Concise synthesis and cellular evaluation of 3′-formyl-4′,6′-dihydroxy-2′-methoxy-5′-methylchalcone (FMC) and its analogues

Article abstract of DOI:10.1080/00397911.2014.930492

3′-Formyl-4′,6′-dihydroxy-2′-methoxy-5′-methylchalcone (FMC) was a natural product isolated from Cleistocalyx operculatus. A four-step synthetic strategy toward FMC and its four analogues (1b-1e) was first developed. All compounds were synthesized from commercially available 2,4,6-trihydroxyacetophenone; formylation at 3′ position under Vilsmeier-Haack conditions was followed by the introduction of a methyl group at 5′ position. The key step of selective methylation at 2′ position was achieved by trimethylsilyldiazomethane (TMSCHN₂). Then substituted aromatic aldehydes were condensed through Claisen-Schmidt reaction in the presence of potassium hydroxide. All structures were confirmed by ¹H NMR, ¹³C NMR, and high-resolution mass spectra. FMC and analogues were screened for their antiproliferative activity.

Full text of DOI:10.1080/00397911.2014.930492

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Concise Synthesis and Cellular Evaluation
of 3′-Formyl-4′,6′-dihydroxy-2′-
methoxy-5′-methylchalcone (FMC) and
Its Analogues
Xiang Zhuo a b , Li En-Zhen b , Liang Hai b c , Guo Hong-Ju b , Shi
Ning b , Zhang Xue-Hui b , Qian Qi-Fang b & Wu Jiu-Hong a b c
a School of Pharmacy , Fourth Military Medical University , Xi'an ,
China
b Department of Pharmacy, 306 Hospital of PLA , Beijing , China
c School of Pharmacy , Anhui Medical University , Hefei , China
Accepted author version posted online: 24 Jun 2014.Published
online: 20 Aug 2014.
To cite this article: Xiang Zhuo , Li En-Zhen , Liang Hai , Guo Hong-Ju , Shi Ning , Zhang Xue-Hui ,
Qian Qi-Fang & Wu Jiu-Hong (2014) Concise Synthesis and Cellular Evaluation of 3′-Formyl-4′,6′-
dihydroxy-2′-methoxy-5′-methylchalcone (FMC) and Its Analogues, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:21, 3139-3147,
DOI: 10.1080/00397911.2014.930492
To link to this article: http://dx.doi.org/10.1080/00397911.2014.930492
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Synthetic Communications1, 44: 3139–3147, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.930492
CONCISE SYNTHESIS AND CELLULAR EVALUATION
OF 3’-FORMYL-4’,6’-DIHYDROXY-2’-METHOXY-5’-
METHYLCHALCONE (FMC) AND ITS ANALOGUES
Xiang Zhuo,1,2 Li En-Zhen,2 Liang Hai,2,3 Guo Hong-Ju,2
Shi Ning,2 Zhang Xue-Hui,2 Qian Qi-Fang,2 and
Wu Jiu-Hong1,2,3
1School of Pharmacy, Fourth Military Medical University, Xi’an, China
2Department of Pharmacy, 306 Hospital of PLA, Beijing, China
3School of Pharmacy, Anhui Medical University, Hefei, China
GRAPHICAL ABSTRACT
Abstract 30-Formyl-40,60-dihydroxy-20-methoxy-50-methylchalcone (FMC) was a natural
product isolated from Cleistocalyx operculatus. A four-step synthetic strategy toward
FMC and its four analogues (1b–1e) was first developed. All compounds were synthesized
from commercially available 2,4,6-trihydroxyacetophenone; formylation at 30 position
under Vilsmeier–Haack conditions was followed by the introduction of a methyl group at
50 position. The key step of selective methylation at 20 position was achieved by trimethyl-
silyldiazomethane (TMSCHN2). Then substituted aromatic aldehydes were condensed
Received April 21, 2014.
Address correspondence to Wu Jiu-Hong, School of Pharmacy, Fourth Military Medical
University, Xi’an 710032, China; or Department of Pharmacy, 306 Hospital of PLA, Beijing 100101,
China. E-mail: wujiuhong306@gmail.com
3139

