Efficient synthesis and in vitro PDT effect of purpurin-18-N-aminoimides

Article abstract of DOI:10.5012/bkcs.2010.31.11.3313

A simple and efficient synthetic route for making purpurin-18-N-aminoimides is described. The purpurin-18-Naminoimides are obtained by treatment of purpurin-18 methyl ester with various amines. These new compounds have long wavelength absorptions in the range of 706 - 711 nm. In preliminary screening, the purpurin-18-N-aminoimides have shown promising photosensitizing activity for the cancer cell by in vitro study in photodynamic therapy.

Full text of DOI:10.5012/bkcs.2010.31.11.3313

PDT Effect of Purpurin-18-N-Aminoimides
Bull. Korean Chem. Soc. 2010, Vol. 31, No. 11 3313
DOI 10.5012/bkcs.2010.31.11.3313
Efficient Synthesis and in vitro PDT Effect of Purpurin-18-N-Aminoimides
Bing Cun Cui, Min Uk Cha, Jia Zhu Li, Ho Sung Park, Il Yoon, and Young Key Shim*
PDT Research Institute, School of Nano System Engineering, Inje University, Gimhae 621-749, Korea
*E-mail: ykshim@inje.ac.kr
Received May 10, 2010, Accepted September 15, 2010
A simple and efficient synthetic route for making purpurin-18-N-aminoimides is described. The purpurin-18-N-
aminoimides are obtained by treatment of purpurin-18 methyl ester with various amines. These new compounds have
long wavelength absorptions in the range of 706 - 711 nm. In preliminary screening, the purpurin-18-N-aminoimides
have shown promising photosensitizing activity for the cancer cell by in vitro study in photodynamic therapy.
Key Words: Purpurin-18 methyl ester, Purpurin-18-N-aminoimide, Photodynamic therapy
NH2
NO2
Introduction
Photodynamic therapy (PDT) is an experimental cancer treat-
ment modality which selectively destroys cancer cells by inter-
action of light with a photosensitizing dye, presumably to form
singlet oxygen.1-3 In continuing efforts to develop candidate
photosensitizers for PDT, the design and synthesis of chlorin
derivatives having well-defined structure with amphiphilic pro-
perties, high selectivity for tumor cell, quick elimination from
health cells and strong absorption in the red region of visible
spectrum are important challenges in the PDT field. In our lab,
we have done a large amount of careful research about the
chlorin-based photosensitizers. For example, research on Gram-
positive bacterial cell S. aureus using troponyl methyl (pyro)
pheophorbides4 and carbohydrate-conjugated chlorin for galec-
tin-3.5
O
N
O
N
O
N
O
O
O
N
N
N
1
2
3
Figure 1. Structures of amonafide 1, mitonafide 2 and azonafide 3.
purpurin-18 methyl ester 5. We also carried out an in vitro assay
of cell viability with A549 cancer cells for the aim of examining
preliminary photosensitizing efficacy of these new purpurini-
mides.
DNA-intercalating agents are those antitumor agents that
intercalate DNA via chromophores.6 DNA intercalating ability
and antitumor activity resides in a wide variety of chemical
entities. Especially, imide derivative compounds have been re-
ported as a potential class of antitumor agents containing amona-
fide 1, mitonafide 2, azonafide 37-9 (Figure 1) and so on. Encour-
aged by this result, a group of photosensitizers featuring a chlo-
rin ring system fused to a six-membered cyclic imide structure
with a basic N-substituent has received considerable attention.
Converting the six-membered anhydride ring of purpurin-18
into a six-membered cyclic imide structure was found to greatly
increased wavelength absorption and good stability for the re-
quirement of an improved photodynamic therapeutic agent.10-19
Although previous report has described the synthesis of pur-
purin-18-N-(N,N-dimethyl)ethylimide from the chlorin p6.14
However, the yield of the purpurinimide formed in this reaction
was low. It is therefore important to develop a new process for
the synthesis of purpurinimide with a good yield. Also, there is
no report regarding its in vitro study.
Experimental
General methods. The 1H-NMR spectra were recorded on a
Varian-500 MHz spectrometer. Chemical shifts are given as δ
values using TMS as the internal standard and J values in Hz.
The mass spectra were measured with a JEOL JMS700 spectro-
meter. The UV-visible spectrums were recorded on Scinco S-
3100 spectrophotometer using dichloromethane as a solvent.
Melting points (uncorrected) were measured on an Electrother-
mal IA9000 Series digital melting point apparatus. Thin-layer
chromatography (TLC) was done on Merck silica gel 60 glass
sheets (Cat. HX948839, layer thickness 0.25 mm). Column
chromatography was performed over silica gel 60 (230 - 400
mesh). In some cases, preparative TLC plates were also used
for the purification (Analtech precoated silica gel GF glass
plate, Cat. 01012, layer thickness 0.5 mm). All photophysical ex-
periments were carried out using spectroscopic grade solvents.
Purpurin-18 methyl ester12 was prepared according to literature
procedure.
By varying the substituent on the anhydride ring nitrogen
atom, the series of available purpurinimides could be extended.
Thus reactions of purpurin-18 with secondary di(tri)amines
could give rise of various biological active imide derivatives. In
this report we wish to present a general and efficient method
for the synthesis of the purpurin-18-N-aminoimides from the
Methyl pheophorbide-a (4). Chlorophyll paste (excrementum
bombycis) (100 g) was dissolved in 500 mL of 5% sulfuric acid
in methanol and stirred at room temperature for 50 h under nitro-
gen atmosphere in dark. Following the standard workup, methyl
pheophorbide-a was obtained in 5.1% yield. The analytical data
are identical with those reported previously.20

