teb 1

Chinese Pharmaceutical Association

Institute of Materia Medica, Chinese Academy of Medical Sciences

Acta Pharmaceutica Sinica B

Acta Pharmaceutica Sinica B 2011;1(2):100–105

2211-3835 & 2011 In

hosting by Elsevier B

Peer review under re

doi:10.1016/j.apsb.20

nCorresponding au

E-mail address: h

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ORIGINAL ARTICLE

Synthesis and antidiabetic activity of b-acetamido ketones

Xing-hua Zhanga, Ju-fang Yanb, Li Fana, Gong-bao Wanga, Da-cheng Yanga,n

aSchool of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, ChinabCenter for Drug Screening, Chengdu Di Ao Pharmaceutical Group Co., Ltd, Chengdu 610041, China

Received 7 March 2011; revised 13 April 2011; accepted 28 April 2011

KEY WORDS

Diabetes mellitus;

Dakin–West reaction;

Trifluoroacetic acid;

b-Acetamido ketone;

4-Chloroacetophenone

stitute of Materia M

.V. All rights rese

sponsibility of Inst

11.06.006

thor. Tel.: þ13640

[email protected]

Abstract This paper reports the use of trifluoroacetic acid as a catalyst in the Dakin–West

reaction for the synthesis of b-acetamido ketones. The method has several advantages such as

requiring only mild conditions and a low concentration of catalyst. Screening of 19 b-acetamido

ketones for antidiabetic activity in vitro showed that their activity as peroxisome proliferator-

activated receptor (PPAR) agonists and as dipeptidyl peptidase 4 (DPP-IV) inhibitors was

fairly weak.

& 2011 Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical

Association. Production and hosting by Elsevier B.V. All rights reserved.

edica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Production and

rved.

itute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.

566978.

(Da-cheng Yang).

www.elsevier.com/locate/apsb

www.sciencedirect.com

dx.doi.org/10.1016/j.apsb.2011.06.006

mailto:[email protected]

dx.doi.org/10.1016/j.apsb.2011.06.006

Scheme 1 The model Dakin–West reaction using TFA as a

catalyst.

Table 1 The effect of amounts of TFA on the yield of the

model reaction shown in Scheme 1.

Reaction TFA (mol%) Time (h) Yield (%)

1 0.00 24 Trace

2 0.15 22 88.6

3 0.30 22 95.2

4 0.45 22 95.5

Scheme 2 Synthesis of b-acetamido ketones catalyzed by TFA.

Synthesis and antidiabetic activity of b-acetamido ketones 101

1. Introduction

Diabetes mellitus (DM) is a chronic disease caused by

inherited or acquired deficiency in insulin secretion and/or

insulin resistance. The disease is characterized by increased

blood glucose levels which, in turn, can damage many

physiological systems including blood vessels and nerves1.

Noninsulin-dependent or type 2 diabetes mellitus (T2DM)

accounts for about 95% of all DM and, according to the

World Health Organization (WHO), will likely exceed an

alarming 350 million cases by the year 20302. Owing to this

increasing prevalence, multidisciplinary studies aimed at pre-

venting and treating diabetes is a worldwide research priority.

The generally agreed treatment goal in T2DM is to maintain

near-normal levels of glycemic control in both the fasting and

postprandial states. Although diet and exercise are the first steps

toward achieving this goal, oral antidiabetic pharmacotherapy

also plays an important role. Successfully marketed T2DM drugs

may be classified into insulin secretagogues (meglitinides and

sulfonylureas), insulin sensitizers, aldose reductase inhibitors,

glucose absorption effectors (such as a-glucosidase inhibitors)

and the newly introduced dipeptidyl peptidase 4 (DPP-IV)

inhibitors3. Although these drugs are useful in the treatment of

T2DM, their long-term use may lead to a variety of adverse effects

including hepatotoxicity, weight gain, edema and indigestion.

Thus there remains an urgent need to develop new antidiabetic

agents with higher efficacy and lower toxicity for the long term

treatment of T2DM.

