Quinocidin, acytotoxic antibiotic with anunusual 3,4-dihydroquinolizinium ring and michael acceptor reactivity toward thiols

Article abstract of DOI:10.1002/chem.201704729

Cytotoxicity-guided fractionation of the culture broth of Actinomadura sp. TP-A0019 led to the isolation of quinocidin (1), acytotoxic antibiotic with an unusual 3,4-dihydroquinolizinium ring. The structural assignment was made on the basis of high-field NMR experiments and chemical synthesis. Comparison ofthe spectral properties of 1 with those of its synthetic counterparts revealed that 1 is aracemic mixture of two enantiomers, which showed similar cytotoxicity against HeLa-S3 cells. Nucleophile-trap-ping experiments demonstrated that 1 captured 2-mer-captoethanol and N-acetyl-l-cysteine by means of aMi-chael addition-type reaction, but was inert toward 2-ami-noethanol and glycolic acid. Notably, the addition of 1 to thiols proceeded smoothly in neutral aqueous media at room temperature. In view of the thiol-trapping ability and the unusual structure, 1 provides aunique scaffold for designing drug leads and protein-labeling probes.

Full text of DOI:10.1002/chem.201704729

A Journal of
Accepted Article
Title: Quinocidin, a Cytotoxic Antibiotic with an Unusual 3,4-
Dihydroquinolizinium Ring and Michael Acceptor Reactivity
toward Thiols
Authors: Yu Nakagawa, Yuki Sawaki, Takahiro Kimura, Tomohiko
Tomura, Yasuhiro Igarashi, and Makoto Ojika
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201704729
Link to VoR: http://dx.doi.org/10.1002/chem.201704729
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COMMUNICATION
Quinocidin, a Cytotoxic Antibiotic with an Unusual 3,4-
Dihydroquinolizinium Ring and Michael Acceptor Reactivity
Toward Thiols
Yu Nakagawa,*[a] Yuki Sawaki,[a] Takahiro Kimura,[a] Tomohiko Tomura,[a] Yasuhiro Igarashi,[b] and
Makoto Ojika[a]
Abstract: Cytotoxicity-guided fractionation of the culture broth of
Actinomadura sp. TP-A0019 led to the isolation of quinocidin (1), a
cytotoxic antibiotic with an unusual 3,4-dihydroquinolizinium ring.
The structural assignment was made on the basis of high-field NMR
experiments and chemical synthesis. Comparison of the spectral
properties of 1 with those of its synthetic counterparts revealed that
1 is a racemic mixture of two enantiomers, which showed similar
cytotoxicity against HeLa-S3 cells. Nucleophile-trapping experiments
demonstrated that 1 captured 2-mercaptoethanol and N-acetyl-L-
cysteine via a Michael addition-type reaction, but was inert toward 2-
aminoethanol and glycolic acid. Notably, the addition of 1 to thiols
proceeded smoothly in neutral aqueous media at room temperature.
In view of the thiol-trapping ability and the unusual structure, 1
provides a unique scaffold for designing drug leads and protein-
labeling probes.
Quinocidin (1) was isolated by cytotoxicity-guided
fractionation of the culture broth of Actinomadura sp. TP-A0019.
Two-step fractionation of the culture broth (300 mL) by flash
column chromatography on Diaion HP-20 and ODS followed by
reversed-phase HPLC purification afforded 6.6 mg of 1 as a
trifluoroacetate salt. The HR-ESI-MS showed
a positive
molecular ion peak at m/z 270.2219 [M]+, consistent with a
1
molecular formula of C19H28N. The H- and 13C-NMR spectra of
1 in CD3OD displayed two sets of signals in a ratio of about 1:1,
suggesting the presence of diastereomers or conformers (Table
1
1). The H-NMR spectrum revealed the presence of five methyl
groups (H310, H316, H317, H318, and H319). The 1H-1H COSY
spectrum indicated a continued spin system from one of the
methyl protons (H316) to an olefinic proton (H12) through three
methylene protons (H213, H214, H215). Another methyl proton
(H310) showed a COSY correlation to a methine proton (H3),
which was further correlated to the methylene protons (H4a and
H4b) and the mutually coupled olefinic protons (H1, H2). The
coupling constant of the olefinic protons (J = 9.6 Hz for both
stereoisomers) suggested a cis configuration of the double bond
at C1–C2. The other three methyl protons appeared as singlets
(H317, H318, and H319) and were assigned by HMBC
experiment, which showed correlations from the H317 protons to
the aromatic C6 carbon and the olefinic C11 and C12 carbons.
