Organic & Biomolecular Chemistry
Page 4 of 6
COMMUNICATION
DOI: 10.1039/C4OB02107J
for the dehydroalanine residue, and the thiazole dipeptide28 was Nꢀ
Boc protected (16) (see ESI†). Thus, the synthesized linear peptides
18 were subjected to PyBOPꢀmediated macrocyclization to yield 19,
followed by an oxidation–elimination reaction to afford the desired
argyrin A 20h and related analogues 20a-g. The purity of the cyclic
peptides were established by 1H NMR and reversedꢀphase HPLC.
Notes and references
aSchool of Pharmacy, Centre for Biomolecular Sciences, University of
Nottingham, University Park, Nottingham NG7 2RD, U.K.
*Corresponding author: Eꢀmail: weng.chan@nottingham.ac.uk; phone:
+44ꢀ115ꢀ9515080.
¶C.H.C. and S.G. contributed equally
.
†Electronic Supplementary Information (ESI) available: Detailed
experimental procedures for the chemical synthesis and characterization
of Trp analogues and their synthetic intermediates, as well as argyrin
analogues and their antimicrobial tests. See DOI: 10.1039/c000000x/
100
90
80
70
60
50
40
30
20
10
20g
20h
1
2
E. Selva, L. Gastaldo, G. S. Saddler, G. Toppo, P. Ferrari, G.
Carniti and B.P. Goldstein, J. Antibiot., 1996, 49, 145ꢀ149.
F. Sasse, H. Steinmetz, T. Schupp, F. Petersen, K. Memmert,
H. Hofmann, C. Heusser, V. Brinkmann, P. von Matt, G.
Hofle and H. Reichenbach, J. Antibiot., 2002, 55, 543ꢀ551.
P. Ferrari, K. Vekey, M. Galimberti, G. G. Gallo, E. Selva
and L. F. Zerilli, J. Antibiot., 1996, 49, 150ꢀ154.
L. Vollbrecht, H. Steinmetz and G. Hofle, J. Antibiot., 2002,
55, 715ꢀ721.
I. Nickeleit, S. Zender, F. Sasse, R. Geffers, G. Brandes, I.
Soerensen, H. Steinmetz, S. Kubicka, T. Carlomagno, D.
Menche, I. Guetgemann, J. Buer, A. Gossler, M. P. Manns,
3
4
5
0
1
2
Concentration of antibacterial agent (Log µM)
Figure 2 The effects of argyrin A 20h and analogue 20g on the
growth of amoxicillinꢀresistant P. aeruginosa PAO1 in Muller–
Hinton broth at 13 h.
M. Kalesse, R. Frank and N. P. Malek, Cancer Cell, 2008, 14
,
23ꢀ35.
6
7
L. Buelow, I. Nickeleit, A.ꢀK. Girbig, T. Brodmann, A.
Rentsch, U. Eggert, F. Sasse, H. Steinmetz, R. Frank, T.
The antibacterial activity of a selection of argyrin analogues was
evaluated against two Gramꢀnegative bacteria, Pseudomonas
aeruginosa PAO1 and Proteus mirabilis Hauser 1885 (ESI† Table
S1). While the activity of argyrin A 20h against P. aeruginosa
PAO1 (MIC50 = 19.8 ± 1.6 µM) is comparable to a reported value8
(Figure 2), we were pleasantly surprised that the argyrin analogue
20g, comprised of a (S)ꢀ5ꢀmethoxyꢀtryptophan residue, showed
MIC50 of 90–100 µM against both bacteria. In contrast, the (S)ꢀ5ꢀ
chloroꢀ and (S)ꢀ5ꢀmethylꢀtryptophan containing analogues 20c and
20f were essentially inactive. The experimental complex structure
between bacterial EFꢀG and argyrin B shows a Hꢀbond from Ser417
to the O of the 4ꢀmethoxy group in the Trp residue.7 Preliminary
inspection of the complex structure suggests that either the Hꢀbond is
maintained but weaker due to an increased distance, or the 5ꢀOMe is
capable of Hꢀbond interaction with Tyr683. However, argyrin
analogues lacking a Hꢀbond acceptor in a suitable position (20c
and 20f) were inactive.