In the course of our previous work, we observed that

b-amino ketones possess remarkable antidiabetic activity4–11.

One issue with the synthesis of such molecules containing

multiple aromatic rings is their bulky space volume. In order

to reduce the space volume of this kind of molecule, we have

designed and synthesized a series of b-acetamidoketones in

which the arylamino group of b-amino ketones is replaced

with an acetamido group.

b-Acetamido ketones are versatile intermediates and useful

building blocks in the synthesis of other important organic

molecules like 1.3-amino alcohols12,13 and antibiotic drugs14,15.

This class of compounds was previously prepared via acylation

of b-amino ketones16, Michael addition of a,b-unsaturatedketones17,18 or photoisomerization of phthalimides19. However,

the most classical and facile method for the synthesis of

b-acetamido ketones is the Dakin–West reaction. Over recent

years, several catalysts for the Dakin–West reaction have been

developed and now include SnCl2 � 2H2O20, CeCl3 � 7H2O

21,

ZnO22, SiCl4–ZnCl223, heteropoly-acids24, Zr(HSO4)4 and

Mg(HSO4)225, PMA/SiO2

26, polyaniline supported acid27,

Mn(bpdo)2Cl2/MCM-4128, P2O5-HMDS29, sulfamic acid30

and cellulose sulfuric acid31. Although these catalysts possess

some attractive properties, they also have certain disadvantages

such as requiring a tedious workup, high temperatures, expen-

sive reagents and/or an inert atmosphere as well as producing a

low yield. Therefore, further research and development of new

catalysts is highly desirable.

Trifluoroacetic acid (TFA) is not only a useful agent in the

synthesis of fluorine-containing organic compounds and fluor-

opolymers, but is also an important reactant in the acylation

of amino acids32 and the deprotection of peptides33. As a

strongly acidic compound, TFA has been extensively used in

alkylation34 and acylation of aromatic compounds as well as

in the polymerization of olefins. However, the use of TFA as a

catalyst in the Dakin–West reaction has not been reported.

Herein, we report the synthesis of a series of b-acetamido

ketones by the TFA-catalyzed Dakin–West reaction and an

evaluation of their antidiabetic activity.

2. Results and discussion

In order to establish the efficiency of TFA as a catalyst in the

Dakin–West reaction, a model reaction of 4-chloroacetophe-

none (1 mmol) with 4-methylbenzaldehyde (1 mmol) and

acetyl chloride (0.4 mL) was carried out in the presence of

different amounts of TFA in acetonitrile at room temperature

(Scheme 1).

The results (Table 1) show that TFA is necessary for the

reaction to proceed with around 0.30 mol% being the optimal

amount.

To evaluate the scope of the reaction, other aldehydes and

ketones were used (Scheme 2) with the results shown in

Table 2.

Based on the results in Table 2, it is clear that the nature of

the aromatic aldehyde has a major impact on the yield of the

reaction. Thus aromatic aldehydes with electron-withdrawing

groups react more readily than those with electron-donating

groups although reactions 10, 12, 13 and 16 still produce good

yields. In addition, aromatic aldehydes with ortho- or para-

substituents (reactions 4, 5, 9 and 13) react faster than those

with meta-substituents (reactions 3, 7 and 12) with the

exception of nitrobenzaldehyde (reactions 1 and 2). As for

the liquid aldehydes (reactions 7, 8, 9, 11 and 13), reactions

proceeded with the formation of large quantities of solid

products and gave correspondingly high yields (around 90%).

Unexpectedly, the reaction of 4-methoxybenzaldehyde with

4-chloroacetophenone yielded only the corresponding chal-

cone despite stirring the chalcone (1 mmol) in acetonitrile

(3 mL) containing TFA (0.30 mol%) and acetyl chloride

(0.4 mL) for 12 h. Interestingly, aromatic aldehydes with

hydroxy groups yielded corresponding b-acetamido ketones

Table 2 Synthesis of b-acetamido ketones according to Scheme 2.

