This research was supported in part by the Intramural Research Program of the NIH, National institute on Aging. In addition, SB, NV,
WDF funded by a Wellcome Trust-NIH PhD Scholarship (Grant number: 098252/Z/12/Z).
Competing Interests
Authors NG, NV, WDF, DT, SB and WL have patents on these compounds. US patent application No. US2016/054430.
Supplementary Data
Supplementary data associated with this article can be found, in the online version, at
References
1
(a) For a recent review on redox signaling and oxidative stress, see: Schieber, M.; Chandel, N. S. Current Biology 2014, 24, R453-
R462. (b) Shahani, N.; Sawa, A. Antioxid. Redox Signal. 2011, 14(8), 1493. (c) Chung, K. K.; David, K. K. Nitric Oxide 2010, 22(4),
90.
2
2
(a) Moncada, S.; Palmer, R. M. J.; Higgs, E. A. Biochemical Pharmacology 1989, 38(11), 1709. (b) Aldskogius, H.; Liu, L.;
Syensson, M. J. Neurosci. Res. 1999, 58, 33.
3
(
a) Saxena S.; Caroni P. Neuron 2001, 71, 35. (b) Bredesen D. E. Mol Neurodegener. 2009, 4:27.
4
(a) Swardfager, W.; Lanctot, K.; Rothenburg, L.; Wong, A.; Cappell, J.; Herrmann, N. Biol Psychiatry 2010, 68(10), 930.
(b)
Locksley, RM.; Killeen, N.; Lenardo, MJ. Cell 2001, 104(4), 487. (c) Dowlati, Y.; Herrmann, N.; Swardfager, W.; Liu, H.; Sham, L.;
Reim, EK. Biol Psychiatry 2010, 67(5), 446. (d) Brynskov, J.; Foegh, P.; Pedersen, G.; Ellervik, C.; Kirkegaard, T.; Bingham, A. Gut
2
002, 51(1), 37. (e) Frankola, K. A.; Greig, N. H.; Luo, W.; Tweedie, D. CNS & Neurological Disorders - Drug Targets 2011, 10, 391.
(f) Tweedie, D.; Luo, W; Short, R. G.; Brossi, A.; Holloway, H. W.; Li, Y.; Yu, Q.; Greig, N. H. J. Neumeth. 2009, 183, 182. (g)
Carmeliet, P.; Jain, R. K. Nature 2000, 407, 249. (h) Coussens, L. M.; Werb, Z. Nature 2002, 420, 860. (i) Balkwill, F.; Coussens, L.
M. Nature 2004, 431, 405.
5
Tarkowski E.; Blennow, K.; Wallin, A.; Tarkowski, A. J. Clin. Immunol. 1999, 19, 223.
Tarkowski, E.; Andreasen, N.; Tarkowski, A.; Blennow, K. J. Neurol. Neurosurg. Psychiatry 2003, 74, 1200.
6
7
(a) Ohkuma, S.; Katsura, M. Progress in Neurobiology 2001, 64, 97. (b) Bloodsworth, A.; O’Donnell, V. B.; Freeman, B. A.
Arterioscler Thromb Vasc Biol 2000, 20, 1707.
8
(a) Knowles, R. G.; Palacios, M.; Palmer, R. M.; Moncada, S. Proc Natl Acad Sci USA 1989, 86, 5119. (b) Snyder, S. H.; Bredt, D. S.
Trends Pharmacol Sci 1991, 12, 125. (c) Law, A.; Gauthier, S.; Quirion, R. Brain Research Reviews 2001, 35, 73. (d) Hoffman, M. A.
Science 1991, 252, 1788. (e) Lancaster, F. E. Alcohol Clin Exp Res 1992, 16, 539. (f) Nowicki, J. P.; Duval, D.; Poignet, H.; Scatton,
B. Eur J Pharmacol 1991, 204, 339. (g) Eliasson, M. J.; Huang, Z.; Ferrante, R. J.; Sasamata, M.; Molliver, M. E.; Snyder, S. H.;
Moskowitz, M. A. J. Neurosci 1999, 19, 5910.
9
Goodwin, J. L.; Uemura, E.; Cunnick, J. E. Brain Research 1995 692, 207.
