An efficient synthesis of SK-658 and its analogs as potent histone deacetylase inhibitors

Article abstract of DOI:10.1016/j.bioorg.2015.02.009

SK-658 is a potent histone deacetylase (HDAC) inhibitor that showed higher activity than SAHA due to the presence of extended hydrophobic group. We designed and synthesized thioester and SS-hybrid bearing SK-658 analogs as HDAC inhibitors. All the compoun

Full text of DOI:10.1016/j.bioorg.2015.02.009

Bioorganic Chemistry 59 (2015) 145–150
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
An efficient synthesis of SK-658 and its analogs as potent histone
deacetylase inhibitors
Md. Shahidul Islam a,b, , Md. Nurul Islam a,b, Md. Ashraful Hoque a,c, Norikazu Nishino a, Tamaki Kato a,
⇑
Hyun-Jung Kim d, Akihiro Ito e, Minoru Yoshida e
a Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu 808-0196, Japan
b Department of Chemistry, Faculty of Science, University of Rajshahi, Rajshahi 6205, Bangladesh
c Department of Biochemistry and Molecular Biology, Faculty of Science, University of Rajshahi, Rajshahi 6205, Bangladesh
d BioRunxInc., Seoul 110-749, Republic of Korea
e Chemical Genetics Laboratory/Chemical Genomics Research Group, RIKEN Advanced Science Institute, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 November 2014
Available online 7 March 2015
SK-658 is a potent histone deacetylase (HDAC) inhibitor that showed higher activity than SAHA due to
the presence of extended hydrophobic group. We designed and synthesized thioester and SS-hybrid
bearing SK-658 analogs as HDAC inhibitors. All the compounds were active in nano molar range and
showed higher inhibitory activity than SAHA and SK-658. Among these, disulfide compounds showed
the highest activity.
Keywords:
Histone deacetylase inhibitor
Zinc binding group
SK-658 analogs
SS-hybrid
Ó 2015 Elsevier Inc. All rights reserved.
1. Introduction
trifluoromethylketone [10], methoxymethylketone, azide, acry-
lamide, chloroacetamide, triazolyl [16], borate [17], mercaptan,
The increased focus on inhibitors of HDAC enzymes as targets
for cancer treatment originates from their ability to alter several
cellular functions. The search for compounds with anti-tumor
activities to develop novel HDAC inhibitors with potency and
safety is still going on and with no doubt, very promising area
for cancer chemotherapy. Efficacy of HDAC inhibitors is generally
considered to be dependent upon the three groups: (1) the term-
inal zinc binding group which interacts with the active site, (2) a
linker group which occupies the tube-like hydrophobic channel
and (3) a surface recognition group which interacts with residues
on the surface of the active site. The linker group has been
optimized as five or six methylene units [1,2]. Targeting surface
recognition group modification and zinc binding group optimiza-
tion, a large number of structurally diverse HDAC inhibitors have
been reported in the literatures and patented as the possible can-
didates for cancer drug. The surface binding groups reported so
far are aliphatic [3], aromatic [4], non-peptides [5], mono-peptides
[6], cyclic tetrapeptides [7–11], bicyclic tetrapeptides [12,13] etc.
and the zinc binding groups are, for instance, hydroxamic acid
[14], retro-hydroxamic acid [11], o-aminoanilide, thioether [4],
carboxyl [18], phosphate [19] and so on.
Now the burning question is to find out potent and isoform
selective HDAC inhibitors to avoid various side effects. One of the
ways is the combination of surface recognition and zinc binding
groups. Several reports, for instance, thiol based SAHA analogs
[4], chlamydocin analogs [15] etc, on the combination of surface
recognition and zinc binding groups have been published.
The release of anticancer drug, ISTODAXÒ (FK228) (Fig. 1) for
the treatment of cutaneous T-cell lymphoma (CTCL) [20] draws
special attention for sulfur containing zinc binding groups. Very
recently, we reported mono and bicyclic tetrapeptides thioester
[21] and CHAP31, trapoxin
B and HC-toxin based bicyclic
tetrapeptides disulfide [22,23] as potent histone deacetylase
inhibitors. In the present study, we report the design and synthesis
of SK-658 analog HDAC inhibitors by replacing hydroxamic acid
group with different thioesters and SS-hybrids.