Reaction X R1 R2 Time (h) m.p. (1C) Yield (%)a

1 4-NO2 4-ClC6H4 H 64 139.5–140.6 83.0

2 3-NO2 4-ClC6H4 H 47 115.4–117.4 87.7

3 3,4-diCl 4-ClC6H4 H 36 221.0–224.0 89.4

4 2,4-diCl 4-ClC6H4 H 24 150.0–151.2 77.5

5 4-Cl 4-ClC6H4 H 16 134.5–136.2 95.5

6 4-Br 4-ClC6H4 H 22 133.6–134.4 83.4

7 3-Cl 4-ClC6H4 H 60 113.0–116.2 90.1

8 3-F 4-ClC6H4 H 28 119.0–121.4 94.0

9 2-Cl 4-ClC6H4 H 28 168.0–170.3 89.0

10 3-CH3O 4-ClC6H4 H 90 107.4–109.7 80.0

11 H 4-ClC6H4 H 22 107.5–109.0 90.0

12 3-CH3 4-ClC6H4 H 110 119.0–122.0 86.3

13 4-CH3 4-ClC6H4 H 22 130.9–133.5 95.2

14 3-CH3O-4-HO 4-ClC6H4 H 36 150.0–152.4 43.5

15 4-HO 4-ClC6H4 H 66 227.9–229.6 53.5

16 3,4,5-triCH3O 4-ClC6H4 H 15 177.2–178.9 85.0

17 H 3-NO2C6H4 H 65 132.1–133.2 96.0

18 2-Cl 4-CH3OC6H4 H 12 155.2–156.7 81.7

19 H CH3 COCH3 24 132.0–133.5 69.0

aIsolated yield.

Table 3 Biological activity of b-acetylamino ketones.

Compound Concentration

(nmol/mL)aPPAR

activation

(%)

DPP-IV

Inhibition

(%)

1 28.8 2.84 9.53

2 28.8 1.08 4.24

3 26.9 18.45 8.76

4 26.9 �1.49 3.79

5 29.7 �0.73 8.47

6 26.3 12.21 �0.26

7 29.7 �0.93 12.71

8 31.0 �0.89 �7.94

9 29.7 �1.53 11.35

10 30.1 �0.53 6.30

11 33.1 3.24 �4.34

12 31.7 14.17 �1.22

13 31.7 16.61 �0.48

14 28.8 19.05 4.41

15 31.5 22.86 3.56

16 25.5 14.17 3.61

17 32.0 �11.70 –

18 30.1 20.75 –

19 35.5 – –

Positive

controlb100 73.11

aThe concentration of test compounds is 10.0 mg/mL (the

corresponding nmol/mL is shown).bPositive controls for PPRE agonist activity and DPP-IV

inhibition activity are pioglitazone (0.78 mg/mL) and KR-62436

(6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylami-

no]ethylamino}nicotinonitrile) (0.78 mg/mL), respectively.

Xing-hua Zhang et al.102

(reactions 14 and 15) without further acetylation of the

hydroxy group albeit giving lower yields. However, the

a-substituted enolisable alkyl ketone, 2,4-pentanedione (reac-

tion 19) produced only a moderate yield of the corresponding

b-acetamido ketone. The structure of all products was estab-

lished based on their 1H and 13C NMR spectra.

Given that in previous studies, b-acetamido compounds

displayed no a-glucosidase inhibition activity, we designed the

current series of compounds to target the peroxisome prolif-

erator-activated receptor response element (PPRE) and dipepti-

dyl peptidase 4 (DPP-IV). In evaluating this type of antidiabetic

activity at a concentration of 10.0 mg/mL (Table 3), it was found

that both PPAR agonist activity and DPP-IV inhibition activity

were weak. Nevertheless, the structure–activity relationship

(SAR) for PPAR agonist activity demonstrated that products

with electron-donating groups on the aromatic aldehyde ring

possessed better activity than those with electron-withdrawing

groups in the order: 15 (4-OH)413 (4-CH3)46 (4-Br)41

(4-NO2). Based on these results, we propose that the OH group

in the product of reaction 15 improves water-solubility and

results in stronger binding to the PPAR. The product of reaction

14 is a little less active than that of reaction 15, suggesting that

the additional 3-OCH3 group does not favor the interaction with

PPAR as also seen in the product of reaction 10. Furthermore,

the products of reactions of halogen substituted aromatic

aldehydes (reactions 4, 5, 7, 8 and 9) exhibit some antagonistic

effects.

