synthesis of psoralen derivatives and their blocking effect of...

Arch Pharm Res Vol 30, No 2, 155-160, 2007

155

http://apr.psk.or.kr

Synthesis of Psoralen Derivatives and Their Blocking Effect of

hKv1.5 Channel

Jae Soon Eun, Kwang Sik Kim, Han Na Kim1, Seon Ah Park1, Tian-Ze Ma1, Kyung A Lee, Dae Keun Kim,

Hyung Kyo Kim2, In Su Kim2, Young Hoon Jung2, Ok Pyo Zee2, Dong Jin Yoo3, and Yong Geun Kwak1

College of Pharmacy, Woosuk University, Samrye 565-701, Korea, 1Department of Pharmacology, Chonbuk

National University Medical School, Jeonju, Jeonbuk 560-182, Korea, 2College of Pharmacy, SungKyunKwan Uni-

versity, Suwon 440-746, Korea, and 3Department of Chemistry, Seonam University, Namwon 590-711, Korea

(Received September 12, 2006)

Previously, we found that a furocoumarin derivative, psoralen (7H-furo[3,2-g][1]benzopyran-7-one), blocked a human Kv1.5 potassium channel (hKv1.5) and has a potential antiarrhythmiceffect. In the present study, to develop more potent hKv1.5 blockers or antiarrhythmic drugs,we synthesized ten psoralen derivatives and examined their blocking effects on hKv1.5 stablyexpressed in Ltk- cells. Among the newly synthesized psoralen derivatives, three derivatives(Compounds 5, 9 and 10) showed the open channel-blocking effect. Compound 9 among themwas the most potent in blocking hKv1.5. We found that compound 9, one of the psoralen deriv-atives, inhibited the hKv1.5 current in a concentration-, use- and voltage-dependent mannerwith an IC50 value of 27.4 ± 5.1 nM at +60 mV. Compound 9 accelerated the inactivation kinet-ics of the hKv1.5 channel, slowed the deactivation kinetics of hKv1.5 current resulting in a tailcrossover phenomenon. Compound 9 inhibited hKv1.5 current in a use-dependent manner.These results indicate that compound 9, one of psoralen derivatives, acts on hKv1.5 channelas an open channel blocker and is much more potent than psoralen in blocking hKv1.5 chan-nel. If further studies were done, compound 9 might be an ideal antiarrhythmic drug for atrialfibrillation.

Key words: hKv1.5 channel blocker, Psoralen derivatives, Antiarrhythmic drug

INTRODUCTION

Psoralen is one of the major constituents of Heracleum

moellendorffii Hance. Psoralen has been used in vitiligo

(Kostovic et al., 2003), fungal infection (Smith et al., 2004)

and cancer (Carneiro et al., 2004). Recently, we found

that a furocoumarin derivative, psoralen (7H-furo[3,2-g][1]

benzopyran-7-one), blocked a human Kv1.5 potassium

channel (hKv1.5) and has an antiarrhythmic effect (Eun et

al., 2005).

Arrhythmias are abnormal rhythms of the heart and

cause the heart to pump less effectively. Antiarrhythmic

drugs manage arrhythmias through the regulation of the

cardiac action potential duration. However, one of the

major obstacles to the widespread use of antiarrhythmic

drugs is the occurrence of new arrhythmias (Roden,

1998). One of the ways to reduce this proarrhythmic effect

of antiarrhythmic drugs is to develop the lesioned tissue-

specific antiarrhythmic drugs. The voltage-gated K+ (Kv)

channels contribute to cell repolarization and regulate the

action potential duration (Roden and George, 1999). The

hKv1.5 is known to have the same electrophysiological

and pharmacological properties as IKUR, a current specific

in human atrium (Fedida et al., 1998). Development of

highly selective blockers for the hKv1.5 channel will lead

to ideal drugs specific for the treatment of atrial fibrillations.

In the present study, to develop more potent hKv1.5

blockers or antiarrhythmic drugs, we synthesized ten

psoralen derivatives with 5-methoxypsoralen or 8-meth-

oxypsoralen and examined their blocking effects on

cardiac K+ channels expressed in Ltk- cells.

