Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142

Article abstract of DOI:10.1021/acs.orglett.5b02842

JBIR-141 (1) and JBIR-142 (2) were discovered as potent Foxo3a inhibitors that consist of three quite unique substructures, a 1-((dimethylamino)ethyl)-5-methyl-4,5-dihydrooxazole-4-carboxylic acid that is originated from Ala-Thr amino acid residues, a 3-acetoxy-4-amino-7-(hydroxy(nitroso)amino)-2,2-dimethylheptanoic acid, and an α-acyl tetramic acid fused with a 2-methylpropan-1-ol moiety. Their structures involving absolute configurations were determined by spectroscopic data, chemical degradation, anisotropy methods, and LC-MS analyses of diastereomeric derivatives. Compounds 1 and 2 exhibited specific inhibition against Foxo3a transcriptional activity with IC₅₀ values of 23.1 and 166.2 nM, respectively.

Full text of DOI:10.1021/acs.orglett.5b02842

Letter
pubs.acs.org/OrgLett
Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142
Teppei Kawahara,† Noritaka Kagaya,‡ Yuichi Masuda,§ Takayuki Doi,§ Miho Izumikawa,† Kumiko Ohta,⊥
Atsushi Hirao,⊥ and Kazuo Shin-ya*,‡
†Japan Biological Informatics Consortium (JBIC), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan
‡National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan
§Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan
⊥Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University,
Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan
S
* Supporting Information
ABSTRACT: JBIR-141 (1) and JBIR-142 (2) were discovered
as potent Foxo3a inhibitors that consist of three quite unique
substructures, a 1-((dimethylamino)ethyl)-5-methyl-4,5-dihy-
drooxazole-4-carboxylic acid that is originated from Ala-Thr
amino acid residues, a 3-acetoxy-4-amino-7-(hydroxy(nitroso)-
amino)-2,2-dimethylheptanoic acid, and an α-acyl tetramic acid
fused with a 2-methylpropan-1-ol moiety. Their structures
involving absolute configurations were determined by spectro-
scopic data, chemical degradation, anisotropy methods, and
LC−MS analyses of diastereomeric derivatives. Compounds 1
and 2 exhibited specific inhibition against Foxo3a transcriptional
activity with IC50 values of 23.1 and 166.2 nM, respectively.
he Foxo3a transcription factor belongs to the forkhead
Tfamily of class O (Foxo) that plays an important role in
energy metabolism, cell cycle arrest, apoptosis, antioxidation, and
DNA repair by regulating target genes1−4 or direct protein−
protein interactions.5 Although development of BCR−ABL
tyrosine kinase inhibitors has significantly improved the therapy
of chronic myeloid leukemia (CML), it is not absolutely
conquered because a small population of cancer stem cells
gives rise to drug resistance and CML recurrence.6 Recent
studies proved that Foxo3a is critical for the survival and self-
renewal of hematopoietic stem cells7 and leukemia stem cells.8,9
In CML model mice, imatinib administration combined with
Foxo3a ablation successfully reduced leukemia-initiating cells
Figure 1. Structures of JBIR-141 (1) and JBIR-142 (2).
were isolated from the culture broth of a soil-derived Streptomyces
sp. 4587H4S (see the Supporting Information). Herein, the
isolation, structure determination, and biological evaluation of 1
and 2 are presented.
JBIR-141 (1) was obtained as a colorless powder, having a
molecular formula C31H50N6O11, determined by positive mode
HRESIMS at m/z 683.3641 [M + H]+ (calcd for C31H51N6O11,
683.3616). The UV data displayed a peak absorption band at 243
and 288 nm, which suggested the presence of an α-acyl tetramic
acid moiety. The IR spectrum exhibited absorption bands for
hydroxy (3350 cm−1), ester carbonyl (1733 and 1222 cm−1),
amide carbonyl (1616 cm−1), and nitrosohydroxyamino (1457
cm−1) groups.12−15
(LICs). In LICs, PI3K-Akt signaling, an upstream negative
regulator of Foxo3a, is suppressed by TGF-β signaling, and
activated Foxo3a works for stem cell maintenance in the
nucleus.8 Depletion of Foxo3a could induce maturation of
LICs and subsequent cell death.9 A highly malignant population
of cancer stem cells has been reported to contain a large amount
of β-catenin in the nucleus, which can change the function of
transcription factors by binding to them. A complex of β-catenin
and Foxo3a exerts this function on stem cell maintenance
without inducing apoptosis.10 Because difficulties in the
treatment of CML with imatinib are brought on by quiescent
and undifferentiated cancer stem cells, Foxo3a is expected to be a
promising target for eradicating CML stem cells.