The presence of different functional groups in the acetophe-

none ring also appears to produce compounds with different

levels of PPAR agonist activity. For example, the product of

reaction 18 (4-CH3O substituent) shows better PPAR agonist

activity than that of reaction 9 (4-Cl substituent).

The bioactivity of a potential drug is dependent on a

number of factors such as the distribution of electron density,

space volume, hydrogen bond density and molecular flexibil-

ity. Through examination of the ChemDraw 3D structures

(Fig. 1), we conclude that the product of reaction 15 has

poorer molecular flexibility than pioglitazone, making it less

able to fit the space structure of PPAR.

Given the limited activity of the target compounds, we

maintain it is essential to synthesize more of these b-acetamido

Figure 1 Three-dimensional structures of the product of reaction

15 and pioglitazone.


ketones and assay their biological activity to establish

structure–activity relationships. To date, we have synthesized

more than 200 such compounds and evaluation of their

antidiabetic activity is underway.

3. Conclusions

We report the use of TFA as an efficient catalyst of the Dakin–

West reaction of aromatic aldehydes, enolizable ketones and

acetonitrile in the presence of acetyl chloride to produce b-acetamido ketones under mild reaction conditions. We also report

preliminary data on the antidiabetic activity of the b-acetamido

ketones in in vitro assays of PPAR agonist and DPP-IV inhibition

activity. Although the activities were weak, the compounds

represent a valuable starting point in the search for novel

antidiabetic drugs.

4. Experimental procedures

4.1. General methods

All solvents and reagents were of chemical or analytical grade.

The progress of reactions was monitored by TLC using

solvent systems of different polarities. Melting points were

measured using an X-6 micro-melting point apparatus and are

uncalibrated. 1H NMR and 13C NMR spectra were recorded

in DMSO-d6 on a Bruker AV-300 spectrometer; chemical

shifts (d) are expressed in ppm downfield from the TMS

internal standard. Coupling constant (J) values are in Hz.

High resolution mass spectra (HRMS) were recorded on a

Bruker Daltonics Data Analysis 3.2, USA.

4.2. General procedure for the synthesis of

b-acetamido ketones

To a solution of an enolizable ketone (1.0 mmol), an aldehyde

(1.0 mmol) and acetyl chloride (0.4 mL) in acetonitrile

(2.0 mL), TFA (0.30 mol%) was added dropwise and the

mixture stirred for 0.5 h at 0 1C, and then allowed to warm

to ambient temperature. On completion of the reaction, the

mixture was poured into iced water (20.0 mL) and the pH

adjusted to 7 with saturated NaHCO3, which resulted in

precipitation of the desired b-acetamido ketone. The precipi-

tate was filtered, washed with diethyl ether (1.0 mL) and

recrystallized from a mixture of ethyl acetate and diethyl

ether. Most of the reaction products are known compounds,

which were easily characterized by comparison of their 1H and13C NMR spectra with those of authentic samples.

4.3. DPP-IV inhibition activity

A 200 mL reaction system containing DPP-IV (Sigma), a test com-

pound, and 25 mmol/L HEPES buffer (containing 140 mmol/L

NaCl, 1% BSA and 80 mmol/L MgCl2) was preincubated at

room temperature for 10 min. The reaction was initiated by

the addition of dipeptidyl peptidase Gly–Pro–Gly–Gly, and the

reaction mixture incubated at room temperature for 25–45 min.

The fluorescence intensity (F) at excitation 355 nm and emission

460 nm was then measured. A negative control (no test com-

pound) and a blank control (no enzyme) were run simultaneously.

