Synthesis and structure elucidation of polyphenols containing the N′-methyleneformohydrazide scaffold as aurora kinase inhibitors

Full text of DOI:10.1002/mrc.4611

Synthesis and structure elucidation of polyphenols containing the Nʹ-
methyleneformohydrazide scaffold as aurora kinase inhibitors
Short title: Examination of Nʹ-methyleneformohydrazide-containing polyphenols
Dongsoo Koh,1,† Yearam Jung,2, † Seunghyun Ahn,2 Kenneth Hun Mok,3 Soon Young Shin,4,*
and Yoongho Lim2,*
1Department of Applied Chemistry, Dongduk Women’s University, Seoul 136-714, Korea
2Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701,
Korea
3School of Biochemistry and Immunology, Trinity College, University of Dublin, Dublin 2,
Ireland
4Department of Biological Sciences, Konkuk University, Seoul 143-701, Korea
† D. Koh and Y. Jung contributed equally to this work.
Corresponding authors:
Prof. Yoongho Lim, Division of Bioscience and Biotechnology, Konkuk University, 12
0 Neungdong-ro, Gwangjin-gu, Seoul, Korea 05029. Email: yoongho@konkuk.ac.kr, Ph
one: 82-2-450-3760, Fax: 82-2-3437-6106
Dr. Soon Young Shin, Department of Biological Sciences, Konkuk University, 120
Neungdong-ro, Gwangjin-gu, Seoul, Korea 05029, Email: shinsy@konkuk.ac.kr , Phone: 82-
2-2030-7946
Keywords: NMR, 1H NMR, 13C NMR, polyphenols, Nʹ-methyleneformohydrazide, HR/MS,
aurora kinase inhibitors
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Introduction
Aurora kinases play important roles in mitosis and cell division.[1] Three kinases family has
been known as aurora A (aurA), B (aurB), and C (aurC). They have conserved catalytic
domains, but their function and localization are not the same.[2-4] AurA localizes to spindle
poles in mitosis and is essential to centrosome maturation and separation. AurB localizes to
the microtubules interlinking at the spindle and is required for phosphorylation of histone
H3.[5,6] Unlike aurA and aurB, aurC has not been studied well. It was found aurA and aurB
were overexpressed in colon and breast tumors.[7,8] Other researches revealed aurA was
overexpressed in gastric, ovarian, and pancreatic tumors.[9-12] Similar results were found from
aurB.[5] Because their overexpression associates with tumorigenesis, they are targeted for
cancer therapy.[2,13,14] Of many possible ways to inhibit the enzymatic activities of aurora
kinases, one is to use small compounds as inhibitors. Several effective inhibitors have been
known as follows: N-[(3Z)-2-oxo-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-
1H-indol-5-yl]ethanesulfonamide (named as hesperadine, Suppl. Fig. 1A), N-(2-
chlorophenyl)-4-[[2-[[4-[2-(4-ethyl-1-piperazinyl)-2-oxoethyl]phenyl]amino]-5-fluoro-4-
pyrimidinyl]amino]-benzamide (named as TC-S7010, Suppl. Fig. 1B), N-[4-[[6-methoxy-7-
(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]phenyl]benzamide (named as ZM447439,
Suppl. Fig. 1C), and N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-
yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide (named as VX-680,
Suppl. Fig. 1D).[13-16] Besides, it has been reported flavones [Fig. 1A] inhibit aurB.[17]
Benzochalcones bearing pyrazoline moieties [Fig. 1B] show the inhibitory effects on aurora
kinases.[18] Chromenylchalcones [Fig. 1C] bind to aurA based on their in silico docking
study.[19] They all belong to polyphenols. We designed and synthesized 33 polyphenols
containing the Nʹ-methyleneformohydrazide scaffold based on moieties contained in Figs. 1A,
B, and C as listed in Table 1. To confirm whether they show the inhibitory effects on aurA, in
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vitro kinase assay was performed. Their half-maximal inhibitory concentration (IC50) ranged
1
13
between 1.14 and 98.93 µM. We report here the assignments of their H and C NMR data
and high-resolution mass spectral data. These data can help us design a series of compounds
containing novel aurora kinase inhibitor pharmacophores and identify newly synthesized
polyphenols containing the Nʹ-methyleneformohydrazide scaffold.
Experimental
General synthetic route
A synthetic scheme outlining the preparation of the polyphenol derivatives containing the Nʹ-
methyleneformohydrazide scaffold (i.e., derivatives 1–33) is shown in Scheme 1. For the
preparation of derivatives 1–20, the intermediate chromone aldehydes II were synthesized
from substituted 2-hydroxy acetophenones under Vilsmeier reaction conditions. Substituted
2-hydroxy acetophenone (I) was treated with an excess of phosphorous oxychloride and
anhydrous N,N-dimethylformamide to afford chromone aldehyde (II), which was
subsequently treated with benzohydrazide to give the corresponding derivatives 1–20.
Resveratrol derived aldehyde III was also employed under the same reaction conditions to
obtain the desired compounds 21–26 and 29–30.[20] Typical synthetic procedures for the
preparation of derivatives 9 and 22 are described as follows.
Preparation
of
(E)-Nʹ-((6-chloro-4-oxo-4H-chromen-3-yl)methylene)-3-hydroxybenzo
hydrazide (9)
A mixture of anhydrous N,N-dimethylformamide (15 mL, 193 mmol) and phosphoryl
chloride (1.5 mL, 23 mmol) was heated at 60–65 °C for 1.5 h, after which time 2-hydroxy-5-
chloroacetophenone (5 mmol, 850 mg) was added, and the resulting mixture stirred at the
same temperature for a further 2 h. The reaction progress was monitored by TLC. After
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reaching completion, the reaction mixture was cooled to room temperature and poured into
ice-water (400 mL), then neutralized using a saturated NaHCO3 solution. This resulted in
precipitation of the crude 6-chloro-3-formylchromone product, which was subsequently
filtered then purified by recrystallization in ethanol (Yield: 80%; m.p: 166–168 °C). The
purified 6-chloro-3-formylchromone (60 mg, 0.3 mmol) was then dissolved in ethanol
(10 mL) containing m-hydroxybenzohydrazide (45 mg, 0.3 mmol). A catalytic amount of
glacial acetic acid was added, and the resulting reaction mixture was heated under reflux at
85 °C for 5 h. After this time, the reaction mixture was cooled to room temperature, the
solvent was removed under vacuum, and the resulting residue was purified by column
chromatography to give the analytically pure compound 9 (Yield: 77%; m.p: 196–202 °C).