Moreover, correlations from the H318 protons to the C6, C7, and
C8 carbons, and from the remaining H319 protons to the C8, C9,
and C9a carbons allowed the assignment of all aromatic
carbons. The HMBC cross-peaks from the H1 proton to the C9a
carbon and from the H4a and H4b protons to the C6 carbon,
together with the presence of a nitrogen atom in the molecular
formula, suggested the presence of a 3,4-dihydroquinolizinium
ring in the structure of 1. The E geometry of the double bond at
C11–C12 was determined by the strong NOESY correlation
between the H313 and H217 protons. Thus, the planar structure
of 1 was established as shown in Figure 1 (right). Such 3,4-
dihydroquinolizinium scaffold has very rarely been observed in
natural products, while quinolizinium and 1,2,3,4-tetrahydro-
quionolizinium are present in a variety of alkaloids.[4]
Heterocyclic compounds of natural origin play a highly significant
role in the drug discovery and development process.[1] Besides
their successful use as drug leads, the intrinsic versatility and
physicochemical properties of their heterocyclic rings have
attracted growing interest in drug development research.[2]
A
recent substructure search using the Drug Data Report
database showed that more than 70% of previously approved
drugs and over 80% of compounds currently in preclinical trials
contain at least one heterocyclic ring.[1a] Hence, biologically
active natural products containing unexplored heterocyclic ring
systems provide an opportunity to create a new platform for drug
discovery and development. Herein, we report the isolation,
structure elucidation, and synthesis of quinocidin (1), a novel
cytotoxic antibiotic with a 3,4-dihydroquinolizinium ring, which
has hardly been observed in natural products. The unusual
heterocyclic system of 1 was demonstrated to capture thiols in
neutral aqueous media at room temperature, providing a novel
scaffold for the design of drug leads and protein-labeling probes
that form covalent bonds with the cysteine residues of their
target proteins.[3]
[a]
[b]
Dr. Y. Nakagawa, Y. Sawaki, T. Kimura, Dr. T. Tomura, Prof. Dr. M.
Ojika
Department of Applied Molecular Biosciences, Graduate School of
Bioagricultural Sciences, Nagoya University
Furo-cho, Chikusa-ku, Nagoya 464-8601 (Japan)
E-mail: yu@agr.nagoya-u.ac.jp
Prof. Dr. Y. Igarashi
Biotechnology Research Center, Toyama Prefectural University
5180 Kurokawa, Imazu, Toyama 939-0398 (Japan)
13
15
18
12
11
14
17
16
7
8
6
5
N
N
4
9
+
+
19
9a
1H–1H COSY
HMBC
1
3
2
10
Quinocidin (1)
Supporting information for this article is given via a link at the end of
the document.
Figure 1. Left: structure of quinocidin (1). Right: key 2D NMR correlations.
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10.1002/chem.201704729
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Table 1. 1H- and 13C-NMR (CD3OD, 600 and 150 MHz)
assignments for two rotamers of quinocidin (1).
OH
OTBDPS
OTBDPS
Rotamer A
δH (m, J in Hz)
Rotamer B
δH (m, J in Hz)
a
b
position
1
δC
δC
MeO2C
OHC
6.99 (d, 9.7)
120.6/
120.5[b]
145.9
30.3
6.99 (d, 9.7)
120.6/
120.5[b]
145.9
30.0
2
3
4
2
3
6.85 (dd, 9.7, 4.4)
2.98 (br. m)
6.87 (dd, 9.7, 4.5)
2.98 (br. m)
4a
4b
6
7
8
4.42 (dd, 13.8, 8.4)
4.51 (dd, 13.8, 5.5)
4.35 (dd, 13.9, 8.0)
4.59 (dd, 13.9, 5.5)
57.5
57.4
Scheme 1. Synthesis of alkyne 4. Reagents and conditions: (a) (i) TBDPS-Cl,
imidazole, DMF, rt; (ii) DIBAL-H, toluene, –78 °C to rt; (iii) SO3·pyridine, Et3N,
DMSO, CH2Cl2, 0 °C to rt (78%). (b) (i) PPh3, CBr4, CH2Cl2, 0 °C; (ii) n-BuLi,
THF, –78 °C to rt (66%).
157.2
137.2
150.0/
149.9[c]
135.2
145.8
16.7
129.1
140.3/
140.2[d]
29.6
32.8
24.5
15.1
16.5
20.0/
19.9[e]
19.0
157.2
137.2
150.0/
149.9[c]
135.2
145.8
16.8
128.9
140.3/
140.2[d]
29.6
32.7
24.5
15.1
17.1
20.0/
19.9[e]
19.0
8.22/8.23[a] (s)
8.22/8.23[a] (s)
9
9a
10
11
12
1.17 (d, 7.2)
1.18 (d, 7.2)
derivative 8 was prepared from 3,5-lutidine (5) (Scheme 2).