MATERIALS AND METHODS

Commercially available reagents were used without ad-

Correspondence to: Yong Geun Kwak, Department of Pharmacol-ogy, Chonbuk National University Medical School, Jeonju, Jeon-buk 560-182, KoreaTel: 82-63-270-3091, Fax: 82-63-275-2855E-mail: [email protected]

156 J. S. Eun et al.

ditional purification, unless otherwise stated. All anhydrous

solvents were distilled over CaH2 or P2O5. 5-Methoxy-

psoralen and 8-methoxypsoralen were obtained from

Aldrich Chemical Co. All reactions were performed under

an inert atmosphere of nitrogen or argon. Nuclear magnetic

resonance spectra (1H- and 13C-NMR) were recorded on

a Varian Unity Inova 500 MHz spectrometer for CDCl3solutions and chemical shifts are reported as parts per

million (ppm) relative to, respectively, residual CHCl3 δH

(7.26 ppm) and CDCl3 δC (77.0 ppm) as internal standards.

Resonance patterns are reported with the notations s

(singlet), d (doublet), t (triplet), q (quartet), and m (multiplet).

In addition, the notation br is used to indicate a broad

signal. Coupling constants (J) are reported in hertz (Hz).

IR spectra were recorded on a Nicolet 205 Infrared spec-

trophotometer or Bruker Vector 22 Infrared spectrophoto-

meter and are reported as cm-1. Thin layer chromatography

was carried out using plates coated with Kieselgel 60 F254

(Merck). For flash column chromatography, E. Merck

Kieselgel 60 (230-400 mesh) was used.

General procedure for synthesis of the 4-Phenyla-

cetoxy-7H-furo[3,2-g][1]benzopyran-7-one (2)

To a solution of 5-hydroxypsoralen (0.012 g, 0.059 mmol)

in anhydrous CH2Cl2 (3 mL) was added dicyclohexylcar-

bodiimide (0.029 g, 0.143 mmol), 4-N,N-dimethylamino-

pyridine (0.004 g, 0.030 mmol), and phenyl acetic acid

(0.019 g, 0.143 mmol). The resulting mixture was stirred

for 3.5 h and quenched with H2O. The aqueous layer was

extracted with CH2Cl2 and the organic layer was washed

with H2O, brine, dried over MgSO4, filtered and concentrated

in vacuo. The residue was purified by flash chromatography

(Hexane : EtOAc = 3 : 1) to give compound 2 (0.016 g,

85% yield) as a white solid: Rf= 0.29 (Hexane : EtOAc = 3

: 1); 1H-NMR (500 MHz, CDCl3) δ 4.01 (s, 2H), 6.28 (d,

1H, J = 9.5 Hz), 6.39 (d, 1H, J = 2.0 Hz), 7.26 (s, 1H),

7.37-7.48 (m, 5H), 7.52 (d, 1H, J = 9.5 Hz), 7.58 (d, 1H, J

= 2.0 Hz); IR (neat) 1733, 1633, 1125 cm-1.

4-(1-Oxobutoxy)-7H-furo[3,2-g][1]benzopyran-7-one (3)

Yield 94%; white solid; Rf= 0.28 (Hexane : EtOAc = 3 : 1);1H NMR (500 MHz, CDCl3) δ 1.29 (t, 3H, J = 7.0 Hz), 1.90

(tq, 2H, J = 7.5, 7.0 Hz), 2.74 (t, 2H, J = 7.5 Hz), 6.38 (d,

1H, J = 10.0 Hz), 6.64 (d, 1H, J = 2.0 Hz), 7.39 (s, 1H),

7.64 (d, 1H, J = 2.0 Hz), 7.82 (d, 1H, J = 10.0 Hz); IR

(neat) 1733, 1639, 1142 cm-1.

General procedure for synthesis of 4-Methoxyethoxy-

methoxy-7H-furo[3,2-g][1]benzopyran-7-one (4)

