991, 115, 887.
14. Kozak, M. J. Biol. Chem. 1991, 266, 19867.
42. Malkov, A. V.; Figlus, M.; Stoncius, S.; Kocovsky, P. J. Org. Chem. 2007, 72, 1315.
43. Stable and transient transfection into KLN-205 and CRL-2351, respectively,
utilized in this study are described elsewhere (see Ref. 6). Cells were seeded at
the density of 105 in 60-mm dish (stable transfection) or 104 cells per well of
96-well plate (transient transfection) and transfected one day later using the
Lipofectamine 2000 (Invitrogen). For selection of stable cell lines, transfected
cells were transferred to 100-mm plates and selected with appropriate
antibiotics.
15. De Benedetti, A.; Graff, J. R. Oncogene 2004, 23, 3189.
16. Zarghi, A.; Kakhgi, S.; Hadipoor, A.; Daraee, B.; Dadrass, O. G.; Hedayati, M.
Bioorg. Med. Chem. Lett. 2008, 18, 1336.
17. Zhao, G.; Souers, A. J.; Voorbach, M.; Falls, H. D.; Droz, B.; Brodjian, S.; Lau, Y. Y.;
Iyengar, R. R.; Gao, J.; Judd, A. S.; Wagaw, S. H.; Ravn, M. M.; Engstrom, K. M.;
Lynch, J. K.; Mulhern, M. M.; Freeman, J.; Dayton, B. D.; Wang, X.; Grihalde, N.;
Fry, D.; Beno, D. W.; Marsh, K. C.; Su, Z.; Diaz, G. J.; Collins, C. A.; Sham, H.;
Reilly, R. M.; Brune, M. E.; Kym, P. R. J. Med. Chem. 2008, 51, 380.
18. Huang, D.; Luthi, U.; Kolb, P.; Edler, K.; Cecchini, M.; Audetat, S.; Barberis, A.;
Caflisch, A. J. Med. Chem. 2005, 48, 5108.
19. Asano, S.; Ban, H.; Kino, K.; Ioriya, K.; Muraoka, M. Bioorg. Med. Chem. Lett.
2009, 19, 1062.
20. Davidson, W.; Frego, L.; Peet, G. W.; Kroe, R. R.; Labadia, M. E.; Lukas, S. M.;
Snow, R. J.; Jakes, S.; Grygon, C. A.; Pargellis, C.; Werneburg, B. G. Biochemistry
2004, 43, 11658.
44. Plasmids and Ternary complex assay. Briefly, we modified bi-directional
mammalian expression vector pBI (Clontech, CA) to expand the multiple
cloning sites (MCSs) and designated it thereafter as pBISA. This vector contains
seven copies of the tetracycline-regulated transactivator response element
(TRE), which together act as core promoter/enhancer. The TRE is flanked on
both sides by minimal human cytomegalovirus (CMV) minimal promoters
allowing bi-directional transcription and two MCSs. Firefly and renilla
luciferases were subcloned into MCS-I and MCS-II, respectively. This plasmid,
designated pBISA-DL, transcribes two mRNAs that contain the 90 nucleotide
plasmid derived 50UTR (same sequence in both mRNAs), and the ORF encoding
either firefly or renilla luciferase followed by a polyadenylation sequence (see
Ref. 45). This plasmid was further modified by inserting the 50UTR of ATF-4 into
MCS-I in front of the firefly luciferase mRNA. Transcription from this direction
generates an mRNA that contains the firefly luciferase ORF preceded by a 50UTR
composed of 90 nucleotides derived from the plasmid and 267 nucleotides
derived from the 50UTR of ATF-4 mRNA. Transcription from the other direction
generates an mRNA that contains the renilla luciferase ORF proceeded only by
the 90-nucleotide plasmid-derived sequence in the 50UTR. This expression
plasmid is called pBISA-DL(ATF-4). In the dual luciferase assay, cells expressing
firefly and renilla luciferases were lysed and the extracts assayed with a Dual-
Glo Luciferase assay kit, per manufacturer’s instruction (Promega Inc.,
Madison, WI). The data calculations were carried out as the ratio of firefly to
renilla luciferase signal (see Ref. 6).
21. Guichou, J. F.; Viaud, J.; Mettling, C.; Subra, G.; Lin, Y. L.; Chavanieu, A. J. Med.
Chem. 2006, 49, 900.
22. Valgeirsson, J.; Nielsen, E. O.; Peters, D.; Mathiesen, C.; Kristensen, A. S.;
Madsen, U. J. Med. Chem. 2004, 47, 6948.
23. Jin, Q.; Nie, H.; McCleland, B. W.; Widdowson, K. L.; Palovich, M. R.; Elliott, J. D.;
Goodman, R. M.; Burman, M.; Sarau, H. M.; Ward, K. W.; Nord, M.;
Orr, B. M.; Gorycki, P. D.; Busch-Petersen, J. Bioorg. Med. Chem. Lett. 2004, 14,
4375.