Chlorination via regioselective lithiation at the C2 position of 5
using the superbase n-BuLi–Me2N(CH2)2OLi gave the 2-chloro
derivative 6 (92%).[8] Lithiation at the C6 position[9] of 6 followed
by reaction with 2-heptanone provided tertiary alcohol 7 (35%).
Next, dehydration with H2SO4 and AcOH produced a ~10:3
mixture of the desired alkene 8 and its regioisomer 9, and
subsequent isomerization with n-BuLi afforded 8 in 49% yield
over two steps. Sonogashira coupling between 2-chloropyridine
derivative 8 and alkyne 4 followed by desilylation gave 10 (55%
over two steps), which was reduced to the corresponding cis-
alkene 11 by hydrogenation over Lindlar catalyst (67%). Finally,
cyclization was achieved via the mesylate intermediate to
provide the desired 3S isomer of 1 (45%) as a trifluoroacetate
salt. The 3R isomer was similarly prepared using methyl (S)-
5.76 (tq, 7.4, 1.3)
5.80 (tq, 7.2, 1.3)
13
14
15
16
17
18
2.41 (m)
1.55 (m)
1.47 (m)
1.01 (t, 7.3)
2.04 (s)
2.41 (m)
1.55 (m)
1.47 (m)
1.01 (t, 7.3)
2.03 (s)
2.41 (s)
2.41 (s)
19
2.54 (s)
2.54 (s)
[a],[b],[c],[d],[e]The signals of rotamers A and B could not be assigned.
Careful analysis of the NOESY spectrum suggests that the
two isomers differed by the orientation of the alkenyl side chain
(rotamers A and B; Figure 2). In rotamer A, the H4b proton
showed strong NOESY correlations with the H3 and H317
protons. On the other hand, the H4b proton of rotamer B
showed NOESY correlation with the H3 proton, but not with the
H317 protons; moreover, a strong correlation between the H4a
and H317 protons was observed. These results confirm that
doubling of the NMR signals was due to the presence of two
rotamers, resulting from hindered rotation around the C6–C11
bond. Signal coalescence did not occur even at 60 °C, indicating
a considerably high rotation barrier.
hydroxyisobutyrate as
Information).
a
starting material (Supporting
OH
a
b
c
N
N
N
Cl
Cl
In order to confirm the structure of 1 and determine the C3
stereochemistry, the 3S and 3R isomers of 1 were synthesized
separately. The synthesis of the 3S isomer started with the
preparation of alkyne 4, shown in Scheme 1. After protection of
the hydroxyl group of commercially available methyl (R)-
hydroxyisobutyrate (2) with a TBDPS (tert-butyldiphenylsilyl)
group, the ester was reduced with DIBAL-H (diisobutylaluminium
hydride). The resulting alcohol was oxidized to aldehyde 3 under
Parikh-Doering conditions[5] (78% over three steps), and the
following Corey-Fuchs one-carbon homologation[6] provided the
desired alkyne 4 (66%), which was used for Sonogashira
coupling.[7] The other coupling partner, i.e., 2-chloropyridine
5
6
7
d
e
+
8
N
N
Cl
Cl
8
9
f
g
N
N
OH
N
+
H
17
Me
Me
Me
12
OH
3S isomer of 1
10
11
C4H9
H
3
H
3
Me
Me
+
N
+
N
17
Hb
Me
Hb
C4H9
Scheme 2. Synthesis of the 3S isomer of 1. Reagents and conditions: (a) n-
BuLi–Me2N(CH2)2OLi, n-hexane, 0 °C then C2Cl6, –78 °C (92%). (b) n-BuLi–
Me2N(CH2)2OLi, n-hexane, 0 °C then 2-heptanone, –30 °C to rt (35%). (c)
H2SO4, AcOH, 70 °C. (d) n-BuLi, n-hexane, 0 °C (49% over two steps). (e) (i) 4,
PdCl2(PPh3)2, PPh3, Et2NH, DMF, 120 °C; (ii) TBAF, THF, rt (55%). (f) H2,
Lindlar catalyst, quinoline, MeOH, rt (67%). (g) MsCl, Et3N, CH2Cl2, –20 °C
(45%).
