Chemistry - A European Journal
10.1002/chem.201602953
COMMUNICATION
discussions, and Dr. Jeffrey Bacon (Boston University) and
Matthew Benning (Bruker AXS) for X-ray crystal structure
analysis. NMR (CHE-0619339) and MS (CHE-0443618) facilities
at Boston University are supported by the NSF. Work at the BU-
CMD is supported by R24GM111625.
Figure 4. A. Effect of aza-rocaglates on in vitro translation of FF/HCV/Ren. B.
Assessing translation inhibition activity of 26 on HeLa cells.
Keywords: Rocaglate • Photocycloaddition • ESIPT• Flow
Chemistry • Heterocycle
Consistent with these findings, we also found no evidence for
translation inhibition over a 24 h period at concentrations up to
10 M using a whole cell assay based on constitutive expression
of the rapidly turned-over reporter protein firefly luciferase
(Figure 5A). Likewise the compounds had minimal cytotoxic
activity in a standard 3-day growth assay over the same
concentration range (Figure 5B). Together, these results indicate
that aza-rocaglates do not possess the same inhibitory potency
towards protein synthesis in comparison to related rocaglates
such as RHT.[19c]
[1]
[2]
[3]
F. N. Ko, T. S. Wu, M. J. Liou, T. F. Huang, C. M. Teng, Eur. J.
Pharmacol. 1992, 218, 129.
M. L. King, C. Chiang, H. Ling, E. Fujita, M. Ochiai, M. T. Andrew, J.
Chem. Soc., Chem. Commun. 1982, 20, 1150.
For recent reports on the chemistry and biology of flavaglines: a) C.
Basmadjian, F. Thuaud, N. Ribeiro, L.Désaubry, Future Med. Chem.
2013, 5, 2185. b) N. Ribeiro, F. Thuaud, C. Nebigil, L. Désaubry, Bioorg.
Med. Chem. 2012, 20, 1857. c) S. S. Ebada, N. J. Lajkiewicz, J. A.
Porco, Jr., M. Li-Weber, P. Proksch, Prog. Chem. Org. Nat. Prod. 2011,
94, 1. d) L. Pan, J. L. Woodard, D. M. Lucas, J. R. Fuchs, A. D.
Kinghorn, Nat. Prod. Rep. 2014, 31, 924. e) J. Chu, R. Cencic, W.
Wang, J. A. Porco, Jr., J. Pelletier, Mol. Cancer. Ther. 2016, 15, 136. f)
S. Liu, W. Wang, L. E. Brown, C. Qiu, N. J. Lajkiewicz, T. Zhao, J. Zhou,
J. A. Porco, Jr., T. T. Wang, EBioMedicine 2015, 11, 1600.
[4]
For recent studies on the synthesis of flavaglines, see: a) F. Thuaud, N.
Ribeiro, C. Gaiddon, T. Cresteil, L. Désaubry, J. Med. Chem. 2011, 54,
411. b) B. C. Hawkins, L. M. Lindqvist, D. Nhu, P. P. Sharp, D. Segal, A.
K. Powell, M. Campbell, E. Ryan, J. M. Chambers, J. M. White, M. A.
Rizzacasa, G. Lessene, D. C. S. Huang, C. J. Burns, ChemMedChem
2014, 9, 1556. c) T. Liu, S. J. Nair, A. Lescarbeau, J. Belani, S. Peluso,
J. Conley, B. Tilloston, P. O'Hearn, S. Smith, K. Slocum, K. West, J.
Helble, M. Douglas, A. Bahadoor, J. Ali, K. McGovern, C. Fritz, V. J.
Palombella, A. Wylie, A. C. Castro, M. R. Tremblay, J. Med. Chem.
2012, 55, 8859. d) N. J. Lajkiewicz, A. B. Cognetta, III; M. J. Niphakis,
B. F. Cravatt, J. A. Porco, Jr., J. Am. Chem. Soc. 2014, 136, 2659.
I. Bruce, N. G. Cooke, L. J. Diorazio, R. G. Hall, E. Irving, Tetrahedron
Lett. 1999, 40, 4279.