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X. ZHUO ET AL.
through Claisen–Schmidt reaction in the presence of potassium hydroxide. All structures
were confirmed by 1H NMR, 13C NMR, and high-resolution mass spectra. FMC and
analogues were screened for their antiproliferative activity.
Keywords Antiproliferative activity; chalcones; FMC; synthesis
INTRODUCTION
Chalcones, also known as chalconoids, are polyketide natural products contain-
ing an aromatic ketone and an enone moiety, which represent the central core for
a variety of important biological compounds. The closure of chalcones leads to the
formation of the flavonoids, which are substances in the plant secondary metabolism
with an array of biological activities. Chalcone and its derivatives have become one of
the most pursued classes of natural product in recent years for their various biological
activities, including antidiabetic,[1] anticancer,[2–5] anti-inflammatory,[4] antioxi-
dant,[4,5] antifungal,[5,7] antimalarial,[8] and anti-HIV[9,10] properties.
Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae), distributed in
southern China, has buds widely used in folk medicines and tonic drinks.[11] In 2004,
Ye et al.[12] isolated two new natural products, 30-formyl-40,60-dihydroxy-20-methoxy-
50-methylchalcone (FMC) and (2S)-8-formyl-5-hydroxy-7-methoxy-6-methylflavanone
(FMF), from the buds of Cleistocalyx operculatus (Fig. 1). Biological evaluation of
FMC (compound 1) showed good antioxidant activity and antiproliferative activity
against different cancer cell lines.[13] To date, neither synthesis nor structure–activity
relationship (SAR) studies have been done on FMC (1) and its pharmacological
profile and therapeutic potentials remain largely unknown. Based on previous studies
on chalcones and flavonoids,[14,15] modification of the terminal phenyl ring could
enhance the cytotoxicity. We proposed that its anticancer activity can be possibly
improved with modifications on the ring B. Therefore, as part of our studies on the
discovery of anticancer chalcone derivatives, we initiated the synthesis and biological
evaluation of FMC (1) and its analogues bearing different substituents at chalcone
terminal. These aromatic aldehydes with substituents at different positions included
4-bromobenzaldehyde and 2-fluorobenzaldehyde and with different steric hindrance
included benzaldehyde, 2-(trifluoromethyl)benzaldehyde, and 2-naphthaldehyde.
FMC (1) has a common chalcone skeleton with a unique fully substituted ring
A: a methoxyl group at 20 position, dihydroxy groups at 40 and 60 position, a formyl
group at 30 position, and methyl group at 50 position. The preliminary retrosynthesis
Figure 1. Structures of FMC and FMF.

SYNTHESIS AND BIOEVALUATION OF FMC AND ANALOGUES
3141
analysis showed that the selective methylation of the hydroxy group at 20 position
has been the most challenging step (limiting synthetic factor). Accordingly, our
group recently established a synthetic methodology that was able to selectively meth-
ylate the hydroxyl group of 3-acetyl-2,4,6-trihydroxy-5-methylbenzaldehyde (8) in
good yield.[16,17] Based on this finding, we designed and accomplished a four-step
concise synthesis of 1 and its derivatives. In general, starting from commercially
available 2,4,6-trihydroxyacetophenone, formylation at 30 position under Vilsmeier–
Haack condition was followed by the introduction of methyl group at 50 position.
The key step of selective methylation at 20 position was achieved by trimethylsilyl-
diazomethane (TMSCHN2) and afforded the common intermediate (2) with
good regioselectivity and yield (51%) after optimization. Then various substituted
aromatic aldehydes were condensed through Claisen–Schmidt reaction in the
presence of potassium hydroxide. As the first reported synthesis of FMC and its
analogues, our synthesis enabled efficient and concise access to the key intermediate
and made the parallel synthesis of its analogues feasible, which could potentially
enhance the development of this compound class into clinical use.
RESULTS AND DISCUSSION
Chemistry: Synthesis of FMC (1) and Its Analogues
Claisen–Schmidt condensation between benzaldehyde and acetophenone was
one of the most popular methods for the synthesis of chalcones. Given the significant
amount of substituted benzaldehydes that are commercially available, this method
was applied in our synthesis of FMC (1) and its derivatives. The synthesis of the
key intermediate 2, 3-acetyl-4,6-dihydroxy-2-methoxy-5-methyl benzaldehyde, was
investigated.
In our initial synthesis, starting from 2,4,6-trihydroxybenzaldehyde, the formyl
group was reduced to methyl group by sodium cyanoborohydride, and then the
acetyl group was introduced to provide compound 4 with a decent overall yield
(about 68%) (Scheme 1). The first effort to synthesis of the key intermediate, com-
pound 2, was to directly methylate the hydroxyl group at 60 position with an adjacent
acetyl as proximal directing group. Unfortunately, treatment of compound 4 with
methyl iodide and bases (potassium hydroxide=potassium carbonate) mostly
afforded compound 5, with the methylation occurring at 40 position instead of
60 position.
Additional efforts to methylate compound 4 with dimethyl sulfate[18] in the
presence of sodium hydroxide led to two dimethoxy positional isomers, compounds
6a and 6b, in 59% and 14% yields respectively. However, selective removal of the
Scheme 1. Methylation of compound 3. Reagents and conditions: (a) NaBH3CN, HCl, rt, 20 h;
(b) BF3 ꢀ Et2O, HOAc ꢀ Ac2O; and (c) CH3I, KOH, or CH3I, K2CO3, reflux, 4 h.

