10.1002/chem.201704074
Chemistry - A European Journal
COMMUNICATION
The comparison of the MS/MS spectra of the synthetic derivatives
3-10 with the corresponding spectra from the spectral networking
approach proved that the postulated structures are correct (cf. SI).
Notably, the aromatic regions of the NMR spectra of the two
diastereomers 8a and 8b of β-OMe-Asn-albicidin differ
remarkably (Figure 3). The comparison with a low concentrated
NMR sample of isolated β-OMe-Asn-albicidin 8 unambiguously
confirmed the natural configuration as 2S,3R.
Experimental Section
Detailed experimental procedure, synthetic protocols and additional
spectroscopic data can be found in the Supporting Information (SI).
Acknowledgements
Taking into account that β-OMe-Asn is also the central building
block of related compounds, cystobactamid and coralmycin, we
synthesized four analogues (24a-d, Figure 4) to study the
influence of the N-terminal pNBA building block, of isopropyl
substituents and of the hydroxylation pattern at the rings D and E
on bioactivity. In general, we followed the same synthesis strategy
as for the albicidins. However, the synthesis of 24c and d required
an inverted protecting group strategy due to instability and
solubility issues (for an alternative protocol to β-OMe-Asn, and its
implementation cf. SI).
Finally, the MIC values for all synthetic albicidins and
cystobactamid/coralmycin analogues were compared against
several Gram-positive and Gram-negative bacteria (Table 1).
While all of the derivatives proved to be active, the natural
(2S,3R)-configured derivatives mostly showed slightly higher
activity than the corresponding diastereomers. An N-terminal
aromatic group (MCA/pNBA) seems to be crucial for the activity,
since propionyl-albicidin 3 is completely inactive.[9] Furthermore,
a higher substitution of the two C-terminal building blocks seems
to increase the activity (cf. albicidins 1 + 4 vs. 5 + 6 and
cystobactamid-type 24a vs. 24b vs. 24c) as earlier suggested by
Kim et al.[21] In comparison to the analogues 24a-d, MCA seems
to be beneficial for antimicrobial activity (cf. 8b vs. 24a) over
pNBA. Finally, the isopropyl group at ring E can restore bioactivity
for a lack in substituents at rings E and F (24c vs. 24d).
In conclusion, the application of our bioactivity-guided spectral
networking workflow shows high potential for future natural
product discovery studies. The combination of bioactivity-guided
selection, non-targeted high-throughput analysis using
LC-MS/MS and bioinformatic data analysis will push the
molecular search for bioactive and novel compounds to the scale
of contemporary genomic and meta-genomic studies. The total
synthesis of the new albicidin derivatives, including two
diastereomers of the non-proteinogenic amino acid β-OMe-Asn,
is paralleled by independent studies from the Kirschning[22] and
the Trauner[23] groups. Unlike their synthesis protocols, our
approach allowed for the direct synthesis of L-β-OMe-Asn in both
stereoconfigurations. Hence, our protocol also avoids
racemization-prone intermediates as acyl chlorides[22] or late
stage aminolysis steps over easily racemizable aspartimides.[23,24]
Furthermore, the new coupling strategy allows the efficient
synthesis of further building block C variants.[8] Finally, the
comparison of results for four synthetic analogues gave further
insight into the structure-activity relationships of albicidins and
cystobactamid/coralmycins in the search for a new class of
antibiotic agents.
This work was supported by grants from the Deutsche
Forschungsgemeinschaft (DFG, SU 239/11-1 and PE 2600/1-1),
the BMBF (VIP grant) and the Agence Nationale de la Recherche
(ANR-09-BLANC-0413-01).
Keywords: albicidin • molecular networking • total synthesis •
antibiotic • bioactivity screening
[1]
[2]
S. C. Davies, T. Fowler, J. Watson, D. M. Livermore, D. Walker, The
Lancet 2013, 381, 1606–1609.
J. M. A. Blair, M. A. Webber, A. J. Baylay, D. O. Ogbolu, L. J. V.
Piddock, Nat. Rev. Microbiol. 2015, 13, 42–51.
[3]
[4]
C. W. Johnston, N. A. Magarvey, Nat. Chem. Biol. 2015, 11, 177–178.
S. Cociancich, A. Pesic, D. Petras, S. Uhlmann, J. Kretz, V. Schubert,
L. Vieweg, S. Duplan, M. Marguerettaz, J. Noëll, et al., Nat. Chem.
Biol. 2015, 11, 195–197.