3314 Bull. Korean Chem. Soc. 2010, Vol. 31, No. 11
Bing Cun Cui et al.
7.00; N, 12.68. Found: C, 70.69; H, 7.06; N, 12.61.
General procedure for the preparation of purpurin-18-N-
aminoimides. In topical experiment, purpurin-18 methyl ester
5 (200 mg) and excess of corresponding amine (0.1 mL) was
dissolved in toluene (20 mL), and the mixture was refluxed
under nitrogen atmosphere for 2 h. After monitoring of complete
consumption of purpurin-18 methyl ester by TLC, the mixture
was cooled to room temperature, solvent and excess amines
were removed in vacuum. The crude product was purified by
silica column chromatography or preparative TLC plate with
an eluent of 10% methanol in dichloromethane to give corres-
ponding purpurinimide 6a, 6b, 6c, 6dand 6e as a purple solid,
respectively.
Purpurin-18-N-(N,N-dimethylpropylamino)propylimide
6d. Yield: 97%. mp 95 - 97 oC. UV-vis in CH2Cl2, λmax (nm, rel.
intensity log ε), 419.1 (0.98), 481.0 (0.04), 511.7 (0.06), 550.0
(0.17), 651.3 (0.07), 706.9 (0.35). 1H NMR (500 MHz, CDCl3)
δ 9.52 (s, 1H, for 10H), 9.29 (s, 1H, for 5H), 8.55 (s, 1H, for
20H), 7.86 (dd, J = 17.5, 13.5 Hz, 1H, 31H), 6.28 (d, J = 18.0 Hz,
1H, trans-32H), 6.15 (d, J = 11.5 Hz, 1H, cis-32H), 5.31 (m, 1H
for 17H), 4.56 (m, 2H, N-CH2-CH2-CH2-NH-), 4.35 (q, J = 7.0
Hz, 1H, 18H), 3.75 (s, 3H, 12-CH3), 3.57 (q, J = 8.5 Hz, 2H,
81CH2), 3.55 (s, 3H, 172CO2CH3), 3.33 (s, 3H, 2CH3), 3.10 (s,
3H, 7CH3), 2.70-2.62, 2.41-2.10 (m, 8H, N-CH2-CH2-CH2-NH-
CH2-CH2-CH2-N-(CH3), 2 × 171H and 2 × 172H), 2.05 (s, 6H,
N-(CH3)2) 1.76 (d, J = 7.5 Hz, 3H, 18CH3), 1.63 (t, J = 7.0 Hz,
3H, 82CH3), 1.36 (m, 2H, N-CH2-CH2-CH2-NH-CH2-CH2-CH2-
N-(CH3)), 0.08 and ‒0.01 (each br s, 1H, 2NH). Anal. calcd for
C42H53N7O4: C, 70.07; H, 7.42; N, 13.62. Found: C, 70.02; H,