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X. ZHUO ET AL.
Scheme 2. Dimethylation of compound 4.
4-hydroxyl group of 6a by sodium ethanethiolate[19] failed to afford the desired
compound 2 (Scheme 2).
The methylation reaction can be directed by the adjacent proximal groups,
which can facilitate the reaction by guiding the methyl group to the site of reaction.
Additional carbonyl groups may stabilize the intermediate anion formed with the
methylating agents at the desired position, and so an alternative strategy was sought
to introduce the formyl group at an adjacent place before methylation. As shown in
Scheme 3, compound 7, 3-acetyl-2,4,6-trihydroxybenzaldehyde, was prepared in
64.7% yield from the commercially available 2,4,6-trihydroxyacetophenone by Vils-
meier–Haack reaction.[16] Treatment of compound 7 with 3 equivalents of methyl
iodide[16] in the presence of potassium hydroxide afforded compound 8 in 62% yield.
With the installation of the formyl group, better selectivity for the monomethy-
lation at 60 position was observed when treating compound 8 at room temperature
with equivalent trimethylsilyldiazomethane (TMSCHN2, 2 M, solution in Et2O),
an alternative to diazomethane. The desired monoalkylated product, compound 8,
was obtained in 8% yield accompanied with 21% of dialkylated species. This
observation was quite exciting; the selective monomethylation was facilitated by
the adjacent acetyl group when TMSCHN2 was used as methylating agent.[17]
Further optimizations were conducted toward the stoichiometric amount of
TMSCHN2 and reaction temperature. When treating compound 8 with 2 M
TMSCHN2 at ꢁ40 ꢂC, compound 2 was obtained in 51% yield and 26% of starting
Scheme 3. Synthesis of compound 2. Reagents and conditions: (a) DMF, POCl3, rt, 1 h; (b) MeI, KOH,
reflux, 2 h; and (c) TMSCHN2, ꢁ40 ꢂC, 6 h.

SYNTHESIS AND BIOEVALUATION OF FMC AND ANALOGUES
3143
Scheme 4. Synthesis of compound FMC and its derivative.
materials were recovered, which could be reused after purification. The structure of
compound 2 was confirmed by two-dimensional (2D) NMR analysis, nuclear
Overhauser effect spectrometry (NOESY) and heteronuclear multiple bond corre-
lation (HMBC), as shown in Scheme 4. The NOE cross peaks between the formyl
proton and ene proton were observed.
As shown in Scheme 4, compound 1 and four derivatives were finally prepared
via Claisen–Schmidt reaction. Treatment of compound 2 with the corresponding
substituted benzaldehydes in the presence of 30% KOH aqueous solution afforded
the desired compounds in good yields (40.7–59.5%). The structure of 1 was
confirmed by MS, NMR, HMBC, and NOESY studies, and the results are consistent
with prior findings in the literature.[12]
Biological Evaluation
FMC (1) has been reported to exhibit cytotoxicity on five human tumor cell
lines with IC50 values ranged from 79.8 ꢃ 2.6 mM to 165.7 ꢃ 6.1 mM,[13] showing an
enhanced inhibitory effect compared to several potential antitumor flavonoids that
isolated from Chinese herbal medicines.[20–22] All synthesized FMC (1) and analo-
gues 1b–1e were evaluated for their in vitro anticancer activity against a panel of
human cancer cell lines, including A549 lung carcinoma cells, DU-145 prostate
cancer cells, HCT-8 colon adenocarcinoma cells, HL-60 acute leukemia cells,
GNM lymph node metastasis of cancer cells, and human endothelial HUVEC cells,
a normal cell useful for assessing anti-angiogenic potential. As the results show in
Table S1 (available online in the Supporting Information), compound 1 and its ana-
logues 1c, 1d, and 1e showed no overt cell killing or growth inhibition with IC50
values greater than 50 mM, which was consistent with prior results in the literature
(79.8 ꢃ 2.6 mM to 165.7 ꢃ 6.1 mM). The analogue 1b with a bromine at 40 position
on ring B exhibited the moderate activity against HCT-8, A549, GNM, DU-145,
HL-60, and HUVEC cancer cell lines with IC50 values of 17.9 ꢃ 0.6, 15.5 ꢃ 0.8,
18.1 ꢃ 1.0, 20.2 ꢃ 1.6, 10.8 ꢃ 0.9, and 16.3 ꢃ 1.2 mM respectively, which were up to
10 times more potent than the parent compound 1.