A solution of 5-hydroxypsoralen (0.015 g, 0.074 mmol)

in DMF (3 mL) was cooled to 0oC. NaH (0.004g, 0.089

mmol, 60% in mineral oil) was added slowly for 10 min

and then the mixture was stirred for 2 h at 0oC. MEMCl

(0.017 mL, 0.148 mmol) was added dropwise and the

reaction mixture was stirred for 16 h at room temperature

and extracted with EtOAc. The organic layer was washed

with brine, dried over MgSO4, filtered and concentrated in

vacuo. The residue was purified by flash chromatography

(Hexane : EtOAc = 2 : 1) to give compound 4 (0.017 g,

78% yield) as a white solid; Rf= 0.17 (Hexane : EtOAc = 2

: 1); 1H-NMR (500 MHz, CDCl3) δ 3.39 (s, 3H), 3.60 (d,

2H, J = 4.5 Hz), 3.95 (d, 2H, J = 4.5 Hz), 5.52 (s, 2H),

6.30 (d, 1H, J = 9.5 Hz), 7.10 (d, 1H, J = 2.0 Hz), 7.19 (s,

1H), 7.59 (d, 1H, J = 2.0 Hz), 8.19 (d, 1H, J = 9.5 Hz); IR

(neat) 2922, 1729, 1619, 1122, 1047 cm-1.

4-Butoxy-7H-furo[3,2-g][1]benzopyran-7-one (5)

Yield 41%; white solid; Rf= 0.37 (Hexane : EtOAc = 4 :

1); 1H-NMR (500 MHz, CDCl3) δ 1.04 (t, 3H, J = 7.5 Hz),

1.59 (tq, 2H, J = 8.0, 7.5 Hz), 1.88 (tt, 2H, J = 8.0, 6.5 Hz),

4.47 (t, 2H, J = 6.5 Hz), 6.29 (d, 1H, J = 9.5 Hz), 6.96 (d,

1H, J = 2.5 Hz), 7.15 (s, 1H), 7.59 (d, 1H, J = 2.5 Hz),

8.18 (d, 1H, J = 9.5 Hz); IR (neat) 1725, 1622 cm-1.

9-Phenylacetoxy-7H-furo[3,2-g][1]benzopyran-7-one (7)


1); 1H-NMR (500 MHz, CDCl3) δ 4.13 (s, 2H), 6.39 (d, 1H,

J = 9.5 Hz), 6.84 (d, 1H, J = 2.5 Hz), 7.33-7.52 (m, 5H),

7.56 (s, 1H), 7.70 (d, 1.2H, J = 2.5 Hz), 7.78 (d, 1H, J =

9.5 Hz); IR (neat) 1734, 1587, 1133 cm-1.

9-(1-Oxobutoxy)-7H-furo[3,2-g][1]benzopyran-7-one (8)



1.90 (tq, 2H, J = 7.5, 7.0 Hz), 2.77 (t, 2H, J = 7.0 Hz), 6.36

(d, 1H, J = 9.5 Hz), 6.84 (d, 1H, J = 2.0 Hz), 7.59 (s, 1H),

7.68 (d, 1H, J = 2.0 Hz), 7.77 (d, 1H, J = 9.5 Hz); IR (neat)

1739, 1136 cm-1.

9-Methoxyethoxymethoxy-7H-furo[3,2-g][1]benzopyran-

7-one (9)


1); 1H-NMR (500 MHz, CDCl3) δ 3.33 (s, 3H), 3.58 (d, 2H,

J = 4.5 Hz), 4.14 (d, 2H, J = 4.5 Hz), 5.58 (s, 2H), 6.37 (d,

1H, J = 9.5 Hz), 6.83 (d, 1H, J = 2.0 Hz), 7.43 (s, 1H),

7.69 (d, 1H, J = 2.0 Hz), 7.78 (d, 1H, J = 9.5 Hz); IR (neat)

1712, 1103 cm-1.

9-Butoxy-7H-furo[3,2-g][1]benzopyran-7-one (10)



1.52 (tq, 2H, J = 8.0, 7.5 Hz), 1.77 (tt, 2H, J = 8.0, 6.0 Hz),

4.42 (t, 2H, J = 6.0 Hz), 6.29 (d, 1H, J = 9.5 Hz), 6.73 (d,

1H, J = 2.5 Hz), 7.27 (s, 1H), 7.61 (d, 1H, J = 2.5 Hz),

7.68 (d, 1H, J = 9.5 Hz); IR (neat) 1716, 1592, 1095 cm-1.

Open Channel Block of hKv1.5 by Psoralen Derivatives 157

Cell culture and transfectionThe method used to establish hKv1.5 expression in a

clonal mouse Ltk- cell line is the same as it was described

previously (Snyders et al., 1992). The transfected cells

were cultured in Dulbecco’s modified Eagle’s medium

supplemented with 10% horse serum and 0.25 µg/mL of

G418, under a 5% CO2 atmosphere. Before the experi-

ment the subconfluent cultures were incubated with 2 µM

dexamethasone for 12 h to induce the expression of the

hKv1.5 channels. The cells were removed from the dish

with a rubber policeman, a procedure that left the majority

of the cells intact.