12
4
Me
4
H
Ha
Ha
Me
Rotamer A
Rotamer B
Figure 2. Key NOESY correlations in rotamers A and B of 1. The 3R isomer is
shown as an example.
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150ꢀ
100ꢀ
50ꢀ
0
N
+
16ꢀ
N
15ꢀ
N
N
+
+
2 hꢀ
0 hꢀ
12
13
S
16ꢀ
OH
10ꢀ 12ꢀ 14ꢀ 16ꢀ 18ꢀ
Retention Time [min]ꢀ
15ꢀ
Figure 3. Structures of 12 and 13.
The 1H- and 13C-NMR spectra of the synthetic 3S and 3R
isomers were in perfect agreement with those of isolated 1.
Figure 5. HPLC chromatograms of the reaction mixtures of 2-
mercaptoethanol with 15.
25
However, the specific rotation of 1 ([α]D = –1.9, c = 0.35,
MeOH) was found to be inconsistent with that of either of the two
It is well known that α,β-unsaturated iminium salts are highly
25
isomers ([α]D25 = +42.5, c = 0.33, MeOH for the 3S isomer; [α]D
susceptible
to
nucleophilic
attack.[10]
The
3,4-
= –45.4, c = 0.26, MeOH for the 3R isomer). The low specific
rotation of the natural sample indicates that 1 is a racemic
mixture, confirming the structure of 1 as shown in Figure 1 (left).
The racemate formation seems to be, at least in part, abiotic
since two-month storage of the 3S isomer at –20 °C led to a
dihydroquinolizinium ring includes the α,β-unsaturated iminium
moiety (C2-C1-C9a-N5), raising the possibility of adduct
formation between 1 and nucleophiles. To explore this aspect,
the reactivity of 1 toward 2-aminoethanol, glycolic acid, and 2-
mercaptoethanol was examined. After treatment of the 3R
isomer of 1 with 10 equivalents of each nucleophile in PBS (pho-
sphate-buffered saline, pH 7.4) at room temperature for 2, 4, 8,
24, and 48 h, the reaction mixture was analyzed by HPLC
(Figure 4). Intriguingly, whereas the 3R isomer of 1 was inert to
2-aminoethanol and glycolic acid, time-dependent adduct
formation was clearly observed in the reaction with 2-
mercaptoethanol. In a scale-up experiment, the adduct could be
identified as 14 (for structural determination, see Supporting
Information), suggesting that the reaction proceeded via a
Michael addition-type mechanism. Notably, under the same
conditions, N-acetyl-L-cysteine also afforded the corresponding
adduct (Supporting Information). To our knowledge, this is the
first demonstration that the 3,4-dihydroquinolizinium ring can
capture thiols in neutral aqueous media at room temperature.
Moreover, rapid adduct formation was observed in the reaction
of 2-mercaptoethanol with the core structure 15 (Figure 5; for
details, see Supporting Information), suggesting the possibility
that the reactivity might be controlled by the steric hindrance at
the C3 position.
25
decreased specific rotation ([α]D = +24.2, c = 0.09, MeOH). On
the other hand, to investigate the effect of the alkenyl side chain
on the conformation of 1, the corresponding compound lacking
the alkenyl side chain (12) was prepared (Figure 3). As expected,
only one set of signals was detected in the 1H- and 13C-NMR
spectra of 12 (Supporting Information), supporting our
conclusion that the duplicate signals of 1 derived from the
orientation of the alkenyl side chain.
Next, 1 and its synthetic isomers were evaluated for their
cytotoxicity against HeLa-S3 cells derived from human cervical
carcinoma. Their activities were almost indistinguishable (IC50
=
0.63 µg/mL for 1, 0.60 µg/mL for the 3S isomer, and 0.64 µg/mL
for the 3R isomer), clearly indicating the trivial role of the C3
stereochemistry on the cytotoxic activity of 1. On the other hand,
12, which lacks the alkenyl side chain, and 13, which contains a
pyridine ring instead of the 3,4-dihydroquinolizinium ring (Figure
3; for its preparation, see Supporting Information), exhibited
significantly lower activities (IC50
=
>30 µg/mL).
These
combined results suggest that the 3,4-dihydroquinolizinium ring
is necessary but insufficient for the cytotoxic activity of 1.
In conclusion, quinocidin (1), a novel 3,4-dihydroquinolizinium
compound with cytotoxicity against HeLa-S3 tumor cells, was
isolated from the culture broth of Actinomadura sp. TP-A0019.