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X. ZHUO ET AL.
CONCLUSION
In summary, the first total synthesis of FMC (1) was accomplished. A facile
synthetic route was reported and all compounds were synthesized from 2,4,6-trihy-
droxyacetophenone through a four-step sequence, which could be used to rapidly
produce analogues for SAR studies toward to activity and pharmacological proper-
ties. The analogue with bromide at C-4 on ring B was optimal for tumor cell growth
inhibition with IC50 values ranging from 10.8 ꢃ 0.9 to 20.2 ꢃ 1.6 mM, showing a
10-fold improved activity compared to the lead compound 1. Further modifications
on this compound series and investigations of their mechanism of action are
undergoing and results will be reported in due course.
EXPERIMENTAL
All melting points were measured on a YuHua X-4 melting-point apparatus
without correction. Progress of the reactions was monitored with thin-layer chroma-
tography (TLC) using aluminium sheets with silica gel 60 F254 from Merck. The
spectra of 1H NMR and 13C NMR were recorded in solution in CDCl3 or dimethyl-
sulfoxide (DMSO-d6) on a Bruker ARX 500-MHz spectrometer. The chemical shifts
are expressed in parts per million (ppm) using tetramethylsilane (TMS) as internal
reference. HRMS was recorded on Bruker microTOF-Q II mass spectrometers.
4-Bromobenzaldehyde, 2-naphthaldehyde, 2-fluorobenzaldehyde, and 2-trifluoro-
methylbenzaldehyde were purchased from Acros Organics (New Jersey, USA).
Other chemicals were purchased from SCRC (Beijing, China). All reagents and
solvents were analytical grade.
All experiments, which were sensitive to moisture or air, were carried out
under N2 atmosphere. Commercial reagents were used as received without further
purification unless otherwise noted. EtOAc was washed with an equal volume of
5% Na2CO3 and dried over CaCl2.
3-Acetyl-2,4,6-trihydroxybenzaldehyde (7)
DMF (0.4 ml, 5 mmol) and phosphoryl chloride (0.5 mL, 5.5 mmol) to the
solution of 2,4,6-trihydroxyacetophenone (841 mg, 5 mmol) and EtOAc (10 mL) in
an ice bath. Then the reaction mixture was further stirred for 60 min at room tem-
perature. Ice water was added to the reaction mixture and extracted with EtOAc.
The EtOAc layer was washed with brine solution, dried over Na2SO4, and concen-
trated to afford the crude product. The residue was purified by column chromato-
graphy on silica gel with petroleum ether–EtOAc (5:1 to 7:3 v=v) as an eluent to
obtain 7 (635 mg, 64.7%) as colorless solid, which was used directly in the next
1
reaction without recrystallization. Mp: 162–163 ꢂC. HNMR (500 MHz, DMSO-d6)
d: 14.84 (1H, s, chelated-OH-2), 13.65 (1H, s, chelated-OH-4), 12.22 (1H, s,
chelated-OH-6), 9.99 (1H, s, CHO), 5.88 (1H, s, Ph-5), 2.52 [3H, s, C(O)CH3]. 13C
NMR (125 MHz, DMSO-d6) d: 203.8 (CO), 192.3 (CHO), 171.2 (C-6), 170.3
(C-2), 168.1 (C-4), 104.3 (C-5), 103.9 (C-3), 94.9 (C-1), 32.8 [C(O)CH3]. HRMS
m=z: calcd. for C9H7O5: 195.0293 [M – H]þ; found: 195.0306.

