Synthesis of Multiring Fused 2-Pyridones via a Nitrene Insertion Reaction: Fluorescent Modulators of α-Synuclein Amyloid Formation

Article abstract of DOI:10.1021/acs.orglett.5b03190

An efficient, straightforward method for the synthesis of thiazolo-2-pyridone embedded peptidomimetic polyheterocycles via a catalyst-free, microwave-assisted, intramolecular C-H amination reaction is reported. All the synthesized polyheterocycles were ev

Full text of DOI:10.1021/acs.orglett.5b03190

Letter
pubs.acs.org/OrgLett
Synthesis of Multiring Fused 2‑Pyridones via a Nitrene Insertion
Reaction: Fluorescent Modulators of α‑Synuclein Amyloid Formation
†
†
§
†
†
Pardeep Singh, Erik Chorell, K. Syam Krishnan, Tomas Kindahl, Jorgen Åden,
̈
Pernilla Wittung-Stafshede,† and Fredrik Almqvist*
,‡
,†
†Umea
̊
̊
University, Department of Chemistry, 90187 Umea, Sweden
*
S Supporting Information
ABSTRACT: An efficient, straightforward method for the
synthesis of thiazolo-2-pyridone embedded peptidomimetic
polyheterocycles via a catalyst-free, microwave-assisted, intra-
molecular C−H amination reaction is reported. All the
synthesized polyheterocycles were evaluated for their
fluorescent properties and effect on α-synuclein amyloid
formation.
olyheterocycles are found in a number of biologically
important synthetic and natural products. Furthermore,
compounds 5 and 6 (Figure 1), with an extended peptidomi-
metic backbone, are inhibitors. Thus, it is evident from the
previous studies that the nature of the substituents on the central
fragment is crucial to the biological effect. Thiazolo-2-pyridones
have served as versatile substrates for the construction of
1
,2
P
aiming at biologically active compounds, the construction of
polyheterocycles around privileged substructures has attracted
3
considerable attention. This approach requires a bioactive
8a−f
substructure which can be easily equipped with reactive centers
and subsequently transformed into polyheterocyclic structures.
One such moiety is the 2-pyridone scaffold, which has
contributed significantly in pharmaceutical, polymer, and
structurally diverse tricyclic to polyheterocyclic skeletons.
Aware of the optical properties of our previously reported
8f
polyheterocyclic 2-pyridones and the biological role played by
7d
scaffolds with an extended peptidomimetic backbone, we
became interested in 2-pyridone based bioactive fluorophores.
We envisioned that intramolecular C−N bond formation via
nitrene insertion would be an attractive way to synthesize
fluorescent 2-pyridone annulated polyheterocycles with an
extended peptidomimetic backbone (Figure 2).
4
material chemistry. 2-Pyridone derived polyheterocycles are
present in many natural products, for example, camptothecin, 1,
and sempervilam, 2 (Figure 1), and are associated with
5
interesting biological and pharmacological activities.
In recent years, azides have been utilized as convenient starting9
materials in the synthesis of N-heterocycles via nitrene insertion.
10
11
12
Thermal, photo-, or transition metal catalyzed decom-
position of an azide generates a nitrene which has the potential to
accomplish C−H insertion, forming a carbon−nitrogen bond.
Figure 1. 2-Pyridone containing natural products (1 and 2), pilicide (3),
curlicide (4), and α-synuclein inhibitors (5 and 6).
Thiazolo-2-pyridones are bicyclic peptidomimetic scaffolds
known for their ability to inhibit bacterial virulence. Some
6a−d
derivatives, termed pilicides
(3, Figure 1, peptidomimetic
backbone highlighted in red), interfere with pili biogenesis in
uropathogenic E. coli, while others with larger substituents (e.g.,
m-CF -phenyl, 4) inhibit formation of the bacterial amyloid
3
7a−c
known as curli and Alzheimer β-peptides
(4, Figure 1).
Figure 2. Outlined approach to polyheterocycles.
