Synthesis, antibacterial and cytotoxic evaluation of flavipucine and its derivatives

Article abstract of DOI:10.1016/j.bmcl.2019.03.034

The antibacterial and cytotoxic activity of seven racemic lactams and both enantiomers of flavipucine were evaluated. Of the compounds tested in this study, flavipucine and phenylflavipucine displayed bactericidal activity against Bacillus subtilis. These

Full text of DOI:10.1016/j.bmcl.2019.03.034

Accepted Manuscript
Synthesis, antibacterial and cytotoxic evaluation of flavipucine and its deriva-
tives
Yasuha Kusakabe, Shoma Mizutani, Shogo Kamo, Tatsuki Yoshimoto, Shusuke
Tomoshige, Tsuneomi Kawasaki, Ryoko Takasawa, Kazunori Tsubaki, Kouji
Kuramochi
PII:
S0960-894X(19)30173-8
https://doi.org/10.1016/j.bmcl.2019.03.034
BMCL 26348
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
23 January 2019
13 March 2019
23 March 2019
Please cite this article as: Kusakabe, Y., Mizutani, S., Kamo, S., Yoshimoto, T., Tomoshige, S., Kawasaki, T.,
Takasawa, R., Tsubaki, K., Kuramochi, K., Synthesis, antibacterial and cytotoxic evaluation of flavipucine and its
derivatives, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.03.034
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Bioorganic & Medicinal Chemistry Letters
Synthesis, antibacterial and cytotoxic evaluation of flavipucine and its
derivatives
a
b
a,b
a
a
Yasuha Kusakabe, Shoma Mizutani, Shogo Kamo, Tatsuki Yoshimoto, Shusuke Tomoshige,
c
d
b
a,*
Tsuneomi Kawasaki, Ryoko Takasawa, Kazunori Tsubaki, Kouji Kuramochi,
a
Department of Applied Biological Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Sakyo-ku, Kyoto 606-8522, Japan
b
c
Department of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
d
Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
The antibacterial and cytotoxic activity of seven racemic lactams and both enantiomers of
flavipucine were evaluated. Of the compounds tested in this study, flavipucine and
phenylflavipucine displayed bactericidal activity against Bacillus subtilis. These results indicate
that the pyridione epoxide moiety is a pharmacophore for antibacterial activity against B.
subtilis. Flavipucine showed cytotoxic activity against several cancer cells. The cytotoxic
activity of flavipucine against human leukemia HL-60 cells is as strong as that of SN-38, the
active metabolite of irinotecan. In contrast, the cytotoxic activity of flavipucine against
nonneoplastic HEK293 cells and human normal MRC-5 cells is weaker than that of SN-38. No
significant differences in the biological activity of the racemates or enantiomers of flavipucine
were observed.
Keywords:
Lactam
Natural product
Antibacterial activity
Cytotoxicity
(
)-Flavipucine [(−)-1, Figure 1] has been isolated from
1,2
Aspergillus flavipes, the fungus-caused Macrophoma fruit rot
of the apple, as well as from cultures of Cladobotryum
rubrobrunnescens. ()-Flavipucine [(+)-1] was isolated from the
culture extract of Phoma sp. Both enantiomers of flavipucine
3
4
5
1
,4-6
reportedly show antibacterial and antifungal activity.
The
absolute configuration of (+)-1 was determined by comparison of
5
experimental and calculated CD spectra. Isoflavipucine (2) was
isolated in racemic form from Aspergillus flavipes and Phoma
5
,7
sp. This compound is produced via rearrangement of
8
-11
flavipucine. Isoflavipucine possesses moderate inhibitory
5
activity against Phytophthora infestans. Berkeleyamide D (3)
has been isolated from the acid lake fungus Penicillium rubrum
Stoll, and was shown to inhibit matrix metalloproteinase-3 and
1
2
caspase-1. Rubrobramide (4) was isolated from Cladobotryum
rubrobrunnescens exhibits weak cytotoxic activity against mouse
lymphocytic leukemia L-1210 cells, and inhibits the germination
Figure 1. Structures of ()-flavipucine [(−)-1], ()-flavipucine
(+)-1], (±)-isoflavipucine (2), berkeleyamide D (3), and
rubrobramide (4).
[
1
3
of Lepidium sativum. The absolute configurations of 3 and 4
were determined via the exciton chirality method in vibrational
1
4,15
circular dichroism.
The racemic total syntheses of 1−4 were achieved using a
regioselective Darzens reaction between isobutylglyoxal (5) and
1
4-16
α-bromo-β-ketoamides 6 by our group (Scheme 1).
When
tert-butoxycarbonyl (Boc)-protected α-bromo-β-ketoamides were