During a screening program for Foxo3a inhibitors from our
natural product library consisting of over 250000 samples,11 two
potent compounds, JBIR-141 (1) and JBIR-142 (2) (Figure 1),
Received: October 1, 2015
Published: October 23, 2015
© 2015 American Chemical Society
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Letter
The appearance of several amide carbonyl carbon signals in the
13C NMR spectrum intimated the peptide-like nature of the
molecule. The planar structure of 1 was mainly elucidated based
on the analyses of DQF-COSY and CT-HMBC16 spectra (Figure
2 and Table S1).
and 99.9, along with a characteristic UV absorption for tetramic
acid chromophore (UV 288 nm), suggested that an α-acyl 1,5-
dimethyltetramic acid moiety17,18 was connected to the valinic
acid moiety.
The remaining one nitrogen and two oxygen atoms, calculated
from the molecular formula, were allowed to be a nitro-
sohydroxyamino group at C-7 because of the specific IR
absorption (1457 cm−1). Hence, the planar structure of 1 was
determined as shown in Figure 1.
The molecular formula of JBIR-142 (2) was determined as
C31H50N6O12 on the basis of HRESI(+)MS, suggestive of an
oxygenated derivative of 1. This difference was assigned as 6-OH
in 2 by the analyses of 1D and 2D NMR spectra (Figure S2 and
Table S1), in which a diagnostic signal (δH 4.26, δC 67.0) for an
oxymethine was observed. Therefore, the planar structure of 2
was determined being a 6-hydroxy 1.
Figure 2. Key correlations in DQF-COSY (bold lines) and CT-HMBC
(arrows) spectra of JBIR-141 (1).
Since 2 possesses an additional chiral center to 1, 2 was
employed for the determination of the absolute configuration.
The desired chemical degradation protocol for the tetramic acid
moiety was previously reported.17,18 According to the protocol,
compound 2 was treated with sodium periodate followed by acid
hydrolysis to afford an N-methylalanine residue. The absolute
structure of the obtained N-methylalanine was determined to be
S by the advanced Marfey’s method19,20 (For detailed
procedures, see the Supporting Information). Consequently,
the absolute configuration at C-25 was established as S.
As a congener of 2, inactive compound 3 (there were no
inhibitory activities at the concentration of 5 μM, Figure 6) was
isolated together with 1 and 2 (detailed isolation and structure
determination of 3 are described in the Supporting Information).
Since 3 was considered to be a good compound for the
establishment of the absolute configuration of a series of these
compounds, chemical degradation was performed on 3 (Scheme
1). To determine the absolute configuration of the remaining
chiral centers, compounds 4 and 5 (partial racemic form) were
obtained by alkaline hydrolysis of 3 followed by chromatographic
The 1H sequence from an oxymethine proton H-3 (δH 5.56, δC
79.0) through a nitrogen-bonded methine proton H-4 (δH 3.93,
δC 50.9), methylene protons H2-5 (δH 1.77, 1.26), and H2-6 (δH
1.75) to deshielded nitrogen-substituted methylene protons H2-
7 (δH 3.95 and 3.90, δC 57.5), together with HMBC correlations
from singlet methyl protons H3-8 (δH 1.13) and H3-9 (δH 1.03)
to an ester carbonyl carbon C-1 (δC 172.2), a quaternary carbon
C-2 (δC 47.2), and an oxymethine carbon C-3 established the
presence of a 4,7-diamino-3-hydroxy-2,2-dimethylheptanoic acid
moiety. Additional HMBC correlations from H-3 and an acetic
methyl proton H3-11 (δH 2.14) to a carbonyl carbon C-10 (δC
172.2) indicate that an acetoxy group is located at C-3.
Methyl protons H3-30 (δH 1.05) and H3-31 (δH 1.06) were
1H−13C long-range coupled to each other and commonly
coupled to a methine carbon C-29 (δC 33.1) and an oxymethine
carbon C-28 (δC 80.5). Additional 1H−13C long-range couplings
from an oxymethine proton H-28 (δH 6.15) and a methine
proton H-29 (δH 2.18) to an α,β-unsaturated carbonyl carbon C-
27 (δC 192.6) and from H-28 to the ester carbonyl carbon C-1
proved that a 2-hydroxy-3-methylbutanoic acid (valinic acid)
residue is substituted at the position of C-1 through an ester
bond.