Preparation of (E)-Nʹ-(2,4-dimethoxy-6-(4-methoxystyryl)benzylidene)-3-methoxybenzo
hydrazide (22)
(E)-2-(4-methoxystyryl)-4,6-dimethoxybenzaldehyde (90 mg, 0.3 mmol) and m-anisic
hydrazide (48 mg, 0.3 mmol) were dissolved in ethanol (10 mL).[20] To this solution was
added a catalytic amount of glacial acetic acid, and the reaction mixture was heated under
reflux at 85 °C for 7 h. After this time, the mixture was cooled to room temperature, the
crude product was precipitated, and the resulting solid was filtered prior to purification by
recrystallization in methanol (Yield: 72%; m.p: 160–164 °C).
NMR spectroscopy
The synthesized polyphenols containing the Nʹ-methyleneformohydrazide scaffold were
dissolved in deuterated dimethyl sulfoxide (DMSO-d6) to a concentration of ~50 mM and
transferred into 2.5 mm NMR tubes. All NMR data were collected using a Bruker AVANCE
400 spectrometer system (9.4 T; Bruker, Karlsruhe, Germany) equipped with a 5-mm inverse
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broadband probehead at room temperature, and the chemical shifts were referenced to TMS
1
(0 ppm). H NMR experiments were performed using the following parameters: relaxation
delay = 1 s, 90° pulse for 11.8 µs, 5500 Hz spectral width, 32 k data points, and
0.34 Hz/point digital resolution. The equivalent parameters for the 13C NMR and DEPT
experiments were 3 s, 15.0 µs, 21000 Hz, 64 k, and 0.64 Hz/point, respectively. Two-
dimensional COSY, NOESY, HMQC, and HMBC experiments were acquired with data
points of 2 k × 256 (t2 × t1). The long-range coupling time for HMBC was 70 ms, and the
mixing time for NOESY was 1.5 s. Processing and analysis of the NMR data were carried
out as previously reported.[21]
General analytical procedures
To confirm the structures of the Nʹ-methyleneformohydrazide-containing polyphenols, ultra-
performance liquid chromatography-hybrid quadrupole-time-of-flight mass spectrometry
(UPLC-TOFMS) was carried out using a Waters ACQUITY UPLC system (Waters, Milford,
MA) with the help of Prof. Choong Hwan Lee at Konkuk University, Korea.[22] All high-
resolution mass spectrometry (HR/MS) data were collected as (M−H)- ions.
In vitro aurora A kinase assay
The substrate used in vitro human aurora A kinase assay was 200µM
LeuArgArgAlaSerLeuGly and the concentration of ATP was 500 cpm/pmol. The detailed
procedure followed to the method provided by EMD Millipore’s KinaseProfiler service assay
protocol (EMD Millipore Corporation, Billerica, MA).[23] TC-S7010 [Suppl. Fig. 1B] was
used as a control. The statistical significance was analyzed using Student’s t-test. All
experiments were performed in triplicate
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Results and Discussion
All 33 derivatives containing the Nʹ-methyleneformohydrazide scaffold are listed in Table 1.
As mentioned previously, these derivatives can be divided into a number of groups. For
example, in the structures of derivatives 1–17, the 4H-chromenyl group is attached to the N-
methylene functionality and the carbonyl group bears a substituted phenyl group. Similarly,
in derivatives 18–20, the 4H-chromenyl group is attached to the N-methylene moiety, but the
carbonyl group bears a substituted pyridine unit. Furthermore, in derivatives 21–26, both the
N-methylene and carbonyl groups bear substituted phenyl groups, while in derivatives 27–30,
a phenyl group is attached to the N-methylene moiety and the carbonyl group bears a
substituted pyridine group. Finally, in derivatives 31–33, methyl and phenyl groups are
attached to the N-methylene functionality, while a substituted phenyl group is found on the
carbonyl group. Of the 33 derivatives, the procedure for assigning the structure of derivative
22,
i.e.,
(E)-Nʹ-((E)-2-((E)-4-methoxystyryl)-4,6-dimethoxybenzylidene)-3-
methoxybenzohydrazide [Fig. 2], is described here as an example.
A total of 24 signals were observed in the 13C NMR spectrum of 22, of which 5 were
present at ~160 ppm. Four of these peaks (with the exception of the signal at 162.6 ppm)
showed long-range couplings with methoxy protons in the HMBC spectrum, allowing the 13C
13
signal at 162.6 ppm to be assigned to the amide carbon, C-1a. In addition, as the two C
signals at 114.1 and 128.4 ppm exhibited double the intensities of the neighboring signals,
they were assigned to the C-3ʹʹ/C-5ʹʹ and C-2ʹʹ/C-6ʹʹ atoms, respectively. The two proton
signals at 6.95 and 7.69 ppm were assigned to the H-3ʹʹ/H-5ʹʹ and H2ʹʹ/H-6ʹʹ atoms,
13
3
respectively. In addition, the C peaks at 130.3 and 159.0 ppm exhibiting JCH couplings
with H-3ʹʹ/H-5ʹʹ and H2ʹʹ/H-6ʹʹ, respectively, were assigned as C-1ʹʹ and C-4ʹʹ, respectively.