[5]
[6]
a) B. Gerard, S. Sangji, D. O’Leary, J. A. Porco, Jr., J. Am. Chem. Soc.
2006, 128, 7754. b) B. Gerard, R. Cencic, J. Pelletier, J. A. Porco, Jr.,
Angew. Chem. 2007, 119, 7977; Angew. Chem., Int. Ed. 2007, 46,
7831. c) S. P. Roche, R. Cencic, J. Pelletier, J. A. Porco, Jr., Angew.
Chem., 2010, 122, 6683; Angew. Chem., Int. Ed. 2010, 49, 6533. d) N.
J. Lajkiewicz, S. P. Roche, B. Gerard, J. A. Porco, Jr., J. Am. Chem.
Soc. 2012, 134, 13108.
Figure 5. A. Translation inhibition (10 M) in whole cells based on
constitutive expression of firefly luciferase. B. 3-day growth assay (Human
293T cancer cells) over the same concentration.
[7]
[8]
B. Xia, B. Gerard, D. M. Solano, J. Wan, G. Jones, II, J. A. Porco,
Jr., Org. Lett. 2011, 13, 1346.
In
summary,
we
have
employed
ESIPT
For previous syntheses of 3-hydroxyquinolinones, see: a) D. A.
Yushchenko, M. D. Bilokin, G. Duportail, Y. Mély, V. G. Pivovarenko,
Tetrahedron Lett. 2006, 47, 905. b) P. Hradil, J. Hlavác, K. Lemr, J.
Heterocyclic Chem.1999, 36, 141. c) P. Hradil, M. Grepl, J. Hlavác, A.
Lycka, Heterocycles 2007, 71, 269. d) P. Hradil, L. Kvapil, J. Hlavác, T.
Weidlich, A. Lycka, K. Lemr, J. Heterocyclic Chem. 2000, 37, 831.
Y. Zhu, D. G. Drueckhammer, J. Org. Chem. 2005, 70, 7755.
photocycloaddition methodology to synthesize aza-
rocaglates. Our studies have uncovered differential
photocycloaddition reactivities between N-H- and N-Me-
substituted 2-aryl-3-hydroxyquinolinone substrates. A novel
method to access 1-alkyl-2-aryl-3-hydroxyquinolinones was
also developed for (3+2) photocycloaddition. Use of a
continuous photoflow reactor facilitated synthesis of aza-
rocaglates with both N-alkyl and N-H substitution. Initial
protein synthesis and translation inhibition data indicates
that aza-rocaglates do not possess activity in comparison to
related rocaglates which provides further information on the
SAR of the natural product scaffold.
[9]
[10] Please see the Supporting Information for details.
[11] S. S. Gandhi, K. L. Bell, M. S. Gibson, Tetrahedron 1995, 51, 13301.
[12] For recent reviews on flow photochemistry, see: a) D. T. McQuade, P.
H. Seeberger, J. Org. Chem. 2013, 78, 6384. b) Y. Su, N. J. W.
Straathof, V. Hessel, T. Noël, Chem. Eur. J. 2014, 20, 10562. c) D.
Cambié, C. Bottecchia, N. J. W. Straathof, V. Hessel, T. Noël, Chem.
Rev., 2016, DOI: 10.1021/acs.chem-rev.5b00707
[13] CCDC 1457719 (21) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge
[14] For the X-ray structure of N-methyl indoline with
Crystallographic
Data
Centre
via
Acknowledgements
a
a
typical
We thank the National Institutes of Health (GM-073855 to J.A.P,
Jr. and R01CA175744 to L.W. and J.A.P, Jr.) and the Canadian
Institutes for Health Research (MOP-115126 to J.P.) for
research support. We thank Dr. Vincent Eschenbrenner-Lux for
computational models, Prof. Aaron Beeler (BU) for helpful
pyrimidalized nitrogen, see: P. A. Chiaroni, N. L. C. Riche, Acta. Cryst.
1977, B33, 3410.
[15] For photophysical studies of 3-hydroxyquinolinones, see: a) D. A.
Yushchenko, V. V. Shvadchak, Y. Mély, V. G. Pivovarenko, New J.