2. Results and discussion
2.1. Design
ketone,
hydroxymethylketone,
carbonyl
[15],
SK-658 has the same linker and zinc binding group region as
SAHA (suberoylanilide hydroxamic acid) [24]. The IC50 values of
SK-658 and SAHA have been reported as 2.5 nM and 200 nM
⇑
Corresponding author.
E-mail address: shahidulchem@yahoo.com (Md. Shahidul Islam).
http://dx.doi.org/10.1016/j.bioorg.2015.02.009
0045-2068/Ó 2015 Elsevier Inc. All rights reserved.

146
Md. Shahidul Islam et al. / Bioorganic Chemistry 59 (2015) 145–150
Fig. 1. Some HDAC inhibitors with different structural features.
Fig. 2. Structures of designed SK-658 analog HDAC inhibitors.
respectively [6]. Therefore, SK-658 is 80-fold more active than
SAHA only due to the presence of extra hydrophobic group in
the surface binding part. Considering the potency of the surface
binding group of SK-658 and sulfur containing zinc binding group,
we designed a series of SK-658 analogs by replacing hydroxamic
acid with different thioester and SS-hybrid HDAC inhibitors
(Fig. 2).
SK-658 analogs were successfully synthesized starting from
2-amino-7-bromoheptanoic acid (H- -Ab-7-OH) (8). The con-
densation between H- -Ab-7-OH and benzyloxycarbonyl chloride
(Z–Cl) was carried out in NaOH and ether at 0 °C. The oily product,
Z- -Ab7-OH (9) was then coupled with AQ in DCM in the presence
of DCC to get the crystalline solid compound Z- -Ab7-QA (10). The
desired thioester compound Z- -Am7(Ac)-QA (1) was obtained by
L
L
L
L
L
treating compound 10 with potassium thioacetate (AcSK) in DMF
at room temperature (Scheme 2).
2.2. Synthesis
The thioester, Z-L-Am7(Ac)-QA (1) was treated with MeNH2/
MeOH in DMF to obtain the corresponding thiol (mercaptan). The
thiol was treated separately with 2-(2-methoxyethoxy)acetyl chlo-
SK-658 was synthesized starting from protected
L-amino sube-
ric acid Z-
L
-Asu(OtBu)-OH (5). Compound 5 was coupled with
ride, 2-marcaptoethanol and iodine to obtain Z-
(2), Z- -Am7(betaMe)-QA (3) and (Z- -Am7(S-)-QA)2 (4) respec-
tively (Scheme 3).
L-Am7(AcEtMe)-QA
8-amino quinoline (AQ) in anhydrous dichloromethane (DCM) in
the presence of coupling agent DCC at room temperature to yield
L
L
Z-L
-Asu(OtBu)-QA (6). After deprotection of tertiary butoxy group
All the synthesized compounds were characterized by high
resolution FAB-MS and high performance liquid chromatography
(HPLC). The purity of the compounds was determined by HPLC
analysis and the synthesized compounds showed purity 97–100%.
by TFA, hydroxamic acid was incorporated by reacting with hydro-
xyl amine hydrochloride (HClÁH2NOH) in presence of coupling
agent BOP to yield SK-658 (see Scheme 1).

Md. Shahidul Islam et al. / Bioorganic Chemistry 59 (2015) 145–150
147
Scheme 1. Synthesis of SK-658. Reagents and conditions: (a) DCC, 8-aminoquinoline, 16 h, 25 °C, 75%; (b) TFA, 3 h, 25 °C, 86%; (c) DMF, HClÁH2NOH, benzotriazol-
1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), DIEA, 30 min, 25 °C, 63%.
Scheme 2. Synthesis of designed compound 1. Reagents and conditions: (a) Z–Cl, NaOH (aq), ether, 0 °C, 3 h, 81%; (b) 8-aminoquinoline, DCC, DCM, 86%; (c) AcSK, DMF, 12 h,
68%.
Scheme 3. Synthesis of designed compounds 2–4. Reagents and conditions: (a) 2-(2-methoxyethoxy)acetyl chloride, MeNH2/MeOH, DMF, 16 h, 25 °C, 27%; (b)
2-marcaptoethanol, MeNH2/MeOH, DMF, I2/EtOH, 5 h, 25 °C, 60%; (c) MeNH2/MeOH, DMF, I2/EtOH, 5 h, 25 °C, 86%.
