A fast and efficient method for the preparation of the 5-lipoxygenase inhibitor myxochelin A

Article abstract of DOI:10.1016/j.tetlet.2016.02.047

Previous studies revealed the natural product myxochelin A to possess potent antitumour activity at non-cytotoxic concentrations. While its antiinvasive properties are possibly due to an inhibition of matrix metalloproteinases, the antileukemic effects of myxochelin A could be traced to an inhibition of human 5-lipoxygenase. These findings make myxochelin A an interesting model compound for pharmacological investigations. Here, we present a concise synthetic route for the preparation of myxochelin A, which only involves three steps.

Full text of DOI:10.1016/j.tetlet.2016.02.047

Tetrahedron Letters 57 (2016) 1359–1360
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A fast and efficient method for the preparation of the 5-lipoxygenase
inhibitor myxochelin A
⇑
Sebastian Schieferdecker , Markus Nett
Junior Research Group ‘Secondary Metabolism of Predatory Bacteria’, Leibniz Institute for Natural Product Research and Infection Biology e.V., Hans-Knöll-Institute, Beutenbergstr.
11a, 07745 Jena, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Previous studies revealed the natural product myxochelin A to possess potent antitumour activity at non-
cytotoxic concentrations. While its antiinvasive properties are possibly due to an inhibition of matrix
metalloproteinases, the antileukemic effects of myxochelin A could be traced to an inhibition of human
Received 19 January 2016
Revised 10 February 2016
Accepted 12 February 2016
Available online 13 February 2016
5-lipoxygenase. These findings make myxochelin A an interesting model compound for pharmacological
investigations. Here, we present a concise synthetic route for the preparation of myxochelin A, which
only involves three steps.
Keywords:
Myxochelin
Anticancer
Ó 2016 Elsevier Ltd. All rights reserved.
5
-Lipoxygenase
Introduction
The active site of 5-LO features a catalytically important non-
1
3
heme–iron atom, suggesting that the complexing properties of
1 might again contribute to its bioactivity. The catechol natural
product 1 is hence a promising tool compound for the functional
interrogation of MMPs and 5-LO. Up to now, only one route for
the total synthesis of 1 has been described with an overall yield
The catechol myxochelin A (1) is a widely distributed natural
product in bacteria. Originally isolated from the culture broth of
the myxobacterium Angiococcus disciformis, it was later also
described from phylogenetically unrelated microorganisms,
1
2
3
3
namely the actinomycete Nonomuraea pusilla and the Chloroflexi
of 23.7%. Here, we describe a concise and more efficient strategy
bacterium Herpetosiphon aurantiacus.4 Myxochelin A is typically
secreted in case of an iron deficiency in order to scavenge this
important metal from the environment and deliver it to the cell.
Aside from its role as a siderophore, 1 was also shown to be mod-
estly active against Gram-positive bacteria.2 Quite recently,
extended bioactivity testing unveiled its potent antitumor
for the synthesis of this natural product with a total yield exceed-
ing 70%.
Results and discussion
The synthetic strategy involves the coupling of commercially
available L-lysine ethyl ester with a protected 2,3-dihydroxybenzoic
3
,5
effects.
Myxochelin A suppresses tumor cell invasion at non-
3
cytotoxic concentrations, which is possibly due to an interference
with the proteolytic action of two matrix metalloproteinases,
acid derivative, the subsequent reduction of ester 2 to alcohol 3 and
finally the deprotection of the catechol moieties (Scheme 1). 2,3-
Dimethoxybenzoic acid was chosen as the starting material for
the coupling reaction, since it is commercially available and the
dealkylation of methoxy groups employing boron tribromide is reli-
able. After evaluation of several coupling methods, among them N,
6
MMP-2 and MMP-9. The catalytic domain of MMPs is known to
harbour a divalent zinc cation.7 Complexation of the latter by the
catecholate units of 1 might thus be a possible explanation for
the observed inhibitory effects.6
The strong antileukemic effects of 1 were traced to an inhibition
of human 5-lipoxygenase (5-LO).5 This enzyme has a key role in
the conversion of arachidonic acid to leukotrienes. The latter are
involved in inflammatory processes,9 and increasing evidence
0
N -dicyclohexyl-carbodiimide and 1-hydroxybenzotriazole (HOBt),
,8
3
-(ethylimino-methyleneamino)-N,N-dimethylpropan-1-amine
and HOBt, isobutyl chloroformate and N-methylmorpholine, benzo-
triazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate
1
0–12
1
4
suggests that they also represent mediators of tumorgenesis.
(
pyBOP) and N,N-diisopropylethylamine (DIPEA), the activation
15
of the carboxylic acid as phosphonium salt with pyBOP proved
to be the best method giving a yield of 85% of ethyl-N ,N -bis(2,3-
dimethoxybenzoyl)- -lysinate (2). The subsequent reduction of
2
6
⇑
Corresponding author.
E-mail address: sebastian.schieferdecker@hki-jena.de (S. Schieferdecker).
L
http://dx.doi.org/10.1016/j.tetlet.2016.02.047
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

