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Pleas eC dh oe mn oi ct a al dS jcu i es tn mc eargins
DOI: 10.1039/C8SC02610F
Journal Name
ARTICLE
In summary, we report for the first time a symbiotic prodrug–
prodrug activation strategy that fully complies with the
principle of bioorthogonality. To illustrate the power of this
new strategy, we showed that a tetrazine prodrug scaffold was
converted into a pyridazine based miR21 inhibitor upon
reaction and decaging of a vinyl ether masked camptothecin.
This demasking takes advantage of the water acceleration
effect (for water dependency of kinetics see Figure S1), which
has been widely exploited and acknowledged in tetrazine
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R. van Brakel, R. C. M. Vulders, R. J. Bokdam, H. Grüll, M. S.
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944.
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chemistry and results in the activation of two drugs without 12 A. B. Neef, C. Schultz, Angew. Chemie Int. Ed., 2009, 48
,
the generation of by-products, such as the phosphine oxide
seen in the Staudinger ligation. Since drug resistance is a major
concern in anti-cancer therapy, which has been linked to an
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3 C.-X. Song, C. He, Acc. Chem. Res., 2011, 44, 709–717.
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4 B. L. Oliveira, Z. Guo, O. Boutureira, A. Guerreiro, G. Jiménez-
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cancer drug such as camptothecin in concert with a miR21 15 B. M. Zeglis, K. K. Sevak, T. Reiner, P. Mohindra, S. D. Carlin,
inhibitor, offers new bioorthogonal prodrug-prodrug
P. Zanzonico, R. Weissleder, J. S. Lewis, J. Nucl. Med., 2013,
, 1389–1396.
,
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overexpression of miRNA, activation of a conventional anti-
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activation strategy and is an exceptionally atom efficient
method of prodrug activation. The dual/traceless prodrug–
prodrug activation strategy opens up new possibilities and
directions in the field of drug delivery, in particular in the field
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6 L. Carroll, H. L. Evans, E. O. Aboagye, A. C. Spivey, Org.
Biomol. Chem., 2013, 11, 5772-5781.
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of combination therapy (administration of two or more drugs) 18 A.C. Knall, C. Slugovc, Chem. Soc. Rev., 2013, 42, 5131–5142.
1
9 J. C. T. Carlson, L. G. Meimetis, S. A. Hilderbrand, R.
Weissleder, Angew. Chem. Int. Ed., 2013, 52, 6917–20.
0 L. G. Meimetis, J. C. T. Carlson, R. J. Giedt, R. H. Kohler, R.
Weissleder, Angew. Chem. Int. Ed., 2014, 53, 7531–7534.
that is the most common clinical used strategy in cancer
therapy.
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It should be noted that the here presented prodrug–prodrug
activation is not only suitable for hydroxyl and pyridazine 21 A. Wieczorek, P. Werther, J. Euchner, R. Wombacher, Chem.
containing drugs. One could imagine, for example that the
traceless Staudinger ligation could be utilised in a similar
manner leading to free drugs containing amines and organo
phosphorous moieties, e.g. cyclophosphamides. In a broader
context, the prodrug-prodrug approach presented here is not
limited to the treatment of cancer and could be useful as a
combination approach in other therapeutic areas.
Sci., 2017, 8, 1506–1510.
2 B. M. Zeglis, C. Brand, D. Abdel-Atti, K. E. Carnazza, B. E.
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Cook, S. Carlin, T. Reiner, J. S. Lewis, Mol. Pharmaceutics,
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015, 12, 3575–3587.
3 J.-P. Meyer, J. L. Houghton, P. Kozlowski, D. Abdel-Atti, T.
Reiner, N. V. K. Pillarsetty, W. W. Scholz, B. M. Zeglis, J. S.
Lewis, Bioconjug. Chem., 2016, 27, 298–301.
4 C. Denk, D. Svatunek, S. Mairinger, J. Stanek, T. Filip, D.
Matscheko, C. Kuntner, T. Wanek, H. Mikula, Bioconjug.
Chem., 2016, 27, 1707–1712.
5 M. Staderini, A. Gambardella, A. Lilienkampf, M. Bradley,
Org. Lett., 2018, 20, 3170–3173.
26 R. M. Versteegen, R. Rossin, W. ten Hoeve, H. M. Janssen, M.
Conflicts of interest
S. Robillard, Angew. Chem. Int. Ed., 2013, 52, 14112–14116.
7 R. Rossin, M. S. Robillard, Curr. Opin. Chem. Biol., 2014, 21
61–169
8 A. K. Steiger, Y. Yang, M. Royzen, M. D. Pluth, Chem.
Commun., 2017, 53, 1378–1380.
9 H. Lebraud, D. J. Wright, C. N. Johnson, T. D. Heightman, ACS
Cent. Sci., 2016, 2, 927–934.
30 K. Neumann, S. Jain, A. Gambardella, S. E. Walker, E. Valero,
A. Lilienkampf, M. Bradley, ChemBioChem, 2017, 18, 91–95.
There are no conflicts to declare.
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Acknowledgements
This work was supported by the European Research Council
(Advanced Grant ADREEM ERC-2013-340469).
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1 E. Jiménez-Moreno, Z. Guo, B. L. Oliveira, I. S. Albuquerque,
A. Kitowski, A. Guerreiro, O. Boutureira, T. Rodrigues, G.
Jiménez-Osés, G. J. L. Bernardes, Angew. Chemie Int. Ed.,
2017, 56, 243–247.
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