The 3JCH coupling of C-4ʹʹ to a methoxy proton at 3.78 ppm allowed this to be assigned as the
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13
4ʹʹ-OCH3 proton, while the C peak at 55.1 ppm was assigned to the 4ʹʹ-OCH3 carbon atom
based on HMQC results. Furthermore, due to the large coupling constants of the two proton
signals at 7.20 and 8.51 ppm (i.e., 16.3 Hz), these signals were assigned to the double bond
protons of the styryl group. Their corresponding carbon atoms were observed at 130.4 and
126.1 ppm, respectively. As a 3JCH coupling between the former carbon atom and the H2ʹʹ/H-
6ʹʹ atoms was observed by HMBC, this carbon atom was assigned as C-1ʹʹa. We also
observed three correlating proton signals at 7.15, 7.44, and 7.56 ppm in the COSY spectrum,
3
where the signal at 7.56 ppm exhibited a JCH coupling with C-1a, and so it was assigned as
H-6. In addition, the carbon atom resonating at 117.4 ppm that was attached directly to the
3
proton resonating at 7.15 ppm exhibited a JCH coupling to H-6, and so the proton signal at
7.15 ppm was assigned to the H-4 atom. The remaining proton signal at 7.44 ppm was
3
assigned to the H-5 atom, while the carbon signal at 159.2 ppm exhibiting a JCH coupling
with H-5 was assigned to the C-3 atom. Furthermore, the methoxy proton signal at 3.85 ppm
3
showed a JCH coupling with the C-3 atom, and it was assigned as 3-OCH3. Moreover, the
3
two carbon signals at 112.7 and 134.9 ppm that exhibited JCH couplings with H-6 and H-5
were labelled C-2 and C-1, respectively. As expected, the most deshielded proton signal at
11.74 ppm was assigned to the NH group, which also exhibited a 3JCH coupling to the carbon
C-1ʹa signal at 145.1 ppm. The signals corresponding to the C-2ʹ and C-6ʹ atoms (at 139.0
3
and 160.3 ppm) were assigned as such due to their JCH couplings with the H-1ʹa signal at
8.86 ppm. We also observed the COSY correlation of the two protons resonating at 7.00 and
6.58 ppm. Since the former was long-range coupled to the C-1ʹʹb signal (126.1 ppm) with
3JCH, it was labeled as H-3ʹ. As a result, the proton signal at 6.58 ppm was assigned to the H-
3
5ʹ atom. Furthermore, as the methoxy proton signal at 3.87 ppm exhibited a JCH coupling
with the C-6ʹ signal, it was assigned as 6ʹ-OCH3. Thus, of the four methoxy protons present,
the final proton signal at 3.89 ppm was assigned to the 4ʹ-OCH3 group. The carbon signal at
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161.1 ppm exhibiting a 3JCH coupling with this methoxy proton was labeled C-4ʹ. Finally, the
carbon signal at 112.8 ppm that exhibited 3JCH couplings with H-3ʹ and H-5ʹ was assigned to
the C-1ʹ atom. The nOe cross peaks among H-1ʹʹb/H-6ʹʹ, H-5ʹʹ/4ʹʹ-OCH3, H-3ʹ/H-1ʹʹa, H-
1ʹʹb/H-1ʹa, NH/H-1ʹa, NH/H-2, and H-2/3-OCH3 were observed in the NOESY spectrum. The
key correlations obtained from the COSY, NOESY, and HMBC spectra of derivative 22 are
shown in Fig. 3.
Similar procedures were employed to assign the NMR data of the other derivatives,
and the complete assignments of the 1H and 13C NMR data for all derivatives containing the
Nʹ-methyleneformohydrazide scaffold (see Table 1) are listed in Tables 2 and 3, respectively.
To confirm the structures of the various derivatives, HR/MS was carried out, and the
calculated molecular masses are listed in Table 1 along with the experimental HR/MS results.
All 1H NMR, 13C NMR, and HR/MS spectra are provided in the Supplementary Materials.
The IC50 values of 33 derivatives for aurora A kinase ranged from 1.14 to 98.93 µM
as listed in Table 1 and they were plotted with error bars [Suppl. Fig. 2]. The IC50 value of
TC-S7010 [Suppl. Fig. 1B] used as a control was 0.25 µM. Derivative 6, (E)-4-fluoro-N'-((4-
oxo-4H-chromen-3-yl)methylene)benzohydrazide showed the best inhibitory effect and
derivative
21,
(E)-N'-((E)-2-((E)-4-methoxystyryl)-4,6-
dimethoxybenzylidene)benzohydrazide did the worst effect. We could therefore conclude that
the analytical data provided herein allows us to identify the novel Nʹ-
methyleneformohydrazide-containing derivatives, and in vitro kinase assay data on aurora A
help us design compounds containing novel aurora kinase inhibitor pharmacophores.
Acknowledgments
This work was supported by the Basic Science Research Program through the National
Research Foundation of Korea (NRF-2016R1D1A1A09919045) and the Agri-Bio Industry
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Technology Development Program (316028-3, Korea Institute of Planning and Evaluation
for Technology in Food, Agriculture, Forestry and Fisheries (IPET)). SY Shin was supported
by the KU Research Professor Program of Konkuk University.
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Table 1. Structures, names, HR/MS data, and IC50 values of polyphenol derivatives (1–33) containing the Nʹ-methyleneformohydrazide scaffold.