The test compounds were initially assayed in duplicate at a

concentration of 10 mg/mL. The % inhibition was calculated as

[1�(Ftest compound�Fblank)/(Fnegative�Fblank)]� 100%. If an inhibi-

tion of more than 50% was observed, the compound was

subsequently consequently tested at six concentrations in duplicate

and the IC50 value calculated using the Xlfit software.

4.4. PPAR agonist activity

HepG2 cells were cultured in low glucose DMEM supple-

mented with 100 U/mL streptomycin and penicillin. One day

prior to transfection, the cells were plated in 96-well plates at

1.5� 104 cells per well. After reaching 70% confluence,

plasmid pPPRE-Luc with firefly luciferase reporter gene and

the control plasmid phRL-TK with renilla luciferase reporter

gene were transfected into the cells. After 24 h, the medium

was replaced with either fresh medium (negative control) or

fresh medium containing a test compound (10 mg/mL) or

pioglitazone (positive control). Non-transfected cells were

used as blank. After a further 24 h, the expression of

luciferases was measured using the Dual-Luciferase Reporter

Gene Assay Kit (Promega). The percent activation (T%)

were calculated as [(L1Sample�L1Blank)/(L1Negative�L1Blank)]/

[(L2Sample�L2Blank)/(L2Negative�L2Blank)]� 100%, where L1

represents the value for firefly luciferase and L2 the value

for Renilla luciferase.

4.5. Characterization of new products

4.5.1. b-Acetamido-b-(4-bromophenyl)-4-

chloropropiophenone (6)1H NMR (DMSO-d6, 300 MHz); d 1.77 (s, 3H, COCH3), 3.37

(dd, J¼6.0 and 17.1 Hz, 1H, CH2), 3.56 (dd, J¼8.4 and

17.1 Hz, 1H, CH2), 5.25–5.32 (m, 1H, CHN)), 7.30 (d, J¼8.4

Hz, 2H, Ar–H), 7.49 (d, J¼8.1 Hz, 2H, Ar–H), 7.58 (d,

J¼8.7 Hz, 2H, Ar–H), 7.95 (d, J¼8.7 Hz, 2H, Ar–H), 8.42 (d,

J¼6.0 Hz, 1H, NH). 13C NMR (DMSO-d6, 75 MHz); d 196.4,

168.9, 142.9, 138.6, 135.6, 131.5, 130.4, 129.4, 129.2, 120.3,

48.8, 44.7, 22.9. HRMS calcd. for C17H15BrClNO2Na

401.9865. Found 401.9867.

4.5.2. b-Acetamido-b-(3-fluorophenyl)-4-chloropropiophenone (8)1H NMR (DMSO-d6, 300 MHz); d 1.80 (s, 3H, COCH3), 3.40


17.4 Hz, 1H, CH2), 5.32–5.39 (m, 1H, CHN), 7.06 (t, J¼8.6

Hz, 1H, Ar–H), 7.20 (d, J¼7.2 Hz, 2H, Ar–H), 7.32–7.39 (m,

1H, Ar–H), 7.59 (d, J¼8.4 Hz, 2H, Ar–H), 7.98 (d, J¼8.7 Hz,

2H, Ar–H), 8.47 (d, J¼7.5 Hz, 1H, NH). 13C NMR (DMSO-d6,

75 MHz); d 196.4, 169.0, 160.9, 146.4, 138.6, 135.6, 130.5,

Xing-hua Zhang et al.104

130.4, 129.2, 123.2, 123.1, 113.9, 48.9, 44.8, 22.9. HRMS

calcd. for C17H15ClFNO2Na 342.0669. Found 342.0668.