Received: November 4, 2015
Recently, we have disclosed that these amyloid inhibitors also act
as modulators for the fiber formation of α-synuclein, an amyloid
7
d,e
forming protein involved in Parkinson’s disease. For example,
compound 4 templates the formation of α-synuclein fibers, but
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Although nitrene insertion reactions of azido-2-pyridones for the
Scheme 2. Synthesis of Benzoquinoline Annulated 2-
Pyridones
1
3
construction of isoxazolo[4,3-c]pyridones, pyrido[2,3-b]-
1
4
[
1,5]benzodiazepines, and indolo[2,3:4,5] pyrido[2,3-d]-
1
5
pyrimidines have been reported, their potential in the synthesis
of 2-pyridone based peptidomimetic polyheterocycles have not
been previously explored. In the present work, we report a
microwave-assisted synthesis of indole/benzoquinoline/benzo-
thienopyridine-2-pyridone annulated peptidomimetics via a
transition-metal-free nitrene insertion reaction. The utilized
protocol allows access to diverse bioactive and fluorescent
polyheterocycles from readily available azido-2-pyridones.
The synthesis of the intermediate 6-amino-2-pyridones 7a and
16
7
b was accomplished using previously reported procedures.
Using these intermediates, 6-azido-2-pyridones 8a and 8b could
be synthesized in good yields by treatment of 6-amino-2-
pyridones 7a and 7b with the sulfuric acid salt of imidazole-1-
1
7
sulfonyl azide in the presence of K CO and CuSO at room
2
3
4
temperature (Scheme 1).
Scheme 1. Synthesis of Indole Annulated 2-Pyridones
Nitrene insertion chemistry has been used extensively for the
1
8
synthesis of indole or polyfused indole rings, and we
accordingly first investigated the possibility of building an indole
ring fused 2-pyridone system by the thermolysis of azido-2-
pyridone 8. The generation of nitrenes from azides usually
requires harsh conditions and/or metal catalysts. However,
thermolysis of pyridone 8a and 8b in 1,2-dichloroethane (DCE)
by heating under microwave irradiation at 120 °C for 5 min
delivered polyheterocycle 9a and 9b in good yields. In all our
previous studies of amyloid modulators it was shown that the
The reaction is believed to proceed through the formation of a
nitrene, which undergoes insertion into the naphthyl C−H bond
to form intermediates 13a−13h, which next oxidize sponta-
neously to the target compounds 14a−14h. The nature of the
substituents did not affect the outcome of the reaction
significantly and excellent yields were obtained in all cases.
Finally, compounds 14a−14h were hydrolyzed to the corre-
sponding acids 15a−15h in good yields.
To further probe the scope of our method we attempted the
cyclization onto a benzothiophene ring. The azido-pyridones 16a
and 16b were synthesized from the corresponding amines as
previously. Subsequent thermolysis of compounds 16a and 16b
resulted in polyheterocycles 17a and 17b in 65% and 69% yield
(Scheme 3), respectively. Hydrolysis of 17a and 17b gave
carboxylic acids 18a and 18b.
The fluorescent properties of the 2-pyridone annulated
polyheterocycles were then examined (Table 1). The benzoqui-
noline annulated 2-pyridones 15a−15h generally showed
quantum yields around 20% except for 15e and 15f that
displayed lower quantum yields, 2% and 1% respectively.
Benzothienopyridine annulated 2-pyridones 18a and 18b also
showed lower quantum yields (7% and 6% respectively)
compared to the benzoquinoline annulated 2-pyridones 15a
and 15b (19% and 21% respectively), thus emphasizing the
importance of the structure of the polycyclic backbone on the
fluorescent properties. The indole annulated 2-pyridone 10a
showed a quantum yield of 11%, but interestingly, its analogue
7d,e
carboxylic acid was essential for activity;
thus, the esters 9a
and 9b were hydrolyzed with LiOH followed by acidic workup to
the corresponding carboxylic acids 10a and 10b.