O
5
H
4
R1
N
R2
N
3
O
O
mass
(calcd./found)
IC50/µM
derivative R1
R2
name
H
H
Phenyl
291.0770/291.0773
321.0875/321.0861
321.0875/321.0886
307.0719/307.0728
368.9875/368.9871
309.0675/309.0664
325.0380/325.0373
355.0486/355.0479
341.0329/341.0313
(E)-N'-((4-oxo-4H-chromen-3-yl)methylene)benzohydrazide
1
2
3
4
5
6
7
8
9
2.96
2.25
2.33
2.01
9.44
1.14
11.36
5.11
1.35
3-Methoxyphenyl
4-Methoxyphenyl
3-Hydroxyphenyl
3-Boromophenyl
4-Fluorophenyl
Phenyl
(E)-3-methoxy-N'-((4-oxo-4H-chromen-3-yl)methylene)benzohydrazide
(E)-4-methoxy-N'-((4-oxo-4H-chromen-3-yl)methylene)benzohydrazide
(E)-3-hydroxy-N'-((4-oxo-4H-chromen-3-yl)methylene)benzohydrazide
(E)-3-bromo-N'-((4-oxo-4H-chromen-3-yl)methylene)benzohydrazide
(E)-4-fluoro-N'-((4-oxo-4H-chromen-3-yl)methylene)benzohydrazide
(E)-N'-((6-chloro-4-oxo-4H-chromen-3-yl)methylene)benzohydrazide
H
H
H
H
Cl
Cl
Cl
3-Methoxyphenyl
3-Hydroxyphenyl
(E)-N'-((6-chloro-4-oxo-4H-chromen-3-yl)methylene)-3-methoxybenzohydrazide
(E)-N'-((6-chloro-4-oxo-4H-chromen-3-yl)methylene)-3-hydroxybenzohydrazide
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Cl
Cl
Br
Br
Br
Br
Br
Br
H
3-Boromophenyl
4-Fluorophenyl
Phenyl
402.9485/402.9488
343.0286/343.0258
368.9875/368.9876
398.9980/398.9986
384.9824/384.9816
446.8980/446.8990
386.9781/386.9756
386.9781/386.9762
292.0722/292.0712
292.0722/292.0705
326.0332/326.0304
(E)-3-bromo-N'-((6-chloro-4-oxo-4H-chromen-3-yl)methylene)benzohydrazide
(E)-N'-((6-chloro-4-oxo-4H-chromen-3-yl)methylene)-4-fluorobenzohydrazide
(E)-N'-((6-bromo-4-oxo-4H-chromen-3-yl)methylene)benzohydrazide
(E)-N'-((6-bromo-4-oxo-4H-chromen-3-yl)methylene)-3-methoxybenzohydrazide
(E)-N'-((6-bromo-4-oxo-4H-chromen-3-yl)methylene)-3-hydroxybenzohydrazide
(E)-3-bromo-N'-((6-bromo-4-oxo-4H-chromen-3-yl)methylene)benzohydrazide
(E)-N'-((6-bromo-4-oxo-4H-chromen-3-yl)methylene)-3-fluorobenzohydrazide
(E)-N'-((6-bromo-4-oxo-4H-chromen-3-yl)methylene)-4-fluorobenzohydrazide
(E)-N'-((4-oxo-4H-chromen-3-yl)methylene)nicotinohydrazide
10
11
12
13
14
15
16
17
18
19
20
16.34
13.28
11.91
2.93
3-Methoxyphenyl
3-Hydroxyphenyl
3-Boromophenyl
3-Fluorophenyl
4-Fluorophenyl
3-Pyridinyl
1.32
13.89
14.83
7.98
2.26
H
4-Pyridinyl
(E)-N'-((4-oxo-4H-chromen-3-yl)methylene)isonicotinohydrazide
1.19
Cl
3-Pyridinyl
(E)-N'-((6-chloro-4-oxo-4H-chromen-3-yl)methylene)nicotinohydrazide
2.72
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R1
R6
H
R2
R3
N
R7
N
O
R5
R4
mass
IC50/µM
derivative
R1
R2
H
H
H
H
H
H
H
R3
R4
H
H
H
H
H
H
R5
R6
H
H
H
H
H
H
H
R7
name
(calcd./found)
(E)-N'-((E)-2-((E)-4-methoxystyryl)-4,6-
dimethoxybenzylidene)benzohydrazide
(E)-N'-((E)-2-((E)-4-methoxystyryl)-4,6-
dimethoxybenzylidene)-3-methoxybenzohydrazide
(E)-N'-((E)-2-((E)-4-methoxystyryl)-4,6-
dimethoxybenzylidene)-4-methoxybenzohydrazide
(E)-N'-((E)-2-((E)-4-methoxystyryl)-4,6-
dimethoxybenzylidene)-3-hydroxybenzohydrazide
(E)-N'-((E)-2-((E)-4-methoxystyryl)-4,6-
dimethoxybenzylidene)-3-bromobenzohydrazide
(E)-N'-((E)-2-((E)-4-methoxystyryl)-4,6-
dimethoxybenzylidene)-4-fluorobenzohydrazide
(E)-N'-(3,4-
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
4-Methoxystyryl
4-Methoxystyryl
4-Methoxystyryl
4-Methoxystyryl
4-Methoxystyryl
4-Methoxystyryl
H
Phenyl
415.1658/415.1658
445.1763/445.1748
445.1763/445.1765
432.1685/431.1608
493.0763/493.0737
433.1564/433.1534
284.1035/284.1039
21
22
23
24
25
26
27
98.93
84.16
96.18
64.89
82.64
98.52
25.29
3-Methoxyphenyl
4-Methoxyphenyl
3-Hydroxyphenyl
3-Boromophenyl
4-Fluorophenyl
4-Pyridinyl
OCH3 OCH3
dimethoxybenzylidene)isonicotinohydrazide
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(E)-N'-(3,5-
H
OCH3
OCH3
H
OCH3
H
H
OCH3
H
H
H
H
4-Pyridinyl
4-Pyridinyl
3-Pyridinyl
Phenyl
284.1035/284.1037
416.1610/416.1622
416.1610/416.1607
267.1134/267.1134
297.1239/297.1234
253.0977/253.0956
28
29
30
31
32
33
29.14
73.69
89.53
34.84
31.15
30.18
dimethoxybenzylidene)isonicotinohydrazide
(E)-N'-((E)-2-((E)-4-methoxystyryl)-4,6-
dimethoxybenzylidene)isonicotinohydrazide
(E)-N'-((E)-2-((E)-4-methoxystyryl)-4,6-
dimethoxybenzylidene)nicotinohydrazide
(E)-N'-(1-(4-
OCH3
OCH3
OCH3
OCH3
H
4-Methoxystyryl
H
H
4-Methoxystyryl
H
H
H
H
H
CH3
CH3
CH3
methoxyphenyl)ethylidene)benzohydrazide
(E)-3-methoxy-N'-(1-(4-
H
H
H
3-Methoxyphenyl
Phenyl
methoxyphenyl)ethylidene)benzohydrazide
(E)-N'-(1-(2-
H
H
H
OH
hydroxyphenyl)ethylidene)benzohydrazide
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1
Table 2. H NMR chemical shifts of the polyphenol derivatives (1–33) containing the Nʹ-methyleneformohydrazide scaffold. DMSO-d6 was
used as the NMR solvent. Multiplicity and coupling constants are given in parentheses; d and s represent doublet and singlet peaks, respectively.