This simple but unusual heterocyclic antibiotic can be easily
synthesized and thus can be tuned for optimal pharmacological
properties, providing a new platform for the development of
anticancer drugs. Of particular interest is the ability of the 3,4-
dihydroquinolizinium ring to capture thiols in neutral aqueous
solution. Although a variety of electrophiles have been used as
3R isomer of 1ꢀ
3R isomer of 1ꢀ
150ꢀ (A)ꢀ
150ꢀ (B)ꢀ
100ꢀ
50ꢀ
0
100ꢀ
50ꢀ
0
48 hꢀ
24 hꢀ
8 hꢀ
4 hꢀ
2 hꢀ
0 hꢀ
48 h
24 hꢀ
8 hꢀ
4 hꢀ
2 hꢀ
0 hꢀ
10ꢀ 12ꢀ 14ꢀ 16ꢀ 18ꢀ
Retention Time [min]ꢀ
10ꢀ 12ꢀ 14ꢀ 16ꢀ 18ꢀ
Retention Time [min]ꢀ
warheads
in
protein-labeling
probes,[3]
the
3,4-
14ꢀ
150ꢀ (C)ꢀ
3R isomer
of 1ꢀ
dihydroquinolizinium ring has not been observed to date in the
system. In particular, the presence of the positive charge is an
intriguing feature of this electrophile, suggesting its potential as
a novel warhead with a preference for cysteine residues near
negatively charged amino acid residues. Further studies of the
biosynthesis, the correlation between thiol-trapping ability and
cytotoxicity, and the electrophilic reactivity of 1 are in progress.
100ꢀ
50ꢀ
0
48 hꢀ
24 hꢀ
8 hꢀ
4 hꢀ
2 hꢀ
0 hꢀ
N
+
S
OH
10ꢀ 12ꢀ 14ꢀ 16ꢀ 18ꢀ
Retention Time [min]ꢀ
14ꢀ
Figure 4. HPLC chromatograms of the reaction mixtures of (A)
2-aminoethanol, (B) glycolic acid, (C) 2-mercaptoethanol with
the synthetic 3R isomer of 1.
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COMMUNICATION
[3]
[4]
a) M. H. Wright, S. A. Sieber, Nat. Prod. Rep. 2016, 33, 681-708; b) P.
Yang, K. Liu, ChemBioChem 2015, 16, 712-724; c) D. A. Shannon, E.
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M. Bogyo, Annu. Rev. Biochem. 2014, 83, 249-273; e) U. Haedke, E. V.
Küttler, O. Vosyka, Y. Yang, S. HL. Verhelst, Curr. Opin. Chem. Biol.
2013, 17, 102-109.
Acknowledgements
This work was partly supported by JSPS KAKENHI Grant
Numbers JP26660099, JP15H04496 and SUNBOR GRANT
from the Suntory Foundation of Life Sciences. We thank Mr.
Kazushi Koga for NMR spectroscopic assistance.
a) N. J. Martin, S. Prado, G. Lecellier, O. P. Thomas, P.
Raharivelomanana, Molecules 2012, 17, 12015-12022; b) A. Schmidt,
Adv. Heterocycl. Chem. 2003, 85, 67-171; c) S. Sperry, P. Crews,
Tetrahedron Lett. 1996, 37, 2389-2390; d) B. D. Krane, M. O. Fragbule,
M. Shamma, J. Nat. Prod. 1984, 47, 1-43; e) T. Kametani, M. Ihara, T.
Honda, Heterocycles 1976, 4, 483-526; f) Y. Kondo, Heterocycles 1976,
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Conflict of interest
The authors declare no conflict of interest.
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Keywords: Drug discovery • Nitrogen heterocycles • Michael
addition • Natural products • Structure elucidation
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MacMillan, Nature 2008, 455, 304-308; d) P. Melchiorre, M. Marigo, A.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Yu Nakagawa*, Yuki Sawaki, Takahiro
Kimura, Tomohiko Tomura, Yasuhiro
Igarashi, and Makoto Ojika
OH
N
+
HS
N
+
N
+
Page No. – Page No.
PBS (pH 7.4)
Room Temperatureꢀ
S
OH
Quinocidinꢀ
Quinocidin, a Cytotoxic Antibiotic
with an Unusual 3,4-
Dihydroquinolizinium Ring and
Michael Acceptor Reactivity Toward
Thiols
Aquatic thiol catcher: Quinocidin, a novel cytotoxic antibiotic with a 3,4-
dihydroquinolizinium ring, was isolated from the culture broth of Actinomadura sp.
TP-A0019. The unusual heterocyclic ring of quinocidin was demonstrated to
capture thiols in neutral aqueous media at room temperature.
This article is protected by copyright. All rights reserved.