Carlomagno, N. P. Malek and M. Kalesse, Chemmedchem
2010, , 832ꢀ836.
,
5
B. Nyfeler, D. Hoepfner, D. Palestrant, C. A. Kirby, L.
Whitehead, R. Yu, G. Deng, R. E. Caughlan, A. L. Woods, A.
K. Jones, S. W. Barnes, J. R. Walker, S. Gaulis, E. Hauy, S.
M. Brachmann, P. Krastel, C. Studer, R. Riedl, D. Estoppey,
T. Aust, N. R. Movva, Z. Wang, M. Salcius, G. A. Michaud,
G. McAllister, L. O. Murphy, J. A. Tallarico, C. J. Wilson, C.
R. Dean, Plos One, 2012, 7, e42657.
8
9
P. Bielecki, P. Lukat, K. Huesecken, A. Doetsch, AH.
Steinmetz, R. W. Hartmann, R. Mueller and S. Haeussler,
Chembiochem, 2012, 13, 2339ꢀ2345.
E. A. Villar, D. Beglov, S. Chennamadhavuni, J. A. Porco Jr,
D. Kozakov, S. Vajda and A. Whitty, Nat. Chem. Biol., 2014,
10, 723ꢀ731.
10 (a) S. V. Ley, A. Priour and C. Heusser, Org. Lett., 2002, 4,
711ꢀ714. (b) G. Blaser, J. M. Sanderson, A. S. Batsanov and
J. A. K. Howard, Tetrahedron Lett., 2008, 49, 2795ꢀ2798. (c)
R. J. M. Goss and P. L. A. Newill, Chem. Commun., 2006,
4924ꢀ4925.
Conclusions
A facile approach for the synthesis of enantiomerically pure
(
S
)ꢀtryptophan with haloꢀ, methoxyꢀ and alkylꢀsubstitution has
been established using inexpensive ( )ꢀmethylbenzylamineꢀ
based chiral auxiliary reagents. Using our range of new ( )ꢀTrp
analogues, we have also discovered that the antimicrobial
activity of argyrin A, although dependent on the ( )ꢀ4ꢀ
methoxyꢀtryptophan residue, tolerates )ꢀ5ꢀmethoxyꢀ
11 J. Ma, W. Yin, H. Zhou, X. Liao and J. M. Cook, J. Org.
Chem., 2009, 74, 264ꢀ73.
12 K. Harada, Nature, 1963, 200, 1201.
13 W. Wu, Z. Li, G. Zhou and S. Jiang, Tetrahedron Lett., 2011,
52, 2488ꢀ2491.
S
S
S
a
(S
14 R. H. Dave and B. D. Hosangadi, Tetrahedron, 1999, 55
,
tryptophan residue. We anticipate this will provide a useful
platform for the design and synthesis of more potent and
speciesꢀspecific antibacterial agent.
11295ꢀ11308.
15 A. Arasappan, S. Venkatraman, A. I. Padilla, W. L. Wu, T.
Meng, Y. Jin, J. Wong, A. Prongay, V. Girijavallabhan and F.
G. Njoroge, Tetrahedron Lett., 2007, 48, 6343ꢀ6347.
16 A. R. Katritzky, B. Pilarski and L. Urogdi, Synthesis-
Stuttgart, 1989, 949ꢀ950.
Acknowledgements
We would like to acknowledge financial support from CS Bio Company
Inc., USA (to C.H.C.) and ViceꢀChancellor’s Scholarship for Research
Excellence, University of Nottingham (to S.G.).
17 E. Vedejs and C. Kongkittingam, J. Org. Chem., 2001, 66
,
7355ꢀ7364.
18 R. Baltzly and P. B. Russell, J. Am. Chem. Soc., 1953, 75
,
5598ꢀ5602.
4 | J. Name., 2012, 00, 1-3
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