The units of the chemical shifts and coupling constants are ppm and Hz, respectively
Position
H2
1
2
3
4
5
6
7
8
9
10
7.93 (dd, 8.0,
2.1)
8.00 (dd, 8.8, 7.92 (dd, 7.7,
7.46 (s)
7.93 (d, 8.8)
7.32 (s)
8.11 (s)
7.45 (s)
7.31 (s)
8.10 (s)
5.5)
7.35 (dd, 8.8,
8.6)
1.7)
7.52 (ddd,
7.7, 7.2, 1.5)
7.59 (dd, 7.2,
1.7)
7.53 (ddd,
8.0, 7.2, 1.9)
7.59 (dd, 7.2,
2.1)
H3
H4
H5
H6
-
7.05 (d, 8.8)
-
-
-
-
-
-
7.16 (d, 8.1)
6.98 (d, 7.9)
7.79 (d, 7.9)
-
7.15 (d, 8.1)
6.98 (d, 8.2)
7.79 (d, 7.9)
7.53 (ddd,
8.0, 7.2, 1.9)
7.93 (dd, 8.0,
2.1)
7.43 (dd, 8.1,
7.8)
7.31 (dd, 7.9, 7.49 (dd, 7.9, 7.35 (dd, 8.8,
7.52 (ddd,
7.7, 7.2, 1.5)
7.92 ( dd,
7.7, 1.7)
7.43 (dd, 8.1, 7.31 (dd, 8.2, 7.49 (dd, 7.9,
7.05 (d, 8.8)
7.93 (d, 8.8)
7.5)
7.8)
8.6)
8.00 (dd, 8.8,
5.5)
7.8)
7.4)
7.8)
7.51 (d, 7.8)
7.35 (d, 7.5)
7.93 (d, 7.8)
7.50 (d, 7.8)
7.34 (d, 7.4)
7.92 (d, 7.8)
H1’a
H2’
8.64 (s)
8.64 (s)
8.83 (s)
8.61 (s)
8.81 (s)
8.62 (s)
8.86 (s)
8.62 (s)
8.84 (s)
8.62 (s)
8.84 (s)
8.59 (s)
8.61 (s)
8.83 (s)
8.59 (s)
8.84 (s)
8.58 (s)
8.85 (s)
8.84 (s)
8.85 (s)
8.13 (dd, 8.0, 8.13 (dd, 8.0, 8.13 (dd, 7.9, 8.13 (dd, 7.9, 8.12 (dd, 7.9, 8.12 (dd, 8.0,
H5’
H6’
H7’
H8’
8.02 (d, 2.6)
-
8.03 (d, 2.6)
-
8.03 (d, 2.5)
-
8.02 (d, 2.6)
-
1.7)
1.3)
1.6)
1.8)
1.7)
1.9)
7.55 (ddd,
8.0, 7.1, 1.2)
7.85 (ddd,
8.5, 7.1, 1.7)
7.54 (ddd,
8.0, 7.1, 1.1)
7.85 (ddd,
8.4, 7.1, 1.3)
7.55 (ddd,
7.9, 7.2, 1.0)
7.85 (ddd,
8.5, 7.2, 1.6)
7.54(ddd,
7.54 (ddd,
7.9, 7.0, 0.7)
7.85 (ddd,
8.4, 7.0, 1.7)
7.54 (ddd,
8.0, 7.4, 1.0)
7.85 (ddd,
8.4, 7.4, 1.9)
7.9, 7.0, 1.1)
7.85 (ddd,
8.4, 7.0, 1.8)
7.87 (dd, 9.0,
2.6)
7.88 (d, 9.0,
2.6)
7.87 (dd, 9.0, 7.87 (dd, 9.0,
2.5)
2.6)
7.72 (dd, 8.5, 7.71 (dd, 8.4, 7.72 (dd, 8.5, 7.71 (dd, 8.4, 7.71 (dd, 8.4, 7.71 (dd, 8.4,
7.77 (d, 9.0)
7.78 (d, 9.0)
7.78 (d, 9.0)
7.78 (d, 9.0)
1.2)
1.1)
1.0)
1.1)
0.7)
1.0)
3-OH
-
-
-
9.78 (s)
-
-
-
-
9.78 (s)
-
3-OCH3
4-OCH3
NH
-
3.83 (s)
-
-
-
-
-
-
3.83 (s)
-
-
-
-
3.83 (s)
11.83 (s)
-
-
-
-
-
-
11.96 (s)
11.91 (s)
11.88 (s)
12.01 (s)
11.97 (s)
11.97 (s)
11.91 (s)
11.90 (s)
11.97 (s)
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Position
H2
11
12
13
14
15
16
17
7.99 (dd, 8.8,
6.1)
18
19
7.84 (dd, 6.0,
1.6)
20
8.00 (dd, 8.9, 7.91 (dd, 7.7,
7.45 (s)
7.30 (s)
8.10 (s)
7.71 (d, 10.2)
9.07 (d, 2.5)
9.07 (d, 2.5)
5.7)
7.36 (dd, 8.9,
8.6)
1.4)
7.52 (ddd,
7.7, 7.4, 1.0)
7.59 (dd, 7.4,
1.4)
7.35 (dd, 8.8,
8.7)
8.78 (dd, 6.0,
1.4)
H3
H4
H5
H6
-
-
-
-
-
-
7.44 (dd, 8.6,
4.4)
8.76 (dd, 4.8,
1.7)
8.76 (dd, 4.8,
1.7)
-
7.15 (d, 8.0)
6.98 (d, 8.0)
7.79 (d, 8.0)
-
-
7.36 (dd, 8.9,
8.6)
7.52 (ddd,
7.7, 7.4, 1.0)
7.43 (dd, 8.0, 7.29 (dd, 8.0, 7.49 (dd, 8.0, 7.57 (dd, 8.2, 7.35 (dd, 8.8, 7.56 (dd, 8.0, 8.78 (dd, 6.0, 7.56 (dd, 8.1,
7.8)
7.4)
7.9)
5.7)
8.7)
7.99 (dd, 8.8,
6.1)
4.8)
1.4)
7.84 (dd, 6.0,
1.6)
4.8)
8.00 (dd, 8.9, 7.91 (dd, 7.7,
8.26 (ddd,
8.0, 2.5, 1.7)
8.62 (s)
8.26 (ddd,
8.1, 2.5, 1.7)
8.64 (s)
7.50 (d, 7.8)
7.34 (d, 7.4)
7.92 (d, 7.9)
7.77 (d, 7.7)
5.7)
1.4)
H1’a
H2’
8.59 (s)
8.85 (s)
8.59 (s)
8.86 (s)
8.60 (s)
8.85 (s)
8.58 (s)
8.83 (s)
8.58 (s)
8.85 (s)
8.59 (s)
8.83 (s)
8.57 (s)
8.84 (s)
8.64 (s)
8.85 (s)
8.85 (s)
8.87 (s)
8.12 (dd, 7.9, 8.12 (dd, 7.9,
H5’
H6’
H7’
H8’
8.04 (d, 2.4)
-
8.16 (d, 2.1)
-
8.17 (d, 2.5)
-
8.16 (d, 2.4)
-
8.16 (d, 2.5)
-
8.15 (d, 2.4)
-
8.15 (d, 2.5)
-
8.04 (d, 2.6)
-
1.8)
1.4)
7.55(ddd,
7.54(ddd,
7.9, 7.2, 1.1)
7.85 (ddd,
8.4, 7.2, 1.8)
7.9, 7.0, 0.9)
7.85 (ddd,
8.4, 7.0, 1.4)
7.88 (dd, 8.9, 7.99 (dd, 8.9, 7.99 (dd, 8.9, 7.99 (dd, 8.9, 7.99 (dd, 8.9, 7.98 (dd, 8.9, 7.97 (dd, 8.9,
7.89 (dd, 9.0,
2.6)
2.4)
2.1)