1
360
S. Schieferdecker, M. Nett / Tetrahedron Letters 57 (2016) 1359–1360
0
Preparation of (S)-N,N -(6-hydroxyhexane-1,5-diyl)bis(2,3-
dimethoxybenzamide) (3)
Compound 3 was prepared by dissolving 2 (1.6 mmol) in 10 ml
dry tetrahydrofurane under an argon atmosphere in an ice water
bath. Lithium borohydride (1.6 mmol) and dry ethanol (10 ml) were
added and the reaction mixture was stirred for 15 min at 4 °C. After-
wards, the solution was allowed to warm to room temperature and
stirring was continued for 16 h. The reaction was quenched by addi-
tion of saturated aqueous ammonium chloride solution (20 ml).
After 15 min of stirring at room temperature, the organic solvents
were evaporated under reduced pressure and the aqueous suspen-
sion was exhaustively extracted with EtOAc. The organic layers
were combined and dried by the addition of sodium sulfate. After
8
evaporation of the solvent, the crude product was purified by C -
HPLC using 80% aqueous methanol as the mobile phase (yield: 88%).
Preparation of 1
For the dealkylation reaction, 3 (1.5 mmol) was dissolved in dry
DCM (10 ml) under an argon atmosphere. Boron tribromide
(
18 mmol) was added as a 1 m solution in DCM. The reaction mix-
ture was stirred at room temperature for 16 h, afterwards the reac-
tion was stopped by the addition of water (5 ml) and the solvent
mixture was evaporated to dryness. The crude product was
extracted with methanol and subsequently purified by C -HPLC
8
using 60% aqueous methanol as the mobile phase (yield: 97%).
Scheme 1. Reagents and conditions: (A) pyBOP, DIPEA, DMF, rt, 16 h, 85%; (B)
LiBH , THF, EtOH, 4 °C, 15 min ? rt, 16 h 88%; (C) BBr , DCM, rt, 16 h, 97%.
4
3
Acknowledgments
the ethyl ester to form 3 was carried out with lithium borohydride.
Finally, the deprotection of the catechol moieties with 12 equiv of
1
6
Financial support from the Bundesministerium für Bildung und
Forschung (BMBF) – Germany within the programme InfectControl
boron tribromide resulted in the formation of 1 in a total yield
of 72.5% over three steps. The measured analytical data of the
synthesized compound are fully consistent with literature values
2
020 (grant# 03ZZ0803A) is gratefully acknowledged.
3
for 1.
Supplementary data
Conclusion
Supplementary data (NMR and HR-ESI-MS spectra of all pre-
pared compounds) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.02.
047.
In this brief Letter, we report an easy method for the prepara-
tion of the antileukemic natural product 1. Using a biomimetic
1
,8
strategy, in which the aromatic residues are attached to a lysine
moiety prior to the reduction of the central carboxylate group, a
step-economical synthesis of 1 has been achieved. In terms of
yield, the presented method is more efficient than the procedure,
in which the reduction reaction precedes the installation of the