2.3. Enzyme inhibition and biological activity
293T cells [25] with the aid of 0.1 mM of dithiothreitol (DTT) which
is known to reduce S–S bond to sulfhydryl group. In addition, to
know the inhibitory activity of these compounds in cell based con-
dition, we carried out p21 promoter assay according to the
The synthesized compounds were assayed for HDAC inhibitory
activity using HDAC1, HDAC4 and HDAC6 enzymes prepared by

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Md. Shahidul Islam et al. / Bioorganic Chemistry 59 (2015) 145–150
Table 1
performed using silica gel 60 (230–400) eluting with solvents as
indicated. All compounds were routinely checked by thin layer
chromatography (TLC) or high performance liquid chromatography
(HPLC). TLC was performed on aluminum-backed silica gel plates
(Merck DC-Alufolien Kieselgel 60 F254) with spots visualized by
UV light. Analytical HPLC were performed on a Hitachi instrument
equipped with a chromolith performance RP-18e column. The
mobile phases used were A: H2O with 0.1% TFA, B: CH3CN with
0.1% TFA using a solvent gradient of A–B over 15 min with detec-
tion at 220 nm with a flow rate of 2 mL/min. FAB-mass spectra
and high resolution mass spectra (HRMS) were measured on a
JEOL JMS-SX 102A instrument.
HDAC inhibitory activity and p21 promoter assay data of synthesized and reported
compounds.
Compounds HPLC
retention
IC50 (nM)
p21 promoter
assay EC1000
(nM)
time (min)
HDAC1 HDAC4 HDAC6
SAHA
SK-658
1
2
3
4
–
290
10
47
19
4.9
8.2
340
11
18
18
2.0
3.4
270
45
34
29
3.2
7.5
1200
12
49
61
82
6.36
7.68
8.19
7.88
10.76
7800
The IC50 and EC1000 values were the means of at least three independent
experiments.
4.2. Synthesis of Z-L-Asu(NHOH)-QA (SK-658)
4.2.1. Synthesis of Z-
L
-Asu(OtBu)-QA (6)
-Asu(OtBu)-OH (5) (0.759 g, 2 mmol)
To a chilled solution of Z-
L
literature [15]. Detailed experimental procedure for the prepara-
tion and assay performed are being explained in Section 4. The
results of HDAC inhibitory activity and the p21 promoter assay
of the compounds are shown in Table 1.
The synthesized compounds were active in nano molar range
against HDAC1, 4 and 6 in both cell free and cell based conditions
and were more active than the approved anticancer drug, SAHA.
The higher inhibitory activity of SS-hybrid compounds 3 and 4
than their mother compound, SK-658 implies that the sulphydryl
group has strong affinity to the active site compared to hydroxamic
acid group. This observation was supported by our previous work
[16].
In cell-free conditions, SS-hybrid compounds 3 and 4 were more
active than thioester compounds 1 and 2. The similar observation
was also reported by Nishino and co-workers [26]. Although both
thioester and SS-hybrid groups reduced to sulfhydryl group by
DTT, the difference in activity may be due to the difference in
reduction mechanism. Hogue et al. reported that the inhibitory
activity of disulfide and thioester were increased in different
extent in presence of DTT. They assumed that the disulfide group
reduced completely while the thioester reduced partially in
presence of DTT [22].
in anhydrous DCM (4 mL), DCC (0.206 g, 1 mmol) was added and
stirred for 1 h. 8-Aminoquinoline (0.346 g, 2.4 mmol) was added
and stirred at room temperature for 3 h. The reaction mixture
was cooled again and DCC (0.289 g, 1.4 mmol) was added and stir-
red for 12 h at room temperature. After completion of the reaction,
DCM was evaporated and the residue was dissolved in EtOAc and
successfully washed with 10% citric acid, 4% NaHCO3 and brine
respectively. The ethyl acetate solution was dried over anhydrous
MgSO4 and concentrated to remain an oily substance which was
purified by silica gel chromatography using a mixture of chloro-
form and methanol (99:1) to yield Z-
1.50 mmol, 75%).