2.5)
2.4)
2.5)
2.4)
2.5)
7.71 (dd, 8.4, 7.72 (dd, 8.4,
7.79 (d, 8.9)
7.71 (d, 8.9)
7.72 (d, 8.9)
7.71 (d, 8.9)
7.71 (d, 8.9)
7.70 (d, 8.9)
7.70 (d, 8.9)
7.79 (d, 9.0)
1.1)
0.9)
3-OH
3-OCH3
NH
-
-
-
9.79 (s)
-
-
-
-
-
-
-
-
-
3.83 (s)
11.92 (s)
-
-
-
-
-
-
11.98 (s)
11.97 (s)
11.90 (s)
12.01 (s)
11.98 (s)
11.97 (s)
12.10 (s)
12.16 (s)
12.12 (s)
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Position
H2
21
22
23
24
25
26
27
28
29
30
31
32
33
7.98 (dd,
7.5, 1.7)
8.06 (dd,
8.9, 5.7)
7.36 (dd,
8.9, 8.7)
7.81 (dd,
4.5, 1.5)
8.78 (dd,
4.5, 1.3)
7.82 (dd,
4.3, 1.9)
8.79 (dd,
4.3, 1.8)
7.89 (dd,
4.4, 1.6)
8.79 (dd,
4.4, 1.6)
7.89 (dd,
8.2, 1.3)
7.95 (dd,
7.8, 1.6)
7.52 (s)
7.97 (d, 7.8)
7.36 (s)
8.17 (s)
9.12 (d, 2.4)
7.41 (s)
7.53 (ddd,
7.5, 7.1, 1.6)
7.59 (dd,
7.1, 1.7)
7.51 (ddd,
8.2, 7.2, 1.0)
7.57 (dd,
7.2, 1.3)
7.55 (ddd,
7.8, 7.4, 1.6)
7.63 (dd,
7.4, 1.6)
H3
H4
H5
H6
-
7.06 (d, 7.8)
-
-
-
-
-
8.76 (dd,
4.9, 1.7)
7.56 (dd,
7.15 (d, 8.2)
7.44 (dd,
6.98 (d, 7.8) 7.79 (d, 8.0)
-
-
-
-
7.14 (d, 7.8)
7.43 (dd,
7.53 (ddd,
7.31 (dd,
7.8, 7.4)
7.50 (dd,
8.0, 7.9)
7.36 (dd,
8.9, 8.7)
8.06 (dd,
8.9, 5.7)
8.85 (s)
-
8.78 (dd,
4.5, 1.3)
7.81 (dd,
4.5, 1.5)
8.39 (s)
8.79 (dd,
4.3, 1.8)
7.82 (dd,
4.3, 1.9)
8.40 (s)
8.79 (dd,
4.4, 1.6)
7.89 (dd,
7.51 (ddd,
7.55 (ddd,
7.06 (d, 7.8)
7.5, 7.1, 1.6) 8.2, 7.8)
7.98 (dd,
8.0, 4.9) 8.2, 7.2, 1.0) 7.8, 7.5) 7.8, 7.4, 1.6)
8.31 (ddd,
7.89 (dd,
7.95 (dd,
7.56 (d, 7.8) 7.97 (d, 7.8) 7.40 (d, 7.4) 7.98 (d, 7.9)
7.47 (d, 7.5)
7.5, 1.7)
8.86 (s)
-
4.4, 1.6) 8.0, 2.4, 1.7) 8.2, 1.3)
7.8, 1.6)
H1’a
H2’
H3’
8.86 (s)
-
8.83 (s)
-
8.84 (s)
-
8.86 (s)
-
8.88 (s)
-
8.85 (s)
-
-
-
-
-
7.36 (d, 1.8) 6.90 (d, 2.1)
7.82 (d, 7.9) 7.81 (d, 8.1)
7.00 (d, 1.8) 7.00 (d, 2.0) 6.99 (d, 2.2) 6.99 (d, 2.0) 7.00 (d, 2.3) 7.00 (d, 2.0)
-
-
7.00 (d, 2.2) 7.00 (d, 2.5) 6.99 (d, 7.9) 6.99 (d, 8.1) 6.93 (d, 7.1)
7.31 (dd,
H4’
-
-
-
-
-
-
-
6.59 (d, 2.1)
-
-
-
-
8.3, 7.1)
6.90 (dd,
8.3, 7.6)
H5’
6.58 (d, 1.8) 6.58 (d, 2.0) 6.58 (d, 2.2) 6.57 (d, 2.0) 6.58 (d, 2.3) 6.58 (d, 2.0) 7.03 (d, 8.3)
7.23 (dd,
-
6.58 (d, 2.2) 6.58 (d, 2.5) 6.99 (d, 7.9) 6.99 (d, 8.1)
H6’
-
-
-
-
-
-
6.90 (d, 2.1)
-
-
7.82 (d, 7.9) 7.81 (d, 8.1) 7.64 (d, 7.6)
8.3, 1.8)
7.20 (d,
16.3)
7.20 (d,
16.3)
7.19 (d,
16.4)
7.20 (d,
16.3)
7.20 (d,
16.2)
7.20 (d,
16.2)
7.20 (d,
16.3)
7.20 (d,
16.3)
H1’’a
H1’’b
-
-
-
-
-
-
-
-
-
8.51 (d,
16.3)
8.51 (d,
16.3)
8.51 (d,
16.4)
8.50 (d,
16.3)
8.51 (d,
16.2)
8.51 (d,
16.2)
8.49 (d,
16.3)
8.50 (d,
16.3)
-
H2’’
H3’’
H5’’
7.69 (d, 8.4) 7.69 (d, 8.5) 7.68 (d, 7.2) 7.68 (d, 8.4) 7.68 (d, 8.6) 7.69 (d, 8.0)
6.95 (d, 8.4) 6.95 (d, 8.5) 6.94 (d, 7.2) 6.94 (d, 8.4) 6.95 (d, 8.6) 6.95 (d, 8.0)
6.95 (d, 8.4) 6.95 (d, 8.5) 6.94 (d, 7.2) 6.94 (d, 8.4) 6.95 (d, 8.6) 6.95 (d, 8.0)
-
-
-
-
-
-
7.68 (d, 8.7) 7.69 (d, 8.5)
6.95 (d, 8.7) 6.95 (d, 8.5)
6.95 (d, 8.7) 6.95 (d, 8.5)
-
-
-
-
-
-
-
-
-
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H6’’
7.69 (d, 8.4) 7.69 (d, 8.5) 7.68 (d, 7.2) 7.68 (d, 8.4) 7.68 (d, 8.6) 7.69 (d, 8.0)
-
-
-
-
7.68 (d, 8.7) 7.69 (d, 8.5)
-
-
-
C1’a-
-
-
-
-
-
-
-
-
2.33 (s)
2.33 (s)
2.49 (s)
CH3
3-OH
-
-
-
9.72 (s)
-
-
-
-
-
-
-
-
-
3-OCH3
4-OCH3
2’-OH
3’-OCH3
4’-OCH3
5’-OCH3
6’-OCH3
4’’-
-
3.85 (s)
-
-
-
-
-
-
-
-
-
3.83 (s)
-
-
-
3.84 (s)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
13.36 (s)
-
-
-
-
-
-
3.82 (s)
3.80 (s)
-
-
-
-
-
-
-
-
3.89 (s)
-
3.89 (s)
-
3.89 (s)
-
3.89 (s)
-
3.89 (s)
-
3.89 (s)
-
3.81 (s)
-
3.90 (s)
-
3.89 (s)
-
3.80 (s)
3.80 (s)
-
-
3.80 (s)
-
-
-
-
-
3.87 (s)
3.87 (s)
3.87 (s)
3.86 (s)
3.87 (s)