4.5.3. b-Acetamido-b-(3-methoxyphenyl)-4-

chloropropiophenone(10)1H NMR (DMSO-d6, 300 MHz) d 1.79 (s, 3H, COCH3), 3.36


16.8 Hz, 1H, CH2), 3.74 (s, 3H, OCH3), 5.27–5.36 (m, 1H,

CHN), 6.79 (d, J¼8.1 Hz, 2H, Ar–H), 6.93 (s, 1H, Ar–H),

7.22 (t, J¼7.8 Hz, 1H, Ar–H), 7.59 (d, J¼8.7 Hz, 2H, Ar–H),

7.97 (d, J¼8.1 Hz, 2H, Ar–H), 8.41 (d, J¼8.1 Hz, 1H, NH).13C NMR (DMSO-d6, 75 MHz); d 196.6, 168.9, 159.6, 144.9,

138.5, 135.6, 130.4, 129.7, 129.2, 119.3, 112.9, 112.5, 55.4, 49.4,

45.1, 22.9. HRMS calcd. for C18H18ClNO3Na 354.0869.

Found 354.0867.

4.5.4. b-Acetamido-b-(3-methylphenyl)-4-


(s, 3H, CH3), 3.34–3.41 (m, 1H, CH2), 3.48–3.52 (m, 1H,

CH2), 5.28–5.33 (m, 1H, CHN), 7.04 (d, J¼8.4 Hz, 1H,

Ar–H), 7.12–7.23 (m, 3H, Ar–H), 7.59 (d, J¼8.7 Hz, 2H,

Ar–H), 7.97 (d, J¼8.7 Hz, 2H, Ar–H), 8.30 (d, J¼8.4 Hz, 1H,

NH). 13C NMR (DMSO-d6, 75 MHz); d 196.7, 168.7, 143.2,

138.5, 137.7, 135.7, 130.4, 129.2, 128.6, 127.9, 127.7, 124.1,

49.4, 45.3, 23.1, 21.5. HRMS calcd. for C18H18ClNO2 Na

338.0922. Found 338.0918.

4.5.5. b-Acetamido-b-(3-methoxy-4-hydroxyphenyl)-4-



16.5 Hz, 1H, CH2), 3.75 (s, 3H, OCH3), 5.22–5.29 (m, 1H,

CHN), 6.68 (d, J¼8.1 Hz, 2H, Ar–H), 6.93 (s, 1H, Ar–H),

7.59 (d, J¼8.4 Hz, 2H, Ar–H), 7.97 (d, J¼8.4 Hz, 2H, Ar–H),

8.32 (d, J¼8.1 Hz, 1H, NH). 13C NMR (DMSO-d6, 75 MHz);

d 197.0, 168.7, 147.8, 145.9, 138.5, 135.8, 134.0, 130.4, 129.2,

119.4, 115.5, 111.6, 56.1, 49.4, 23.0. HRMS calcd. for

C18H18ClNO4 Na 412.0925. Found 412.0917.

4.5.6. b-Acetamido-b-(4-hydroxyphenyl)-4-chloropropiophenone (15)1H NMR (DMSO-d6, 300 MHz); d 1.75 (s, 3H, COCH3),

3.34–3.36 (m, 1H, CH2), 3.40–3.49 (m, 1H, CH2), 5.20–5.27

(m, 1H, CHN), 6.68 (d, J¼8.4 Hz, 2H, Ar–H), 7.06 (d,

J¼8.7 Hz, 2H, Ar–H), 7.57 (d, J¼8.1 Hz, 2H, Ar–H), 7.94

(d, J¼9.0 Hz, 2H, Ar–H), 8.19 (d, J¼8.1 Hz, 1H, NH), 9.28

(s, 1H, OH). 13C NMR (DMSO-d6, 75 MHz); d 196.9, 168.6,

156.7, 138.5, 135.7, 133.3, 130.4, 129.2, 128.2, 48.9, 45.2, 23.0.

HRMS calcd. for C17H16ClNO3 Na 340.0650. Found 340.0646.

Acknowledgments

This project is supported by ‘‘The Fundamental Research

Funds for the Central Universities’’ (XDJK2010C067). The

authors are grateful to Mr. Qunli Luo and Mr NingWang for

their assistance in measuring 1H and 13C NMR spectra.

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