24. Widdowson, K. L.; Elliott, J. D.; Veber, D. F.; Nie, H.; Rutledge, M. C.; McCleland,
B. W.; Xiang, J. N.; Jurewicz, A. J.; Hertzberg, R. P.; Foley, J. J.; Griswold, D. E.;
Martin, L.; Lee, J. M.; White, J. R.; Sarau, H. M. J. Med. Chem. 2004, 47, 1319.
25. Pender, C.; Goldfine, I. D.; Manchem, V. P.; Evans, J. L.; Spevak, W. R.; Shi, S.;
Rao, S.; Bajjalieh, S.; Maddux, B. A.; Youngren, J. F. J. Biol. Chem. 2002, 277,
43565.
26. Teegarden, B. R.; Li, H.; Jayakumar, H.; Strah-Pleynet, S.; Dosa, P. I.; Selaya, S. D.;
Kato, N.; Elwell, K. H.; Davidson, J.; Cheng, K.; Saldana, H.; Frazer, J. M.; Whelan,
K.; Foster, J.; Espitia, S.; Webb, R. R.; Beeley, N. R.; Thomsen, W.; Morairty, S. R.;
Kilduff, T. S.; Al-Shamma, H. A. J. Med. Chem. 2010, 53, 1923.
27. Venkatesan, A. M.; Dehnhardt, C. M.; Delos Santos, E.; Chen, Z.; Dos Santos, O.;
Ayral-Kaloustian, S.; Khafizova, G.; Brooijmans, N.; Mallon, R.; Hollander, I.;
Feldberg, L.; Lucas, J.; Yu, K.; Gibbons, J.; Abraham, R. T.; Chaudhary, I.;
Mansour, T. S. J. Med. Chem. 2010, 53, 2636.
28. Chen, Z.; Venkatesan, A. M.; Dehnhardt, C. M.; Ayral-Kaloustian, S.; Brooijmans,
N.; Mallon, R.; Feldberg, L.; Hollander, I.; Lucas, J.; Yu, K.; Kong, F.; Mansour, T.
S. J. Med. Chem. 2010, 53, 3169.
29. Dai, Y.; Guo, Y.; Frey, R. R.; Ji, Z.; Curtin, M. L.; Ahmed, A. A.; Albert, D. H.;
Arnold, L.; Arries, S. S.; Barlozzari, T.; Bauch, J. L.; Bouska, J. J.; Bousquet, P. F.;
Cunha, G. A.; Glaser, K. B.; Guo, J.; Li, J.; Marcotte, P. A.; Marsh, K. C.; Moskey, M.
D.; Pease, L. J.; Stewart, K. D.; Stoll, V. S.; Tapang, P.; Wishart, N.; Davidsen, S. K.;
Michaelides, M. R. J. Med. Chem. 2005, 48, 6066.
45. Ziegeler, G.; Ming, J.; Koseki, J. C.; Sevinc, S.; Chen, T.; Ergun, S.; Qin, X.; Aktas,
B. H. J. Biol. Chem. 2010, 285, 15408.
46. Western blotting. Cells cultured under recommended media conditions, were
plated and maintained in serum-containing media without antibiotics in 14-
cm plates (Nunc) until reaching 70% confluency. Cells were then treated with
compounds (20 lM for KLN and 5 lM for CRL-2351) for 6 h, washed with cold
PBS once, and lysed with M-PER Mammalian Protein Extraction Reagent
(Pierce) for 1 h on ice. The cell lysates were further centrifuged at 12,000 RPM
for 5 min and the supernatants were transferred to fresh tubes and the
concentrations were determined by BCA methods. Proteins were denatured by
mixing with Laemmli Sample Buffer, heated at 100 °C for 5 min and separated
by SDS–PAGE and probed with anti-phosphoserine-51-eIF2
a (Phos-eIF2a),
anti-total eIF2 -specific antibodies (Total-eIF2 (Biosource International,
a
a)
Hopkinton, MA), anti-CHOP, or anti b-actin (Santa Cruz Biotechnology, CA).
47. Cell growth assay. Adherent mouse (KLN) and human solid tumor cells (CRL-
2351, and CRL-2813) were plated in 96-well plates and maintained for 5 days
30. Dai, Y.; Hartandi, K.; Ji, Z.; Ahmed, A. A.; Albert, D. H.; Bauch, J. L.; Bouska, J. J.;
Bousquet, P. F.; Cunha, G. A.; Glaser, K. B.; Harris, C. M.; Hickman, D.; Guo, J.; Li,
J.; Marcotte, P. A.; Marsh, K. C.; Moskey, M. D.; Martin, R. L.; Olson, A. M.;
in the presence of 0.54–6 lM of individual compound, and cell proliferation