L
-Asu(OtBu)-QA (6) (0.76 g,
4.2.2. Preparation of Z-
L
-Asu-QA (7)
Z-
L
-Asu(OtBu)-QA (6) (0.430 g, 0.85 mmol) was dissolved in TFA
(3 mL) completely and kept at room temperature for 3 h with occa-
sional sacking. After completion of the tertiary butoxide group
de-protection, TFA was evaporated and the residue was crystal-
lized with ether/pet ether to yield Z-Asu-QA (7) (0.33 g, 0.73 mmol,
86%).
However, in cell based condition the reverse trend was
observed. This may be due to the different reduction mechanism
inside the cell [25]. The least in vivo activity of compound 4 can
be explained by transport mechanism of drug molecules through
the cell membrane. Generally lipid soluble molecule easily diffuses
across the cell membrane. Small drug molecule diffuse more
rapidly than large drug molecule [27]. As a large molecule
compared to other compounds (1–3), it is not favorable for this
compound 4 to diffuse across the cell membrane easily and
ultimate results is its less activity.
4.2.3. Synthesis of SK-658
To a solution of Z-
(4 mL), HClÁH2NOH (49 mg, 0.7 mmol), BOP reagent (0.232 g,
0.525 mmol), DIEA (274 L, 1.58 mmol) were added and stirred
L-Asu-QA (7) (0.160 g, 0.35 mmol) in DMF
l
for 30 min at room temperature. After completion of the reaction,
DMF was evaporated and the residue was washed with water and
crystallized with ether to yield Z-L-Asu (NHOH)-QA (0.103 g,
0.22 mmol, 63%). Analytical RP HPLC, retention time 6.36 min, pur-
ity 97%. HRMS (FAB, m/z): (M + H)+ found: 465.2141 (calcd for
C25H29N4O5: 465.2138).
3. Conclusion
4.3. Synthesis of Z- -Am7(Ac)-QA (1)
L
In this paper, we describe the designed and easy synthesis of
SK-658 and its analogs having thioesters and SS-hybrid groups as
HDAC inhibitor. All the compounds were active in nano molar
range. Among these, disulfide compounds 3 and 4 showed the
highest activity. Due to easy synthesis, excellent activity and
stability, these compounds demanding more advanced research
to be potential drug candidates.
4.3.1. Synthesis of Z-
L
-Ab7-OH (9)
To a cooled solution of H-
L
-Ab7-OH (2-amino-7-bromohep-
tanoic acid) (8) (2.23 g, 10 mmol) in 1 M aqueous sodium hydrox-
ide (12 mL) containing ether (3 mL), Z–Cl (0.42 mL, 3 mmol) was
added and stirred for 15 min. To this solution, 1 M aqueous sodium
hydroxide (10 mL) and Z–Cl (1.7 mL, 12 mmol) were added in
separate four portions in every 15 min with stirring. After comple-
tion of the reaction, the aqueous phase was washed with ether
while pH of the aqueous layer was maintained in the basic region.
The acid was extracted into ethyl acetate at pH 3–4 by using solid
citric acid. The organic phase was dried with anhydrous magne-
4. Experimental
4.1. General
sium sulfate, filtered and evaporated to get the oily Z-L-Ab7-OH
Unless otherwise noted, all solvents and reagents were reagent
grade and used without purification. Flash chromatography was
(9) (3.57 g, 10 mmol, 100%). Analytical RP HPLC, retention time
7.19 min, 81%.

Md. Shahidul Islam et al. / Bioorganic Chemistry 59 (2015) 145–150
149
4.3.2. Synthesis of Z-L-Ab7-QA (10)
4.6. Synthesis of (Z-L-Am7(S-)-QA)2 (4)
To a cooled solution of Z-
L-Ab7-OH (9) (3.45 g, 9.7 mmol) in
anhydrous DCM (20 mL), DCC (0.6 equiv, 1.20 g, 5.8 mmol) was
added and stirred for 1 h. 8-aminoquinoline (1.39 g, 9.7 mmol)
was added and stirred for 3 h. The reaction mixture was cooled
again and DCC (0.6 equiv, 1.20 g, 5.8 mmol) was added and stirred
for 12 h at room temperature. After completion of the reaction,
DCM was evaporated and the residue was dissolved in ethyl
acetate and successively washed with 10% citric acid, 4% sodium
bicarbonate and brine respectively. The ethyl acetate solution
was dried over anhydrous MgSO4 and concentrated to remain an
oily substance which was purified by silica gel chromatography
using a mixture of chloroform and methanol (99:1) and crystal-
lized with a mixture of ether and petroleum ether (1:6, v/v) to yield
To a cooled solution of Z-
L
-Am7(Ac)-QA (1) (0.48 g, 1 mmol)
in DMF (10 mL), 40% solution of MeNH2/methanol (1 mL,
9 mmol) was added and stirred at room temperature for 5 h
under argon. DMF was evaporated and the residue was
dissolved in DMF (25 mL) to which iodine (1 equiv, 0.253 g,
1 mmol) solution in ethanol was added drop wise. After comple-
tion of the reaction, DMF was evaporated and the residue was
dissolved in ethyl acetate and washed with brine. The ethyl
acetate solution was dried over anhydrous MgSO4 and concen-
trated to an oily substance which was subjected to gel filtration
to get the crystalline solid (Z-L-Am7(S-)-QA)2 (4) (0.38 g,
0.86 mmol, 86%). Analytical RP HPLC, retention time 7.88 min,
purity 100%. HRMS (FAB, m/z): (M + H)+ found: 873.3457 (calcd
for C48H53N6O6S2: 873.3468).