Having succeeded in constructing the five-membered ring, we
turned our attention toward the possibility of forming a six-
membered ring to rigidify our previously studied amyloid
modulators (e.g., 4 and 5, Figure 1). Thus, a series of azido-
pyridones 12a−12h were synthesized from the corresponding
amino-pyridones 11a−11h following the same conditions as
developed for the indole fused analogues. The substituent at
position C-8 (see Figure 2 for numbering) on the pyridone ring
was varied from alkyl to aryl, heteroaryl, and an alkoxy group to
establish the substrate scope of the reaction and to establish
initial structure−activity relationship information in the
subsequent testing for their ability to modulate α-synuclein
fiber formation. We were pleased to see that our reaction
conditions proved general as thermolysis of azido-pyridones
1
2a−12h furnished benzoquinoline annulated 2-pyridones
1
4a−h in 77−86% yield (Scheme 2).
B
DOI: 10.1021/acs.orglett.5b03190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of Benzothienopyridine Annulated 2-
Pyridones
Figure 3. Affect on α-synuclein aggregation.
Table 1. Quantum Yield of Fluorescence (Φ ) and
f
Fluorescence Lifetime (τ ) of 2-Pyridone Annulated
study we concluded that benzoquinoline fused 2-pyridones or
benzothienopyridines fused 2-pyridones in combination with
smaller C-8 substituents (i.e., Me-, MeO-, and cyclopropyl) may
also be inhibitors. However, all accelerators identified in this
f
Polyheterocycles When Dissolved in Ethanol at 20 °C
a
c
compound
emmax (nm)
Φf
τf (ns)
d
1
1
1
1
1
1
1
1
1
1
1
1
0a
0b
5a
5b
5c
5d
5e
5f
420
420
510
505
510
515
550
580
515
510
505
0.11
0.04
0.19
0.21
0.24
0.23
0.02
0.01
0.19
0.18
0.07
0.06
2.1
study are equipped with a larger substituent (i.e., m-CF Ph or m-
3
d
0.6
OMePh in C-8).
12.1
11.7
12.4
14.0
1.9
To ensure that the observed effect in the ThT assay actually
correlated with α-synuclein amyloid formation and was not an
effect of fluorescence disturbance or ThT binding, we analyzed
the end products from the ThT assay by using fluorescence
microscopy and EM. The fluorescence microscopy did not show
any fluorescent amyloid deposits when inhibitory compounds
were used, whereas fluorescent amyloid deposits were clearly
visible when accelerating compounds were used (Figure 3). Also,
the EM samples showed no or only small amounts of α-synuclein
amyloid fibers in the case of inhibitors, but large deposits of
intertwined α-synuclein amyloid fibers in the case of accelerators
0.7
5g
5h
8a
8b
12.9
10.9
7.2
b
b
500
4.7
a
b
c
d
λex = 355 nm. λ = 335 nm. λ = 404 nm. λ = 375 nm.
ex
ex
ex
(
Figure 3). These data support the ThT assay data, showing both
compounds that can accelerate and others that can reduce the
rate of α-synuclein amyloid formation, depending on their C-8
substituent.
1
0b with m-CF −Ph at position C-8 only showed a quantum
3
yield of 4%. The fluorescence lifetime of the compounds follows
the same trend as the quantum yields, with generally long
lifetimes (11−14 ns) for benzoquinoline annulated 2-pyridones
but with 15e and 15f as exceptions (1.9 and 0.7 ns respectively).
Compounds 18a and 18b showed lifetimes of 7.2 and 4.7 ns,
respectively. The lifetime was also short for the indole annulated
polyheterocycles i.e. 2.1 and 0.6 ns for 10a and 10b respectively.
Analogous polyheterocyclic 2-pyridones with similar photo-
physical properties as 15c, 15d, 15g, and 15h have previously
proven to be useful in biological systems, thus indicating that
these benzoquinoline annulated 2-pyridones can be used as
fluorescent probes or tags in biological systems.
Finally, all compounds were evaluated for their ability to affect
α-synuclein amyloid formation as measured by increased ThT
fluorescence upon amyloid formation. Interestingly, compounds
In conclusion, we have developed methods to synthesize new
peptidomimetic polyheterocycles using an intramolecular C−N
bond formation via a metal-free nitrene insertion reaction under
microwave conditions. The protocol results in a clean and
efficient reaction with easy purifications and excellent yields that
can be used to synthesize new fluorescent and biologically
interesting polyheterocycles. As an example, we synthesized a set
of rigidified analogues of our previously published amyloid
modulators. Biological evaluation of these multiring fused 2-
pyridones revealed both fluorescent accelerators and fluorescent
inhibitors of α-synuclein amyloid formation depending on the C-
8f
8
substituents. Interestingly, the rigidification of the central
fragment for the first time resulted in inhibitory analogues with
smaller C-8 substituents (i.e., methyl, methoxy, cyclopropyl).