Scheme 1. Procedures for the Degradation of 3
The 1H sequence from an α-methine proton H-13 (δH 3.68, δC
75.0) to methyl protons H3-15 (δH 1.11) through an oxymethine
proton H-14 (δH 4.90) and HMBC correlations between H-13
and an amide carbonyl carbon C-12 (δC 172.2) predicted the
presence of a threonine-like moiety. 1H−13C long-range
couplings from H-13 and H-14 to highly low-field shifted
quaternary carbon C-16 (δC 172.4) indicated a methyloxazoline
residue, which was confirmed by acid hydrolysis vide infra.
HMBC couplings from methyl protons H3-18 (δH 1.34) to a
nitrogen-bonded methine carbon C-17 (δC 59.8) and C-16 and
nitrogen-substituted gem-dimethyl protons H3-19 (δH 2.34) and
H3-20 (δH 2.34) to the methine carbon C-17 established that a
dimethylamino ethane moiety is substituted at the C-16 position.
HMBC correlations from the methine proton H-4 to C-12
proved that a 1-((dimethylamino)ethyl)-5-methyl-4,5-dihy-
drooxazole-4-carboxylic acid substructure is substituted at C-4
through amide bond.
1H−13C long-range couplings from H3-26 (δH 1.25) to an
oxygenated sp2 carbon C-24 and a nitrogen-bearing methine
carbon C-25 (δC 62.4) and from an N-methyl proton H3-21 (δH
2.91, δC 26.6) to an amide carbonyl carbon C-22 (δC 173.9) and
C-25 were observed. In addition to these HMBC correlations,
the characteristic 13C chemical shifts of δC 190.1, 194.9, 174.2,
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1
purification. For planar structure elucidation of 5, see the
Supporting Information.
by the J-based configuration analysis using vicinal H−1H and
long-range 1H−13C coupling constants.23,24 At the C-4/C-5 axis,
a large coupling constant between H-4 and Hb-5 (8.0 Hz)
Compound 4 was acid hydrolyzed (6 N HCl, 110 °C, 16 h),
and the solution was dried with blown air. For the assignment of
the stereochemistry at C-17, a chromatographic analysis
determination using phenylglycine methyl ester (PGME)
derivatives was applied.21,22 The hydrolysate was reacted with
(S)- or (R)-PGME, and the amide products were analyzed by
RP-HPLC−MS. The retention times of (S)- and (R)-PGME
derivatives (tR 7.4 and 8.0 min, respectively) were matched with
those of corresponding (S)- and (R)-PGME derivatives of
synthetic N,N-dimethyl-L-alanine standards, indicating that 6 is
in the L-form. Thus, the absolute configuration of C-17 was
established as S.
3
indicated the anti orientation of H-4/Hb-5. A small JH−C
coupling constant (3JHa‑5‑C‑3 < 3 Hz) obtained from the J-
resolved HMBC-225 spectrum showed Ha-5 and C-3 are in the
gauche orientation. These results revealed that C-3/C-6 and 4-
N/Ha-5 are in anti orientations, as shown in Figure 4. For the C-
The absolute configuration of C-13 and C-14 in the threonine
residue were determined as 13S and 14R by LC−MS analyses in
the acid hydrolysate of 4 compared with those of the threonine
standard derivatives (advanced Marfey’s method, see the
Supporting Information).19
Figure 4. J-based configuration analysis of 8.
To obtain 8 as a main component except for amino acid
residues, the acid hydrolysate (6 N HCl, 110 °C, 16 h) of 4 was
purified by RP-HPLC preparation. The molecular formula of 8
was revealed as C9H16ClNO3 by HRESIMS. The nitro-
sohydroxyamino functional group was converted into a chlorine
atom whose existence was further supported by the intensity of
the isotope peaks’ ratio (3:1). The planar structure of 8 was
established by the analysis of DQF-COSY and CT-HMBC
spectra. COSY correlations from an oxymethine proton H-3
(δH/C 3.63/82.6) to chlorinated methylene protons H2-7 (δH/C
3.56, 3.53/50.0) through nitrogen-substituted methine proton
H-4 (δH/C 3.42/57.9), aliphatic methylene protons H2-5 (δH/C
2.06, 1.59/38.9), and an oxymethine proton H-6 (δH/C 3.99/
71.7) and HMBC correlations from gem-methyl protons H3-8
and H3-9 (δH/C 1.14/22.9 and 1.05/18.1, respectively) to an
oxymethine carbon C-3, a quaternary carbon C-2, and a carbonyl
carbon C-1 (δC 182.5) were observed. The relatively low field
shifted 13C chemical shift value against ordinal lactone or lactam
functions along with the lack of low field shifted (acylated shift)
1H chemical shift values at C-3 and C-6 in 8 were suitable to
judge the presence of a γ-lactam ring (Figure S4 and Table S2).