3.87 (s)
3.87 (s)
3.87 (s)
3.78 (s)
3.78 (s)
3.79 (s)
3.78 (s)
3.78 (s)
3.78 (s)
-
-
3.78 (s)
3.78 (s)
-
-
-
OCH3
NH
11.78 (s)
11.74 (s)
11.65 (s)
11.70 (s)
11.85 (s)
11.79 (s)
11.95 (s)
12.07 (s)
11.99 (s)
11.93 (s)
10.69 (s)
10.67 (s)
11.32 (s)
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Table 3. 13C NMR chemical shifts (DMSO-d6) of the polyphenol derivatives (1–33) containing the Nʹ-methyleneformohydrazide scaffold
Position
C1a
C1
1
2
3
4
5
6
7
8
9
10
163.1 161.4 162.0 163.1 162.7 163.1 161.4 162.1 163.2 162.8 163.2 161.3 161.5 162.0 161.6 161.5 161.6
133.2 134.5 125.17 134.6 135.3 129.6 133.1 134.5 134.5 135.2 129.5 133.1 134.5 134.5 135.2 135.4 129.5 128.9 140.2 128.9
127.7 112.8 129.6 114.6 130.2 130.4 127.7 112.8 114.6 130.2 130.5 127.7 112.8 114.6 130.1 114.4 130.4 148.6 121.5 148.6
128.5 159.2 113.7 157.5 121.8 115.5 128.5 159.2 157.5 121.8 115.6 128.6 159.3 157.5 121.7 163.1 115.5
162.0 118.84 134.6 163.0 131.9 117.7 118.9 134.6 163.1 132.0 117.7
11
12
13
14
15
16
17
18
19
20
163.0 162.7 162.3
C2
C3
-
150.4
-
-
C4
131.9 117.7
118.9
134.6 118.8 162.9 152.4
152.4
C5
128.5 129.7 113.7
129.6 130.8 115.5 128.5 129.6 129.6 130.8 115.6
128.6 129.7 129.6 130.7 130.7 115.5 123.7 150.4 123.7
118.2 126.8 123.8 130.4 135.5 121.5 135.5
C6
127.7 119.9
129.6
118.2 126.9 130.4 127.7 119.9 118.2 126.9 130.5 127.7 119.9
C1’a
C2’
140.4 140.5 139.6
154.6 154.6 154.3
140.3 141.0 140.5 140.0 140.0 139.8 140.6 140.2 140.1 140.1 139.9 140.5 140.5 140.1 141.1 141.7 140.7
154.5 154.7 154.6 154.9 154.7 154.8 154.9 155.0 154.9 154.9 154.83 154.8 154.8 154.9 154.8 154.9 155.1
C3’
118.4 118.4
175.1 175.1 175.1
125.2 125.2 125.23 125.2 125.2 125.2 124.2 124.1 124.2 124.2 124.2 127.3 127.3 127.3 127.3 127.2 127.3 125.2 125.2 124.2
118.5
118.5
118.2 118.3 118.5 118.4 118.5 118.3 118.5 118.60 118.6 118.64 118.5 118.5 118.53 118.2 118.1 118.3
C4’
175.1 175.0 175.1 174.1 174.0 174.1 174.0 174.1 174.0 174.0 174.0 173.8 173.8 173.9 175.1 175.0 174.1
C5’
C6’
126.1 126.1 126.0
134.7 134.7 134.6
126.1 126.1 126.1 130.6 130.5 130.5 130.6 130.6 124.9 124.9 124.9 124.8 124.8 124.9 126.2 126.2 130.6
134.7 134.7 134.7 134.6 134.5 134.5 134.5 134.6 137.3 137.3 137.3 137.2 137.2 137.3 134.8 134.8 134.6
118.76 118.7 118.8 121.3 121.2 121.3 121.3 121.3 121.5 121.5 121.5 121.4 121.4 121.5 118.8 118.8 121.3
155.8 155.8 155.8 154.4 154.3 154.4 154.4 154.4 154.8 154.8 154.80 154.7 154.7 154.8 155.8 155.8 154.4
123.4 123.3 123.4 124.5 124.5 124.5 124.5 124.5 118.56 118.5 118.55 118.4 118.4 118.51 123.4 123.3 124.5
C7’
C8’
118.7 118.7
118.7
C9’
155.8 155.8 155.8
123.3 123.3 123.3
C10’
3-OCH3
4-OCH3
-
-
55.4
-
-
-
-
-
-
-
-
-
-
55.3
-
-
-
-
-
-
-
-
-
55.4
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
55.4
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Position
C1a
21
162.9
133.6
127.7
128.4
131.5
128.4
127.7
145.1
112.7
138.9
102.5
161.0
97.5
22
23
162.4
125.6
129.6
113.6
161.8
113.6
129.6
144.4
112.9
138.8
102.5
160.9
97.5
24
163.0
135.0
114.6
157.4
118.5
129.4
118.2
145.0
112.8
138.9
102.5
161.0
97.5
25
161.3
135.7
130.18
121.7
134.3
130.6
126.9
145.6
112.5
139.1
102.6
161.2
97.5
26
161.8
130.0
130.4
115.3
162.8
115.3
130.4
145.1
112.7
139.0
102.6
161.1
97.5
27
28
29
30
31
163.6
134.2
127.8
128.3
131.3
128.3
127.8
155.8
130.5
127.9
113.7
160.4
113.7
127.9
-
32
163.3
135.6
113.0
159.1
117.1
129.5
119.9
156.1
130.4
128.0
113.7
160.4
113.7
128.0
-
33
164.4
133.0
128.1
128.5
131.9
128.5
128.1
158.2
119.4
158.7
117.3
131.2
118.5
128.4
-
162.6
134.9
112.7
159.2
117.4
129.5