Corresponding author. Tel.: +81-4-7122-9413; fax: +81-4-7123-9767; e-mail: kuramoch@rs.tus.ac.jp (K. Kuramochi)

used as substrates for the Darzens reaction, epoxyamides 7 were
obtained (Scheme 1A). When non-protected α-bromo-β-
ketoamides were used as substrates, epoxylactams 8 were
obtained. Compounds 7a, 7b, and 8c were prepared using this
key reaction and used for the syntheses of 1−4. (±)-Flavipucine
A common hybrid polyketide synthase (PKS) and
nonribosomal peptide synthetase (NRPS) system starting from
leucine has been proposed for the biosyntheses of 1, 2, and 4
1
7,18
(Scheme 2A).
According to the proposed biosynthesis of a
19
structurally related natural azaspirene, a similar PKS–NRPS
system can be speculated to be involved in the biosynthesis of 3
(
1) was prepared by treatment of 7a with a catalytic amount of
15
20
PdCl (CH CN) in acetone (Scheme 1B). Formation of (±)-1
(Scheme 2B).
2
3
2
involves removal of the ketal in 7a, removal of the Boc group in
the resultant 9, and formation of the pyridione ring. (±)-
Isoflavipucine (2) was synthesized via thermal isomerization of
8
-11,15
(±)-1.
(±)-Berkeleyamide D (3) was synthesized by removal
of the protective groups in 7b with aqueous HClO solution in
4
16
dichloromethane (Scheme 1C). (±)-Rubrobramide (4) was
prepared by treatment of 8c with p-toluenesulfonic acid
1
5
monohydrate (TsOH·H O).
2
Scheme 2. Proposed biosyntheses of 1, 2, and 4 (A), and 3 (B).
Inspired by the interesting biosynthesis of these natural
lactams, we designed three analogues 10−12 (Figure 2). Both
phenylflavipucine (10) and phenylisoflavipucine (11) have a
benzyl group at the C-6 position. Methylberkeleyamide D (12)
has a methyl group at the C-2 position instead of the benzyl
group in berkeleyamide D (3). Due to the similarities in the
structures and biosynthetic pathways, we speculate that
compounds 10−12 might be isolable from natural sources in the
future. Indeed, talaramide A (13), which possesses a benzyl
group in place of the methyl group in rubrobramide (4), was
recently isolated from the mangrove endophytic fungus
Scheme 1. Key Darzens reactions between isobutylglyoxal and
α-bromo-β-ketoamides (A), synthesis of (±)-1 and (±)-2 from 7a
2
1
Talaromyces sp.
(B), synthesis of (±)-3 from 7b (C), and synthesis of (±)-4 from
8
c (D).