Z-
L-Ab7-QA (10) (4.03 g, 8.34 mmol, 86%). Analytical RP HPLC,
retention time 8.07 min, 100%.
4.7. HDACs preparation and enzyme activity assay
4.3.3. Synthesis of Z-L-Am7(Ac)-QA (1)
To a solution of Z-
L
-Ab7-QA (10) (3.81 g, 7.9 mmol) in DMF
In a 100-mm dish, 293T cells (1–2 Â 106) were grown for 24 h
(63 mL), potassium thioacetate (1.5 equiv, 1.35 g, 11.8 mmol) was
added and stirred for 12 h at room temperature. After completion
of the reaction, DMF was evaporated and the residue was dissolved
in ethyl acetate and successively washed with 10% citric acid and
brine. The ethyl acetate solution was dried over anhydrous
MgSO4 and concentrated to remain an oily substance which was
purified by silica gel chromatography using a mixture of chloro-
form and methanol (99:1) and crystallized with a mixture of ether
and transiently transfected with 10 lg each of the vector
pcDNA3-HDAC1 for human HDAC1, pcDNA3-HDAC4 for human
HDAC4, or pcDNA3-mHDA2/HDAC6 for mouse HDAC6, using the
LipofectAMINE2000 reagent (Invitrogen). After successive cultiva-
tion in DMEM for 24 h, the cells were washed with PBS and lysed
by sonication in lysis buffer containing 50 mM Tris–HCl (pH 7.5),
120 mM NaCl, 5 mM EDTA, and 0.5% NP40. The soluble fraction col-
lected by micro centrifugation was precleared by incubation with
protein A/G plus agarose beads (Santa Cruz Biotechnologies, Inc.).
After the cleared supernatant had been incubated for 1 h at 4 °C
and petroleum ether (1:6, v/v) to yield Z-L-Am7(Ac)-QA (1) (2.57 g,
5.36 mmol, 68%). Analytical RP HPLC, retention time 7.68 min, pur-
ity 100%. HRMS (FAB, m/z): (M + H)+ found: 480.1937 (calcd for
with 4 lg of an anti-FLAG M2 antibody (Sigma–Aldrich Inc.) for
C
26H29N3O4S: 480.1957).
4.4. Synthesis of Z- -Am7(AcEtMe)-QA (2)
To a cooled solution of Z- -Am7(Ac)-QA (1) (1.17 g, 2.45 mmol)
HDAC1, HDAC4 and HDAC6, the agarose beads were washed three
times with lysis buffer and once with histone deacetylase buffer
consisting of 20 mM Tris–HCl (pH 8.0), 150 mM NaCl, and 10%
glycerol. The bound proteins were released from the immune com-
L
L
plex by incubation for 1 h at 4 °C with 40
(Sigma–Aldrich Inc.) in histone deacetylase buffer (200
supernatant was collected by centrifugation. For the enzyme assay,
10 L of the enzyme fraction was added to 1 L of fluorescent sub-
strate (2 mM Ac-KGLGK(Ac)-MCA) and 9 L of histone deacetylase
buffer, and the mixture was incubated at 37 °C for 30 min. The
reaction was stopped by the addition of 30 L of trypsin (20 mg/
lg of the FLAG peptide
in DMF (25 mL), 40% solution of MeNH2/MeOH (3 mL, 27 mmol)
was added and stirred at room temperature for 5 h under argon.