Jenkins, D. C.; Charles, I. G.; Thomsen, L. L.; Moss, D. W.; Homes, L. S.; Baylis, S. A.; Rhodes, P.; Westmore, K.; Emson, P. C.;
10
Moncada, S. Proc. Natl. Acad. Sci. USA 1995, 92, 4392.
1
1
1
2
Greig, N. H.; Luo, W.; Tweedie, D.; Holloway, H. W.; Yu, Q.; Goetzl, E. J. US 8,927,725 B2 2015.
a) Petit, A.; Bihel, F.; Costa, C. A.; Pourquié, O.; Checler, F.; Kraus, J. Nature cell Biology 2001, 3, 507. (b) Christie, G.;
(
Markwell, R. E.; Gray, C. W.; Smith, L.; Godfrey, F.; Mansfield, F.; Wadsworth, H.; King, R.; McLaughlin, M.; Cooper, D. G.; Ward,
R. V.; Howlett, D. R.; Hartmann, T.; Lichtenthaler, S. F.; Beyreuther, K.; Underwood, J.; Gribble, S. K.; Cappai, R.; Masters, C. L.;
Tamaoka, A.; Gardner, R. L.; Rivett, A. J.; Karran, E. H. Allsop, D. J. Neurochem. 1999, 73, 195. (c) Citron, M.; Diehl, T. S.; Capell,
A.; Haass, C.; Teplow, D. B.; Selkoe, D. J. Neuron, 1996, 17, 171. (d) Joubert, J.; Dyk, S.; Green, I. R.; Malan, S. F. Bioorg. Med.
Chem. 2011, 19, 3935. (e) Mizoguchi, K.; Yokoo, H.; Yoshida,M.; Tanaka, T.; Tanaka, M. Brain Research 1994, 662, 255. (f)
Danysz, W.; Parsons, C. G.; Kornhuber, J.; Schmidt, W. J.; Quack, G. Neuroscience and Biobehavioral Reviews 1997, 21(4), 455. (g)
Parsons, C. G.; Danysz, W.; Quack, G. Neuropharmacology 1999, 38, 735. (h) Zou, J. Y.; Crews, F. T. Brain Research 2005, 1034, 11.
(
i) Joubert, J.; Dyk, S.; Malan, S. F. Bioorg. Med. Chem. 2008, 16, 8952. (j) Neuraxon Inc. WO20007118314, 2007.
1
3
(a) Paci, C.; Thomas, A.; Onofrj, M. Nerol Sci 2001, 22, 75. (b) Pinna, A.; Chiara, G. D.; Wardas, J.; Morelli, M. Eur. J. Neurosci.
1
996, 8, 1176. (c) Ferré, S.; O’Connor, W. T.; Fuxe, K.; Ungerstedt, U. The Journal of Neuroscience 1993, 13(12), 5402. (d)
Baldessarini, R. J.; Lipinski, J. F. Chace, K. V. Biochemical Pharmacology 1972, 21, 77. (e) Merello, M.; Nouzeilles, M. I.;
Cammarota, A.; Leiguarda, R. Clinical Neuropharmacology 1999, 22(5), 273. (f) Standaert, D. G.; Young, A. B. “ The
Pharmacological Basis of Therapeutics ” McGraw-Hill, New York, 2001, pp. 549. (g) Moryl, E.; Danysz, W.; Quack, G.
Pharmacology & Toxicology 1993, 72, 394.
1
4
(
a) Beedie, S. L.; Rore, H. M.; Barnett, S.; Chau, C. H.; Luo, W.; Greig, N. H.; Figg, W. D.; Vargesson, N. Oncotarget, 2016, 7(22),
3237. (b) Mahony, C.; Erskine, L.; Niven, J.; Greig, N. H.; Figg, W. D.; Vargesson, N. Proc. Natl. Acad. Sci. USA 2013, 110, 12703.
c) Horvat, M.; Uzelac, L.; Marjanovic, M; Cindro, N.; Frankovic, O.; Mlinaric-Majerski, K.; Kralj, M.; Basaric, N. Chem. Biol. Drug
Des. 2012, 79, 497. (d) Aragon-Ching, J. B.; Li, H.; Gardner, E. R.; Figg, W. D. Recent Pat. Anticancer Drug Discov. 2007, 2, 167.
3
(
15
Mateo, A; Pilar, S; Carmen, L; Angel, A. J. Org. Chem. 2005, 70, 7617.