References and notes
1.
Silakowski, B.; Kunze, B.; Nordsiek, G.; Blöcker, H.; Höfle, G.; Müller, R. Eur. J.
Biochem. 2000, 267, 6476–6485.
3
2. Kunze, B.; Bedorf, N.; Kohl, W.; Höfle, G.; Reichenbach, H. J. Antibiot. 1989, 42,
4–17.
aromatic moieties. A facile access to 1 will now certainly foster
further research activities in the pharmacological field.
1
3.
Miyanaga, S.; Obata, T.; Onaka, H.; Fujita, T.; Saito, N.; Sakurai, H.; Saiki, I.;
Furumai, T.; Igarashi, Y. J. Antibiot. 2006, 59, 698–703.
4
.
Kiss, H.; Nett, M.; Domin, N.; Martin, K.; Maresca, J. A.; Copeland, A.; Lapidus,
A.; Lucas, S.; Berry, K. W.; Glavina Del Rio, T.; Dalin, E.; Tice, H.; Pitluck, S.;
Richardson, P.; Bruce, D.; Goodwin, L.; Han, C.; Detter, J. C.; Schmutz, J.; Brettin,
T.; Land, M.; Hauser, L.; Kyrpides, N. C.; Ivanova, N.; Göker, M.; Woyke, T.;
Klenk, H.; Bryant, D. A. Stand. Genom. Sci. 2011, 5, 356–370.
Experimental section
2
6
Preparation of ethyl-N ,N -bis(2,3-dimethoxybenzoyl)-L-
lysinate (2)
5.
Schieferdecker, S.; König, S.; Koeberle, A.; Dahse, H. M.; Werz, O.; Nett, M. J. Nat.
Prod. 2015, 78, 335–338.
For the preparation of compound 2,
dihydrochloride (2 mmol) was dissolved in 20 ml dry DMF
under an argon atmosphere at room temperature. Subsequently,
L
-lysine ethylester
6. Miyanaga, S.; Sakurai, H.; Saiki, I.; Onaka, H.; Igarashi, Y. Bioorg. Med. Chem.
009, 17, 2724–2732.
2
7
8
.
.
Maskos, K. Biochimie 2005, 87, 249–263.
Korp, J.; König, S.; Schieferdecker, S.; Dahse, H. M.; König, G.; Werz, O.; Nett, M.
ChemBioChem 2015, 16, 2445–2450.
2
,3-dimethoxybenzoic acid (4 mmol), pyBOP (4 mmol) and N,N-
9.
Rådmark, O.; Werz, O.; Steinhilber, D.; Samuelsson, B. Biochim. Biophys. Acta
diisopropylethylamine (6 mmol) were added and the solution
was stirred at room temperature for 16 h. Afterwards, the reaction
solution was poured into 100 ml of ice water. The mixture was
exhaustively extracted with ethyl acetate (EtOAc). The organic
layers were combined and dried by addition of sodium sulfate.
After evaporation of the solvent, the crude product was purified
by silica open column chromatography employing a gradient from
dichloromethane (DCM)/n-hexane 1:1 to DCM to DCM/EtOAc 1:1
2
015, 1851, 331–339.
0. Rådmark, O.; Samuelsson, B. J. Intern. Med. 2010, 268, 5–14.
11. Chen, Y.; Hu, Y.; Zhang, H.; Peng, C.; Li, S. Nat. Genet. 2009, 41, 783–792.
1
12. Guriec, N.; Le Jossic-Corcos, C.; Simon, B.; Ianotto, J. C.; Tempescul, A.; Dréano,
Y.; Salaün, J. P.; Berthou, C.; Corcos, L. Biochim. Biophys. Acta 2014, 1842, 2096–
2105.
13. Ford-Hutchinson, A. W.; Gresser, M.; Young, R. N. Annu. Rev. Biochem. 1994, 63,
383–417.
14. Han, S. Y.; Kim, Y. A. Tetrahedron 2004, 60, 2447–2467.
15. Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31, 205–208.
16. Doyagüez, E. G. Synlett 2005, 1636–1637.
(
yield: 85%).