SYNTHESIS AND BIOEVALUATION OF FMC AND ANALOGUES
3145
3-Acetyl-2,4,6-trihydroxy-5-methylbenzaldehyde (8)
KOH (225 mg, 4 mmol) was added to the solution of 7 (392 mg, 2 mmol) in
methanol (10 mL) and stirred in an ice bath. Then methyl iodide (0.5 mL) was slowly
added to the mixture. The reaction mixture was refluxed for 2 h. Solvent was evapo-
rated and the residue was purified by column chromatography on silica gel with
petroleum ether–EtOAc (5:1 to 2:1 v=v) to obtain 8 (261 mg, 62%) as colorless
solid, which was used directly in the next reaction without recrystallization.
Mp: 153–154 ꢂC.1H NMR (500 MHz, CDCl3) d: 15.23 (1H, s, chelated-OH-2),
14.25 (1H, s, chelated-OH-4), 10.13 (1H, s, CHO), 5.77 (1H, s, chelated-OH-6),
2.73 [3H, s, C(O)CH3], 2.04 (3H, s, CH3-5). 13C NMR (125 MHz, DMSO-d6) d:
204.0 (CO), 193.1 (CHO), 170.0 (C-6), 167.9 (C-2), 165.3 (C-4), 104.7 (C-5), 103.9
(C-3), 103.0 (C-1), 33.0 [C(O)CH3], 7.6 (5-CH3). HRMS m=z: calcd for C10H9O5:
209.0450 [M – H]þ; found: 209.0462.
3-Acetyl-4,6-dihydroxy-2-methoxy-5-methylbenzaldehyde (2)
Compound 8 (2.1 g, 10 mmol) was dissolved in anhydrous EtOAc-MeOH (5:1,
30 mL), TMSCHN2 (10 mL, 20 mmol, 2 M solution in Et2O) was added slowly at
ꢁ40 ꢂC under N2, and the mixture was stirred for 4 h. Then additional TMSCHN2
(5 mL, 10 mmol, 2 M solution in Et2O) was added and stirred at ꢁ40 ꢂC for another
2 h. The reaction mixture was quenched with acetic acid with stirring at room tem-
perature. The solvents were removed under reduced pressure, and the residue was
purified by silica gel using petroleum ether–EtOAc (20:1 to 5:1 v=v) to obtain 2
1
(1.14 g, 51%) as colorless prisms. Mp: 106–107 ꢂC. H NMR (500 MHz, CDCl3) d:
14.07 (1H, s, chelated-OH-6), 12.60 (1H, s, chelated-OH-4), 10.10 (1H, s, CHO),
3.99 (3H, s, OCH3), 2.75 [3H, s, C(O)CH3], 2.08 (3H, s, CH3-5). 13C NMR
(125 MHz, CDCl3) d: 203.2 (CO), 192.4 (CHO), 168.8 (C-6), 166.0 (C-2), 165.9
(C-4), 108.1 (C-5), 100.1 (C-3), 90.8(C-1), 66.7 (OCH3), 31.4 [C(O)CH3],
6.7(5-CH3). HRMS m=z: calcd. for C11H11O5: 223.0606 [M – H]þ; found: 223.0623.
General Procedure for the Claisen–Schmidt Reactions
A solution of 2 (2 mmol) in EtOH (5 mL) and 30% KOH (5 mL) in water
containing an appropriate aldehyde (3 mmol) was stirred at room temperature for
36 h. After the reaction was complete by TLC analysis, the mixture was poured into
ice-cold 1 N HCl and then extracted with CH2Cl2. The extract was washed
with brine, dried over Na2SO4, and concentrated under vacuum. The residue was
chromatographed on silica gel with petroleum ether–EtOAc (20:1 to 3:1 v=v) to
obtain the target compounds 1, 1b, 1c, 1d, and 1e.
Cytotoxic Activity Assay
The cytotoxic activity assay was performed.[3] All cells stock cultures were
grown in 96-well microtiter plates at densities of 5 ꢄ 103 cells per well with test com-
pounds added from DMSO-diluted stock. After 36 h in culture, attached cells were
fixed with cold 50% trichloroacetic acid and then stained with 0.4% sulforhodanmine

3146
X. ZHUO ET AL.
B (SRB). The absorbency at 562 nm was measured using a microplate reader after
solubilizing the bound dye. IC50 values were calculated from five different concentra-
tions and data were reported as mean ꢃ standard deviation (SD). The following
human tumor cell lines were used in the assay: A549 (human lung carcinoma),
DU145 (human prostate cancer cell), HCT-8 (colon adenocarcinoma), HL-60
(human leukemia cell), GNM (lymph node metastasis of cancer cell), and HUVEC
(human endothelial cell). All cell lines were purchased from the American Type
Culture Collection (ATCC) and were cultured at 37 ꢂC in a humidified incubator
with 5% CO2. Culture medium was RPMI-1640 supplemented with 25 nM HEPES,
0.25% sodium bicarbonate, and 10% fetal bovine serum.
FUNDING
This project was supported by the National Natural Science Foundation of
China (No. 81072546).
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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