Electrical recordingsThe currents were recorded by using the whole cell

configuration of the gigaohm-seal patch clamp techniques

(Kwak et al., 1999). The electrical signals were amplified

with a patch clamp amplifier (Axopatch-1D, Axon Instru-

ments, Foster). The currents were digitized by a signal

converter (Digidata 1200, Axon Instruments) and stored

on the hard disk of a computer. The micropipette with a

resistance of 1-2 MΩ (Kimax-51, 1.5-1.8×10 mm) for current

recording, was pulled out by a 2-stage pipette puller (PP-

83, Narishige, Tokyo, Japan). The intracellular pipette-filling

solution for whole cell mode contained 100 mM KCl, 10

mM HEPES, 5 mM K4BAPTA, 5 mM K2ATP and 1 mM

MgCl2 (pH 7.2). The extracellular solution contained 130

mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM

HEPES and 10 mM glucose (pH 7.35).

Statistical analysisThe results were expressed as mean ± SEM. The

student’s t-test were used to calculate the statistical

analysis. A value of p<0.05 was considered statistically

significant.

RESULTS AND DISCUSSION

In view of the above findings it was considered of

interest to undertake the synthesis of new psoralen

derivatives, especially 5- and 8- substituted psoralen (Fig.

1). In the preliminary results, 5- and 8-hydroxypsoralen

were known to be inactive on hKv1.5 current expressed in

the Ltk- cells. Therefore, hydroxyl moiety was converted to

various functional groups as described in Scheme 1.

Demethylation of 5-methoxypsoralen with boron tribromide

afforded the 5-hydroxypsoralen (Okamoto et al., 2001),

which then was acylated to give compounds 2 and 3 and

alkylated to give compounds 4, 5 in consideration of the

hydrophobicity and hydrogen bonding. Demethylation of

8-methoxypsoralen with magnesium iodide furnished the

8-hydroxypsoralen (Vennekamp et al., 2004). Compounds

7-10 were prepared by the similar method to the synthesis

of the 5-substituted psoralen deivatives.

Recently, cardiac Kv channels become one of the major

targets for the treatment of arrhythmias. A selective block

of hKv1.5-like current in human atrial myocytes results in

a significant prolongation of the action potential (Wang et

al., 1993; 1994). We previously reported that a furocou-

marin derivative, psoralen (7H-furo[3,2-g][1]benzopyran-

7-one) purified from the n-hexane soluble fraction of H.

moellendorffii Hance, blocked a human Kv1.5 potassium

channel (hKv1.5) and has an antiarrhythmic effect (Eun et

al., 2005, 2006). To find out more potent derivatives than

psoralen in blocking hKv1.5 current, they could be ideal

antiarrhythmic drugs specific for the treatment of atrial

fibrillations. We thus synthesized ten derivatives of psoralen

using 5-hydroxypsoralen or 8-hydroxypsoralen.

To compare the effects of psoralen derivatives in blocking

hKv1.5 current, we examined the effects of psoralen on

Fig. 1. Chemical structure of psoralen derivatives1. R1=H, R2=OCH3

2. R1=H, R2=OCOCH2C6H5

3. R1=H, R2=OCOCH2CH2CH3

4. R1=H, R2=OCH2OCH2CH2OCH3

5. R1=H, R2=OCH2CH2CH2CH3

6. R1=OCH3, R2=H7. R1=OCOCH2C6H5, R2=H8. R1=OCOCH2CH2CH3, R2=H9. R1=OCH2OCH2CH2OCH3, R2=H10. R1=OCH2CH2CH2CH3, R2=H

Scheme 1. Synthesis of 8-substituted psoralen derivatives


the hKv1.5 currents expressed in the Ltk- cells and summa-

rized their effects in Table I. Among the newly synthesized

psoralen derivatives, three derivatives (compounds 5, 9

and 10) showed the open channel-blocking effect. Com-

pound 9 among them was the most potent in blocking

hKv1.5. Therefore, we used only compound 9 in the other

experiments to clarify its action mechanism. Under control

conditions, depolarization positive to -20 mV elicited

outward currents that progressively increased with further

depolarizations. At +60 mV, after the current reached the

maximum, it declined slowly during the maintained depo-

larization. In the presence of compound 9 (3 µM), both

outward current during depolarizing steps and tail current

were reduced compared to the control group (Fig. 2). Fig.