This knowledge will be important in the design of future
improved α-synuclein modulators. More detailed investigations
will be undertaken in the future to understand how the difference
in substitution pattern and central fragment constitution affect
the biological activity.
1
5d, 18b, and 15b proved to accelerate α-synuclein amyloid
formation almost as efficiently as the previously most effective
accelerating compound FN075 (4, Figure 1). Compounds 15f,
1
5g, and 18a on the other hand significantly reduced the rate of
α-synuclein amyloid formation (Figure 3), but the other
compounds did not significantly effect this system (see
Supporting Information). We have previously shown that small
variations on the central fragment can result in drastic changes in
the effect of the compounds on α-synuclein amyloid formation.
In all previous examples
ASSOCIATED CONTENT
7d
■
7d,e
*
S
Supporting Information
where we have studied bicyclic or
tricyclic 2-pyridones, a larger C-8 substituent has been essential
to see any amyloid modulating properties. Interestingly, in this
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03190.
C
DOI: 10.1021/acs.orglett.5b03190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedure; spectroscopic and analytical data
Letter
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Waksman, G.; Hultgren, S. J.; Almqvist, F. J. Med. Chem. 2010, 53,
for all new compounds; absorption and emission spectra
for final carboxylic acids (PDF)
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AUTHOR INFORMATION
Corresponding Author
E-mail: Fredrik.almqvist@umu.se.
■
*
9
13−919. (c) Andersson, E. K.; Bengtsson, C.; Evans, M. L.; Chorell, E.;
Present Addresses
‡Chalmers University of Technology, Department of Biology
and Biological Engineering, Division of Chemical Biology, 41296
teborg, Sweden.
Department of chemistry, Mannam Memorial NSS College,
Kottiyam, Kollam, 691571 Kerala, India.
Sellstedt, M.; Lindgren, A. E. G.; Hufnagel, D. A.; Bhattacharya, M.;
Tessier, P. M.; Wittung-Stafshede, P.; Almqvist, F.; Chapman, M. R.
Chem. Biol. 2013, 20, 1245−1254. (d) Horvath, I.; Weise, C. F.;
Andersson, E. K.; Chorell, E.; Sellstedt, M.; Bengtsson, C.; Olofsson, A.;
Hultgren, S. J.; Chapman, M. R.; Wolf-Watz, M.; Almqvist, F.; Wittung-
Stafshede, P. J. Am. Chem. Soc. 2012, 134, 3439−3444. (e) Horvath, I.;
Sellstedt, M.; Weise, C.; Nordvall, L.-M.; Prasad, G. K.; Olofsson, A.;
Larsson, G.; Almqvist, F.; Wittung-Stafshede, P. Arch. Biochem. Biophys.
Go
̈
§
Notes
2
(
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
F.A. is grateful to the Swedish Research Council (621-2010-
730), the Knut and Alice Wallenberg Foundation, the Go
Gustafsson Foundation, the Swedish Foundation for Strategic
Research, and the Michael J. Fox Foundation for financial
support. P.S. postdoctoral scholarship was supported by the
5472. (c) Sellstedt, M.; Almqvist, F. Org. Lett. 2011, 13, 5278−5281.
■
4
(d) Sellstedt, M.; Almqvist, F. Org. Lett. 2008, 10, 4005−4007.
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̈
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by the J. C. Kempe Foundation. P.W.S. is grateful to the Swedish
Research Council and the Knut and Alice Wallenberg
Foundation for funding.
Driver, T. G. Org. Lett. 2007, 9, 5191−5194. (c) Shen, M.; Driver, T. G.
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DOI: 10.1021/acs.orglett.5b03190
Org. Lett. XXXX, XXX, XXX−XXX