119.9
145.1
112.8
139.0
102.6
161.1
97.5
161.5
161.7
161.5
140.6
121.6
150.2
-
161.4
129.3
148.7
-
C1
140.6
140.4
C2
121.5
121.5
C3
150.3
150.3
C4
-
-
152.1
123.5
135.4
145.7
112.5
139.1
102.6
161.2
97.5
160.4
130.4
126.1
130.2
128.4
114.1
159.0
114.1
128.4
-
C5
150.3
150.3
150.2
121.6
146.3
112.4
139.2
102.7
161.3
97.5
160.5
130.5
126.0
130.2
128.4
114.1
159.0
114.1
128.4
-
C6
121.5
121.5
C1’a
C1’
149.3
148.9
126.7
136.0
C2’
108.4
105.0
C3’
149.1
160.7
C4’
151.0
102.6
C5’
111.5
160.7
C6’
160.3
130.33
126.1
130.27
128.4
114.1
159.0
114.1
128.4
-
160.3
130.4
126.1
130.3
128.4
114.1
159.0
114.1
128.4
-
160.2
130.31
126.1
130.26
128.4
114.1
159.0
114.1
128.4
-
160.3
130.30
126.1
130.29
128.4
114.1
159.0
114.1
128.4
-
160.4
130.4
126.1
130.24
128.4
114.1
159.0
114.1
128.4
-
160.3
130.31
126.1
130.27
128.4
114.1
159.0
114.1
128.4
-
122.2
105.0
C1’’a
C1’’b
C1’’
C2''
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
C3''
-
-
-
-
-
C4''
-
-
-
-
-
C5''
-
-
-
-
-
C6''
-
-
-
-
-
C1’a-CH3
3-OCH3
4-OCH3
3’-OCH3
-
-
14.4
-
14.5
55.3
-
14.0
-
-
55.4
-
-
-
-
-
-
-
-
-
-
-
-
55.4
-
-
-
-
-
-
-
-
-
-
-
-
-
55.5
55.3
-
-
-
-
-
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4’-OCH3
5’-OCH3
6’-OCH3
4’’-OCH3
55.4
-
55.3
-
55.3
-
55.4
-
55.4
-
55.4
-
55.6
-
55.4
-
55.4
-
55.2
55.2
-
-
-
-
-
-
-
55.3
-
-
-
-
-
-
56.0
55.1
56.0
55.1
56.0
55.1
56.0
55.1
56.0
55.1
56.0
55.1
-
-
56.0
55.1
56.0
55.1
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Figure Captions
Figure 1.
O
O
(A)
(B)
N
NH
O
(C)
O
Figure 1. General structures of (A) flavone, (B) benzochalcone bearing pyrazoline moiety,
and (C) chromenylchalcone.
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Figure 2.
H
N
1a
1
OCH3
N
OCH3
O
1'a
1'
1''a
2'
1''
H3CO
1''b
OCH3
Figure 2. Structure of derivative 22, (E)-Nʹ-((E)-2-((E)-4-methoxystyryl)-4,6-
dimethoxybenzylidene)-3-methoxybenzohydrazide.
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Figure 3.
H
H
H
1
O
H
N
H3C
CH3
1a
O
N
O
H
1'a
H
1'
H
H
H
2'
1''a
1''b
O
H
1''
H
H
CH3
H
H
O
H3C
COSY
NOESY
HMBC
Figure 3. Key correlations obtained from the COSY, NOESY, and HMBC spectra of
derivative 22.
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Scheme 1.
O
O
O
O
O
O
H
H2N
POCl3
anhydrous DMF
R1
R1
CHO
R1
N
R2
N
R2
N
H
O
0  65°C
OH
R2 = Aromatic
II ; R1 = H, Cl, Br
I
1 - 20
H
N
R7
OMe
CHO
OMe N
O
O
H2N
N
R7
H
MeO
MeO
R7 = Aromatic
OMe
OMe
21-26, 29-30
III
O
R6
R6
H2N
H
N
R7
N
R7
H
N
O
MeO
MeO
O
R7 = Aromatic
27-28, 31-33
R6 = H, CH3
Scheme 1. Synthetic route to the various polyphenols containing the Nʹ-
methyleneformohydrazide scaffold (1–33).
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Synthesis and structure elucidation of polyphenols containing the Nʹ-
methyleneformohydrazide scaffold as aurora kinase inhibitors
Dongsoo Koh, Yearam Jung, Seunghyun Ahn, Kenneth Hun Mok, Soon Young Shin,
Yoongho Lim*
We designed polyphenols containing the Nʹ-methyleneformohydrazide scaffold and
synthesized 33 derivatives. To confirm whether they show the inhibitory effects on aurA, in
vitro kinase assay was performed, and their half-maximal inhibitory concentration ranged
1
13
between 1.14 and 98.93 µM. We report here the assignments of their H and C NMR data
and high-resolution mass spectral data. These data can help us design a series of compounds
containing novel aurora kinase inhibitor pharmacophores and identify newly synthesized
polyphenols containing the Nʹ-methyleneformohydrazide scaffold.
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