2B shows the effect of compound 9 on the steady state

current-voltage relationship for the hKv1.5 channel con-

structed by plotting the current amplitudes at the end of

250-ms depolarizations as a function of the test pulse

voltage. In the presence of compound 9 (3 µM), an inhibition

of steady-state currents was observed through the whole

voltage range over which hKv1.5 was activated (n = 6).

The dose-response curve of compound 9 on the block of

hKv1.5 current was shown in Fig. 2C. Plots of steady-

state current as a function of compound 9 concentration

were fitted to the Hill equation. For compound 9-induced

block, a half-maximal inhibitory concentration (IC50) and Hill

coefficient were 27.4 ± 5.1 nM and 1.35 ± 0.16, respectively

(n = 6). Considering that IC50 for psoralen was 180 ± 21 nM

in the previous our report (Eun et al., 2005), compound 9,

one of the psoralen derivatives, is more potent than

psoralen itself in blocking hKv1.5 channel by about 6.6

Table I. Effects of psoralen derivatives on hKv1.5 current expressedin Ltk- cell line

Samples R1 R2 Inhibitoryrate (%)

Psoralen H H 72.8 ± 9.7

Compound 1 H OCH3 62.0 ± 7.5

Compound 2 H OCOCH2C6H5 50.5 ± 6.8

Compound 3 H OCOCH2CH2CH3 35.5 ± 5.1

Compound 4 H OCH2OCH2CH2OCH3 45.5 ± 6.5

Compound 5 H OCH2CH2CH2CH3 85.8 ± 8.9

Compound 6 OCH3 H 17.1 ± 4.3

Compound 7 OCOCH2C6H5 H 18.3 ± 3.5

Compound 8 OCOCH2CH2CH3 H 50.6 ± 6.8

Compound 9 OCH2OCH2CH2OCH3 H 95.9 ± 8.9

Compound 10OCH2CH2CH2CH3 H 90.9 ± 7.7

The hKv1.5 current traces were recorded before and 20 min after

exposure to 10 µM psoralen derivatives. Voltage protocol consisted of

250-ms depolarizing pulses from -80 to +60 mV with 10-mV increments

from a holding potential of -80 mV and repolarization to -50 mV for 400

ms. Steps were repeated at 20-s intervals. Each data represents the

mean ± SEM.

Fig. 2. Effect of compound 9 on hKv1.5 current expressed in Ltk- cell line. hKv1.5 current traces were recorded before (Aa) and 20 min afterexposure to 3 µM compound 9 (Ab). Voltage protocol consisted of 250-ms depolarizing pulses from -80 to +60 mV with 10-mV increments from aholding potential of -80 mV and repolarization to -50 mV for 400 ms. Steps were repeated at 20-s intervals. Â, Current-voltage (I-V) relationship ofsteady-state current taken at the end of the depolarizing pulses in the absence and presence of 3 µM compound 9. C, concentration-responserelationships of hKv1.5 block by compound 9. Steady-state currents taken at the end of the depolarizing pulse of +60 mV were normalized to thecontrol to construct the dose-response curve. Data were fitted with a Hill equation. Each point with vertical bar denotes the mean ± SEM.

Open Channel Block of hKv1.5 by Psoralen Derivatives 159

times. If side effects of compound 9 were much lesser,

compound 9 would be developed as a more potent

antiarrhythmic drug.

To clarify the action mechanism of compound 9 on

hKv1.5 channels, we examined its effects in Ltk- cells

expressing hKv1.5. We first tested the voltage depen-

dence of compound 9 block. To quantify the voltage

dependence of compound 9-induced inhibition of hKv1.5

current, the relative current Icompound 9/Icontrol was plotted as a

function of membrane potential (Fig. 3). In the presence of

psoralen (30 nM), the action of block on hKv1.5 current

increased between -40 and 0 mV, which corresponds to

the voltage range of channel opening (Snyders et al.,

1993). This suggests that compound 9-induced inhibition

of the hKv1.5 occurs preferentially after channels are

open. As shown in Fig. 4, the effect of compound 9 on

deactivation kinetics of hKv1.5 was determined during a

repolarizing step of -50 mV after a depolarizing step to

+60 mV. In the presence of compound 9 (30 nM), the

initial tail current was reduced and the subsequent decline

of the current was slowed, which resulted in a crossover

phenomenon. These results indicate that compound 9

inhibits preferentially hKv1.5 channels at open state, like

as psoralen. Additionally, we examined use-dependence

of compound 9-induced inhibition of hKv1.5 channel (Fig.