[5]
[6]
[7]
[8]
R. Süssmuth, J. Kretz, V. Schubert, A. Pesic, M. Hügelland, M. Royer,
S. Cociancich, P. Rott, D. Kerwat, S. Grätz, Albicidin Derivatives,
Their Use and Synthesis, 2014, WO/2014/125075.
J. Kretz, D. Kerwat, V. Schubert, S. Grätz, A. Pesic, S. Semsary, S.
Cociancich, M. Royer, R. D. Süssmuth, Angew. Chem. Int. Ed. 2015,
54, 1969–1973.
L. Vieweg, J. Kretz, A. Pesic, D. Kerwat, S. Grätz, M. Royer, S.
Cociancich, A. Mainz, R. D. Süssmuth, J. Am. Chem. Soc. 2015, 137,
7608–7611.
S. Grätz, D. Kerwat, J. Kretz, L. von Eckardstein, S. Semsary, M.
Seidel, M. Kunert, J. B. Weston, R. D. Süssmuth, ChemMedChem
2016, 11, 1499–1502.
[9]
D. Kerwat, S. Grätz, J. Kretz, M. Seidel, M. Kunert, J. B. Weston, R.
D. Süssmuth, ChemMedChem 2016, 11, 1899–1903.
M. Wang, J. J. Carver, V. V. Phelan, L. M. Sanchez, N. Garg, Y. Peng,
D. D. Nguyen, J. Watrous, C. A. Kapono, T. Luzzatto-Knaan, et al.,
Nat. Biotechnol. 2016, 34, 828–837.
[10]
[11]
[12]
[13]
J. Watrous, P. Roach, T. Alexandrov, B. S. Heath, J. Y. Yang, R. D.
Kersten, M. van der Voort, K. Pogliano, H. Gross, J. M. Raaijmakers,
et al., Proc. Natl. Acad. Sci. 2012, 109, E1743–E1752.
P. Shannon, A. Markiel, O. Ozier, N. S. Baliga, J. T. Wang, D.
Ramage, N. Amin, B. Schwikowski, T. Ideker, Genome Res. 2003, 13,
2498–2504.
D. Petras, D. Kerwat, A. Pesic, B.-F. Hempel, L. von Eckardstein, S.
Semsary, J. Arasté, M. Marguerettaz, M. Royer, S. Cociancich, et al.,
ACS Chem. Biol. 2016, 11, 1198–1204.
[14]
[15]
[16]
D. L. Boger, R. J. Lee, P. Y. Bounaud, P. Meier, J. Org. Chem. 2000,
65, 6770–6772.
W. Jiang, J. Wanner, R. J. Lee, P.-Y. Bounaud, D. L. Boger, J. Am.
Chem. Soc. 2003, 125, 1877–1887.
J. A. Gómez-Vidal, M. T. Forrester, R. B. Silverman, Org. Lett. 2001,
3, 2477–2479.
[17]
[18]
[19]
V. F. Pozdnev, Tetrahedron Lett. 1995, 36, 7115–7118.
L. N. Mander, C. M. Williams, Tetrahedron 2003, 59, 1105–1136.
C. A. G. N. Montalbetti, V. Falque, Tetrahedron 2005, 61, 10827–
10852.
[20]
[21]
B. Belleau, G. Malek, J. Am. Chem. Soc. 1968, 90, 1651–1652.
Y. J. Kim, H.-J. Kim, G.-W. Kim, K. Cho, S. Takahashi, H. Koshino,
W.-G. Kim, J. Nat. Prod. 2016, 79, 2223–2228.
[22]
R. Müller, S. Hüttel, G. Testolin, J. Herrmann, T. Planke, F. Gille, M.
Moreno, M. Stadler, M. Brönstrup, A. Kirschning, Angew. Chem. Int.
Ed. n.d., n/a-n/a.
[23]
[24]
D. Trauner, B. Cheng, R. Müller, Angew. Chem. Int. Ed. n.d., n/a-n/a.
M. Mergler, F. Dick, B. Sax, P. Weiler, T. Vorherr, J. Pept. Sci. 2003,
9, 36–46.
This article is protected by copyright. All rights reserved.