Figure 2. Structures of phenylflavipucine (10),
phenylisoflavipucine (11), methylberkeleyamide D (12), and
talaramide A (13).
In this study, alternative syntheses of (±)-1 and (±)-4, starting
from epoxyamide 7a, and syntheses of new analogues (±)-11 and
(±)-12 were accomplished. Optical resolution of racemic
flavipucine (1) was also achieved via chiral HPLC. The
antibacterial and cytotoxic activity of racemic 1−4, 10−12, and
both enantiomers of 1 was evaluated. The structure-activity
relationships of flavipucine and its related lactams were also
investigated.
(
±)-Flavipucine (1) and (±)-rubrobramide (4) were
15
synthesized from epoxyamide 7a via alternative synthetic
routes (Scheme 3). Heating 7a at 140 °C gave an unstable and
inseparable mixture of epoxyamide 8c′ and epoxylactam 8c. The
ratio of 8c′ to 8c was determined to be approximately 2.8 : 1 by
Scheme 3. Alternative syntheses of (±)-1 and (±)-4
1
15
the H NMR spectrum. Without purification, the mixture was
treated with a catalytic amount of PdCl (CH CN) in acetone to
2
3
2
yield (±)-1 in 56% yield over two steps from 7a. The formation
of (±)-1 is explained by deprotection of the ethylene ketal in 8c′
and formation of the pyridione ring (Scheme 4A). On the other
hand, when the mixture of 8c′ and 8c was treated with a catalytic
amount of TsOH·H O, (±)-4, (±)-12, and (±)-1 were obtained in
2
1
4%, 19%, and 9% yields, respectively, over two steps from 7a.
Under acidic conditions, the tautomeric equilibrium between 8c
and 8c′ might shift toward 8c (Scheme 4B). Dehydration of 8c,
deprotection of the ethylene ketal in 15, and formation of the
1
5
tricyclic ring affords (±)-4. Deprotection of the ethylene ketal in
8
1
c, followed by intramolecular spirocyclization of 16 affords (±)-
2.
16
Scheme 4. Proposed mechanisms for formation of (±)-1 (A) and
(±)-4 and (±)-12 (B)

1
6
Following our procedure, (±)-phenylflavipucine (10) was
prepared from 7b. Thermal isomerization of 10 in toluene at
1
subtilis) and Gram-negative Escherichia coli (E. coli) were
evaluated via broth microdilution assay. The antibacterial activity
was measured following the standard methods of the Clinical and
60°C in a sealed tube gave (±)-11 in 44% yield (Scheme 5A).
Treatment of 7a with an excess amount of BF ∙Et O in
dichloromethane gave (±)-12 in 66% yield, accompanying (±)-1
in 11% yield (Scheme 5B). Compared to Scheme 3, the use of
BF ∙Et O greatly improves the yield. Deprotection of the Boc
2
2
Laboratory Standards Institute (CLSI). The minimal inhibitory
concentrations (MIC) and minimal bactericidal concentrations
(MBC) of these compounds are summarized in Table 1 (see also
Figure S9 in the Supplementary Material). Ampicillin, a
3
2
3
2
2
3-25
group by BF ∙Et O occurs to furnish 8c. Then, deprotection of the
bactericidal agent,
and chloramphenicol, a bacteriostatic
3
2
2
6
ketal group in 8c and subsequent intramolecular spirocyclization
produces (±)-12. The relative configuration of (±)-12 was
determined by NOESY correlations between H-9 and the
methylene protons of the isobutyl group at C-8 in (±)-12 (Figure
agent, were used as positive controls for the antibacterial assay.
Flavipucine (1) showed antibacterial activity against B. subtilis
with both a MIC and a MBC of 8 μg/mL. Because antibacterial
agents are generally regarded as bactericidal if the MBC is no
more than four times the MIC, the activity is bactericidal rather
than bacteriostatic. Additionally, no difference in the
2
2
3
).
antibacterial activity was observed between (±)-1, (−)-1, and (+)-
1
. Phenylflavipucine [(±)-10] exhibited weak bactericidal activity
against B. subtilis, with a MIC and MBC of 128 μg/mL. In
contrast, compounds 2−4, and 11−12 did not show antibacterial
activity against B. subtilis. These results clearly indicate that the
pyridione epoxide moiety is important for the antibacterial
activity. The substituent at the C-6 position of the pyridione ring
also influences the activity (Figure 4A). None of the compounds
tested in this study showed antibacterial activity against E. coli at
concentrations below 128 μg/mL. Gram-negative bacteria have
an outer cell membrane which is a lipid bilayer composed of
phospholipids, lipopolysaccharides, and lipid-anchored
lipoproteins. Thus, since hydrophilic compounds do not easily
pass through the hydrophobic membrane through passive
diffusion, it is expected that flavipucine (Clog P = 0.47) would
not pass through the outer membrane of E. coli sufficiently to
inhibit its growth.
Scheme 5. Syntheses of (±)-11 (A) and (±)-12 (B)
Table 1.
Antibacterial activity of synthetic compounds against B. subtilis and E.
a
coli.
B. subtilis
E. coli
Compound
MIC
MBC
MIC
MBC
(μg/mL)
(μg/mL)
(μg/mL)
(μg/mL)
(
±)-1
8
8
>128
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
(−)-1
8
8
NT
NT
Figure 3. Selected NOESY correlations in (±)-12. Selected
carbon atoms have been labeled using the IUPAC numbering
system.
(+)-1
8
8
(±)-2
(±)-3
(±)-4
>128
>128
>128
128
>128
>128
<0.5
4
>128
>128
>128
128
>128
>128
<0.5
64
>128
>128
>128
>128
>128
>128
4
Because both enantiomers of flavipucine were isolated from
microorganisms, optical resolution of (±)-1 via high performance
liquid chromatography (HPLC) using a chiral stationary phase
(±)-10
(±)-11
(±)-12
(CSP) was examined. Optical resolution of synthetic (±)-1 using
a CHIRALPAK IA column gave both enantiomers of 1 (>99%
ee, Figure S1 in the Supplementary Material). The specific
b
Ampicillin
2
2
rotation of (−)-1 [[α] = −81.5 (c 0.10, EtOH)] agrees with the
D
b
c
c
2
1
1
Chloramphenicol
NT
NT
literature for natural (−)-1 [[α] = −71.8 (c 1%, EtOH), and
[
D
2
1
2
α] = −88 (c 1%, EtOH) ]. However, the specific rotation of
D
23
a
(
+)-1 [[α] = +72.5 (c 0.10, EtOH)] was smaller than that
MIC and MBC were determined according to the methods outlined by
D
5
2
2 b
reported for natural (+)-1 [[α] = +132 (EtOH)].
the CLSI. Ampicillin and chloramphenicol were used as positive
D
c
controls. NT means “not tested.”
The antibacterial activity of racemic 1−4, 10−12, and both
enantiomers of 1 against Gram-positive Bacillus subtilis (B.