Thus, the planar structure of 8 was established to be a 5-(3-
chloro-2-hydroxypropyl)-4-hydroxy-3,3-dimethyl-2-pyrrolidi-
none.
5/C-6 axis, the large 1H−1H coupling constant (7.5 Hz) between
2
Hb-5 and H-6 and a small JC−H coupling constant (<3 Hz)
between Ha-5 and C-6 inferred that C-4/C-7 and Ha-5/6-O are
in anti orientations. Given these information, the relative
configuration of 8 was deduced as 3R*, 4S*, 6R*.
Determination of the absolute configuration was attempted by
derivatizing 8 with (R)- and (S)-α-methoxy-α-(trifluoromethyl)-
phenylacetyl (MTPA) chloride and applying for the modified
Mosher’s method. Compound 8 was treated with (R)- and (S)-
MTPACl in pyridine to give (S)- and (R)-MTPA diester
derivatives, respectively. The stereochemical determination was
based on the chemical shift differences of the protons as shown in
Figure 5. The Δδ values (δS − δR) of the methyl protons of C-2
The relative configuration of the C-3/C-4 axis in 8 was
determined by NOESY (Figure 3). Strong NOESY correlations
of H-3/H3-8 and H-4/H3-9 were observed, whereas the
correlation of H-3/H3-9 was observed weakly, which was
indicative that H-4 is located on the same side as C-9 and the
opposite side of H-3 and C-8 on the γ-lactam ring. Thus, the
relative configurations of C-3 and C-4 were deduced as 3R* and
4S*. The relative configuration of C-4/C-5/C-6 was established
Figure 5. Δδ values [Δδ (in ppm) = δS − δR] obtained for the (S)- and
(R)-MTPA diesters of 8.
(+0.08, + 0.21) showed positive, while those of H-4 (−0.03) and
one of H2-5 (−0.03) were negative, thus suggesting the 3R-
configuration. The positive Δδ value of one of H2-5 (+0.05) and
negative Δδ values of H2-7 (−0.14, −0.16) were interpreted as
the 6R configuration. Thus, the absolute configuration of 8 was
consequently assigned to be 3R,4S,6R.
Compound 5 was degradated by sodium periodate to yield 2-
hydroxy-3-methylbutanoic acid (valinic acid, 9), whose absolute
configuration was determined to be S by the chromatographic
analyses of the PGME derivatives (see the Supporting
Information). The retention times of (R)- and (S)-PGME
derivatives of 9 (tR 13.8 and 14.2 min, respectively) were
matched with those of (R)- and (S)-PGME derivatives of
authentic (S)-2-hydroxy-3-methylbutanoic acid. Therefore, the
absolute configuration of C-8 of 5 was established to be S. Hence,
the absolute configurations of a series of unique novel
compounds in this study were defined as shown in Figure 1.
Figure 3. Key NOESY correlations (arrow) and 1H−1H coupling
constants of 8.
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Compounds 1 and 2 exhibited exceptionally potent specific
inhibition against Foxo3a transcriptional activity in a cell-based
reporter assay, while compound 3 possessed no detectable
activity. The results are summarized in Figure 6, and IC50 values
Ministry of Economy, Trade and Industry (METI) and in part by
a grant “Project for Development of Innovative Research on
Cancer Therapeutics (P-DIRECT)” from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT).
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02842.
Experimental details and characterization data (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: k-shinya@aist.go.jp.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported in part by a grant “Project focused on
developing key technologies for discovering and manufacturing
drugs for next-generation treatment and diagnosis” from the
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DOI: 10.1021/acs.orglett.5b02842
Org. Lett. 2015, 17, 5476−5479