DMF was evaporated and the residue was dissolved in pyridine
(5 mL) to which 2-(2-methoxyethoxy)acetyl chloride (1 equiv,
2.45 mmol, 0.373 g) was added and stirred overnight at room tem-
perature. After completion of the reaction, pyridine was evapo-
rated and the residue was dissolved in ethyl acetate and washed
with brine. The ethyl acetate solution was dried over anhydrous
MgSO4 and concentrated to an oily substance which was subjected
lL). The
l
l
l
l
mL) and incubated at 37 °C for 15 min. The released amino methyl
coumarin (AMC) was measured using a fluorescence plate reader.
DTT was added simultaneously with drugs to the enzyme solu-
tions. The 50% inhibitory concentrations (IC50) were determined
as the means with SD calculated from at least three independent
dose response curves.
to gel filtration to get the oily Z-L-Am7(AcEtMe)-QA (2) (0.37 g,
0.67 mmol, 27%). Analytical RP HPLC, retention time 8.19 min,
purity 100%. HRMS (FAB, m/z): (M + H)+ found: 554.2350 (calcd
for C29H35N3O6S: 554.2325).
4.8. The p21 promoter assay
4.5. Synthesis of Z-L-Am7(betaMe)-QA (3)
The human wild-type p21 promoter luciferase fusion plasmid,
WWP-Luc, was a kind gift from Dr. B. Vogelstein. A luciferase
reporter plasmid (pGW-FL) was constructed by cloning the 2.4 kb
genomic fragment containing the transcription start site into
HindIII and SmaI sites of the pGL3-Basic plasmid (Promega Co.,
Madison, WI). Mv1Lu (mink lung epitherial cell line) cells were
transfected with the pGW-FL and a phagemid expressing neomy-
cin/kanamycin resistance gene (pBK-CMV, Stratagene, La Jolla, CA)
with the Lipofectamine reagent (Life Technology, Rockville, MD
To a cooled solution of Z-
L
-Am7(Ac)-QA (1) (0.80 g, 1.67 mmol) in
DMF (17 mL), 40% solution of MeNH2/MeOH (2 mL, 18 mmol) was
added and stirred at room temperature for 5 h under argon. DMF
was evaporated and the residue was dissolved in DMF (50 mL) to
which 2-marcaptoethanol (10 equiv, 16.7 mmol, 1.17 mL) was
added and stirred. To this reaction mixture, iodine (5.5 equiv,
2.33 g, 9.19 mmol) solution in ethanol was added drop wise. After
completion of the reaction, DMF was evaporated and the residue
was dissolved in ethyl acetate and washed with brine. The ethyl
acetate solution was dried over anhydrous MgSO4 and concentrated
to an oily substance which was subjected to gel filtration to get the
USA). After the transfected cells had been selected by 400 lg/mL
Geneticin (G418, Life Technology), colonies formed were isolated.
One of the clones was selected and named MFLL-9. MFLL-9
expressed a low level of luciferase, of which activity was enhanced
by TSA in a dose-dependent manner. MFLL-9 cells (1 Â 105) cul-
tured in a 96-well multi-well plate for 6 h were incubated for
oily Z-L-Am7(betaMe)-QA (3) (0.52 g, 1.01 mmol, 60%). Analytical
RP HPLC, retention time 7.88 min, purity 100%. HRMS (FAB, m/z):
(M + H)+ found: 514.1833 (calcd for C26H31N3O4S2: 514.1834).

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Md. Shahidul Islam et al. / Bioorganic Chemistry 59 (2015) 145–150
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Conflict of interest
The authors declare that they have no conflict of interest.
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This study was supported by Kitakyushu Foundation for the
Advancement of Industry, Science and Technology (FAIS), Japan
Student Services Organization (JASSO) and Saneyoshi Scholarship
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Appendix A. Supplementary material
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Amino Acids 46 (2014) 2435–2444.
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009.
[22] M.A. Hoque, T. Arai, N. Nishino, H.J. Kim, A. Ito, M. Yoshida, Bioorg. Med. Chem.
Lett. 22 (2012) 6770–6772.
[23] M.A. Hoque, M.A. Islam, M.N. Islam, T. Kato, N. Nishino, A. Ito, M. Yoshida,
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