Table 2.
a
Cytotoxicity of synthetic compounds against cancer and normal cells (IC50, μM)
IC50 (μM)
Compound
A549
HCT116
Hela
TE8
HL-60
Jurkat
HEK293
MRC-5
(
(
(
(
(
(
±)-1
−)-1
+)-1
±)-2
±)-3
±)-4
32.1 ± 2.7
NT
30.4 ± 2.0
NT
40.5 ± 3.2
NT
21.6 ± 2.3
NT
1.8 ± 0.2
1.6 ± 0.1
1.7 ± 0.0
19.9 ± 1.4
28.0 ± 0.6
37.7 ± 4.6
37.3 ± 4.0
> 50
8.0 ± 0.2
NT
35.9 ± 0.7
NT
33.2 ± 2.6
NT
NT
NT
NT
NT
NT
NT
NT
> 100
> 100
> 100
> 100
> 100
> 100
6.6 ± 3.7
> 100
> 100
> 100
> 100
> 100
> 100
< 1
> 100
> 100
> 100
> 100
> 100
> 100
13.1 ± 3.7
> 100
> 100
> 100
> 100
> 100
> 100
< 1
> 50
> 50
> 50
> 50
> 50
> 50
< 1
> 50
> 50
> 50
> 50
> 50
> 50
< 1
> 50
> 50
> 50
(±)-10
(±)-11
(±)-12
> 50
> 50
> 50
> 50
b
SN-38
2.4 ± 0.1
15.3 ± 5.1
a
Fifty percent inhibitory concentrations (IC ) of cell viability after treatment with various concentration of each compound for 48 h were determined using
5
0
b
the WST-8 assay. IC50 values are expressed as the mean ± SD of triplicate experiments. NT means “not tested.” SN-38 was used as a positive control.
cells. HL-60 (human promyelocytic leukemia), and Jurkat
(human T-cell acute lymphoblastic leukemia) cells are
suspension cells. Interestingly, (±)-1 inhibited proliferation
moderately in A549, HCT116, Hela, and TE8 cells. The other
compounds did not influence proliferation of adherent cancer
cells at concentrations under 100 μM. Compound (±)-1 has
strong cytotoxic activity against HL-60 cells. No difference
between (−)-1 and (+)-1 in the cytotoxicity against HL-60 cells
was observed (Figure 4B). Although compound (±)-1 also
exhibited cytotoxicity against non-neoplastic HEK293 cells and
normal MRC-5 cells, the cytotoxicity of (±)-1 is weaker than that
of SN-38. Compounds (±)-2, (±)-3, (±)-4, and (±)-10 possess
moderate cytotoxic activity against HL-60. DNA fragmentation
was not observed in the HL-60 cells after treatment with (±)-1 for
6
h (Figure S11 in the Supplementary Material). The cell death
induced by (±)-1 was not suppressed by pretreatment with Z-
Asp-CH -DCB, an inhibitor of caspases (Figure S12 in the
2
Supplementary Material). These results suggest the possibility
that the cell death caused by (±)-1 is mediated by non-apoptotic
death mechanisms.
In this study, the syntheses and biological activities of
flavipucine and its derivatives were reported. The target
derivatives were designed based on the biosynthesis of
flavipucine and its related natural products. The compounds were
prepared via a Darzens reaction between isobutylglyoxal and α-
bromo-β-ketoamides. Of the compounds tested, flavipucine (1)
was the most potent bactericide against B. subtilis and showed
the greatest cytotoxic activity against several human cancer cells.
No significant differences in the activity of the enantiomers of
flavipucine were observed. On the other hand, significant
differences in the biological activity of flavipucine and its
derivatives were observed. Phenylflavipucine (10) demonstrated
weak bactericidal activity against B. subtilis. The other
derivatives had no antimicrobial activity. Racemic isoflavipucine
(2), berkeleyamide D (3), and rubrobramide (4) exhibited weak
cytotoxic activity against HL-60 cells. The present findings may
provide valuable information for the design and development of
novel lactam drugs. Further investigations of the mechanism of
Figure 4. Structure- activity relationship of flavipucine against B.
subtilis (A) and cytotoxic activity in human cancer cells (B)
The cytotoxic activity against six cancer cells (A549,
HCT116, Hela, TE8, HL-60, and Jurkat cells), non-neoplastic
cells (HEK293 cells) and normal cells (MRC-5 cells) was
evaluated via the WST-8 method after treatment with test
compounds for 48 h (Table 2, Figure S10 in the Supplementary
2
7
Material). SN-38, the active metabolite of irinotecan, was used
2
8
as a positive control in this study. A549 (human lung
carcinoma), HCT116 (human colon carcinoma), Hela (human
cervix epitheloid carcinoma), TE8 (human esophageal squamous
cell carcinoma), HEK293 {human embryonic kidney cells
transformed with sheared human adenovirus (Ad)5 DNA}, and
MRC (human normal diploid fibroblast) cells are all adherent