5). Original current traces, under control conditions and in

the presence of compound 9 (30 nM), were produced by

twenty repetitive applications of depolarizing pulses at

three different frequencies (1, 2 and 5 Hz). As shown in

Fig. 5, the peak amplitude of the hKv1.5 current decreased

slightly under control conditions. In the presence of com-

pound 9 (30 nM), the peak amplitude of hKv1.5 was not

significantly reduced after the first pulse. The subsequent

trace showed much more progressive decrease in the

peak amplitude of hKv1.5 to a steady level. The faster the

stimulation frequency was, the more the hKv1.5 blocking

effect of compound 9 was. In other words, compound 9

exhibited use-dependent inhibition of hKv1.5. Based on

this result, the hKv1.5-blocking effect of compound 9 would

be more effective under tachyarrhhythmic conditions. It

satisfy one of the factors requested as ideal antiarrhythmic

Fig. 3. Voltage-dependent block of hKv1.5 expressed in Ltk- cells bycompound 9 (30 nM). Voltage protocol consisted of 250-msdepolarizing pulses from -40 to +60 mV with 10-mV increments from aholding potential of -80 mV and repolarization to -50 mV for 400 ms.Steps were repeated at 20-s intervals. Relative currents were obtainedby Icompound 9/Icontrol at each depolarizing potential in the absence andpresence of 30 nM compound 9. Steady-state current amplitude,normalized to control, was plotted as a function of test potential. Eachpoint with vertical bar denotes the mean ± SEM.

Fig. 4. Effect of compound 9 (30 nM) on the deactivation kinetics ofhKv1.5 expressed in Ltk- cells. Deactivation kinetics was investigatedduring a repolarizing step of -50 mV for 400 ms after a 250-msdepolarizing step to +60 mV from a holding potential of -80 mV. Bysuperimposing the tail currents in the absence and presence of 30 nMcompound 9, tail crossover phenomenon (indicated by the arrow) wasobserved.

Fig. 5. Use-dependent inhibition of hKv1.5 expressed in Ltk- cells bycompound 9. A, Original current traces obtained from 20 repetitiveapplications of 125 ms-depolarizing pulses of +60 mV from a holdingpotential of -80 mV at three different frequencies, 1, 2 and 5 Hz, in theabsence and presence of 30 nM compound 9. The dotted linesrepresent zero current. B, Plot of the normalized peak amplitudes ofcurrents under control conditions and in the presence of 30 nMcompound 9 at every pulse versus the pulse numbers in the pulse train.Each point with vertical bar denotes the mean ± SEM.


drugs.

In the present study, compound 9 preferentially interacts

with the open state of the hKv1.5 channel with the follow-

ing results. First, compound 9 accelerated the rate of hKv1.5

current decay with little effect on the initial activation

kinetics. Second, blockade produced by compound 9 was

voltage-dependent and increased steeply in the voltage

range of channel activation. Third, compound 9 slowed

the deactivation of the tail current, thus inducing a tail

crossover phenomenon. This tail crossover phenomenon

suggests an interaction between compound 9 and the

open state of the hKv1.5 channel. Fourth, the effects of

compound 9 were use-dependent. These phenomena are

also cited as evidences of an open-channel blocking

mechanism.

In summary, we synthesized ten psoralen derivatives

and found that compound 9 among them was the most

potent in blocking hKv1.5 (more potent than psoralen by

6.6 times). Compound 9 acts on hKv1.5 channel as an

open channel blocker and an use-dependent blocker.

Taken together, these findings indicate that compound 9

might be a much more potent ideal antiarrhythmic drug for

atrial fibrillation than psoralen.

ACKNOWLEDGEMENTS

This work was supported by the Korea Research

Foundation Grant funded by the Korean Government

(MOEHRD) (the Center for Healthcare Technology

Development, Woosuk University, Republic of Korea) and

funded by the Korean Government (MOEHRD) (Grant

No. E00189).

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