action of flavipucine are currently underway and will be reported
in due course.
Acknowledgments
This study was partly supported by a Grant-in-Aid for
Scientific Research (C) (KAKENHI No. 15K07416).
Conflicts of interest
The authors report no conflicts of interest associated with this
work.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
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Graphical Abstract
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Synthesis, antibacterial and cytotoxic
Leave this area blank for abstract info.
evaluation of flavipucine and its derivatives
a
b
a,b
a
a
Yasuha Kusakabe, Shoma Mizutani, Shogo Kamo, Tatsuki Yoshimoto, Shusuke Tomoshige, Tsuneomi
c
d
b
a,*
Kawasaki, Ryoko Takasawa, Kazunori Tsubaki, Kouji Kuramochi
a
Department of Applied Biological Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Sakyo-ku, Kyoto 606-8522, Japan.
Department of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba
78-8510, Japan.
b
c
d
2

Highlights
·
Biological activity of flavipucine and its derivatives
was evaluated.
Flavipucine displayed bactericidal activity against
Bacillus subtilis.
Flavipucine exhibited cytotoxic activity against several
cancer cells.
Flavipucine showed weak cytotoxic activity against
non-neoplastic and normal cells.
No differences in biological activity between
enantiomers of flavipucine were observed.
·
·
·
·