7.49; N, 13.60.
Purpurin-18-N-(N-imidazolyl)propylimide 6e. Yield: 96%.
mp 86 - 88 oC. UV-vis in CH2Cl2, λmax (nm, rel. intensity log ε),
418.9 (1.04), 480.8 (0.05), 511.9 (0.06), 550.4 (0.18), 651.7
(0.07), 707.6 (0.34). 1H NMR (500 MHz, CDCl3) δ 9.53 (s, 1H,
for 10H), 9.31 (s, 1H, for 5H), 8.56 (s, 1H, for 20H), 7.88 (dd,
J = 18.0, 11.5 Hz, 1H, 31H), 7.15, 7.08 (s, 3H, imidazole-H), 6.29
(d, J = 17.5 Hz, 1H, trans-32H), 6.16 (d, J = 11.5 Hz, 1H, cis-
32H), 5.33 (m, 1H for 17H), 4.35 (q, J = 7.5 Hz, 1H, 18H), 4.55,
4.28 (each m, 2H, N-CH2-CH2-CH2-), 3.77 (s, 3H, 12-CH3), 3.59
(q, J = 8.0 Hz, 2H, 81CH2), 3.53 (s, 3H, 172CO2CH3), 3.34 (s, 3H,
2CH3), 3.13 (s, 3H, 7CH3), 2.78-2.65, 2.55-2.48, 2.45-2.32 and
2.06-1.95(m, 6H, N-CH2-CH2-CH2-, 2 × 171H and 2 × 172H),
1.77(d, J = 7.5 Hz, 3H, 18CH3), 1.64 (t, J = 7.8 Hz, 3H, 82CH3),
0.88 and 0.03 (each br s, 1H, 2NH). Anal. calcd for C40H43N7O4:
C, 70.05; H, 6.32; N, 14.30. Found: C, 70.13; H, 6.37; N, 14.26.
In vitro photosensitizing efficacy.
Purpurin-18-N-(N,N-dimethyl)ethylimide 6a. Yield: 97%.
mp 99 - 101 oC. UV-vis in CH2Cl2, λmax (nm, rel. intensity log ε),
419.2 (0.98), 481.1 (0.04), 511.9 (0.05), 549.8 (0.17), 649.8
(0.06), 706.7 (0.36). 1H NMR (500 MHz, CDCl3) δ 9.55 (s, 1H,
for 10H), 9.32 (s, 1H, for 5H), 8.56 (s, 1H, for 20H), 7.89 (dd,
J = 17.5, 11.5 Hz, 1H, 31H), 6.30 (d, J = 18.0 Hz, 1H, trans-32H),
6.17 (d, J = 11.5 Hz, 1H, cis-32H), 5.33 (m, 1H for 17H), 4.74 (t,
J = 7.0 Hz, 2H, N-CH2-CH2-N-(CH3)2), 4.34 (q, J = 7.5 Hz, 1H,
18H), 3.78 (s, 3H, 12-CH3), 3.61 (q, J = 8.0 Hz, 2H, 81CH2), 3.58
(s, 3H, 172CO2CH3), 3.34 (s, 3H, 2CH3), 3.14 (s, 3H, 7CH3),
2.76 (s, 6H, N-(CH3)2), 2.72-2.68, 2.43-2.37 and 2.05-1.98 (m,
6H, NCH2-CH2-N-(CH3)2, 2 × 171H and 2 × 172H), 1.77 (d, J =
7.5 Hz, 3H, 18CH3), 1.65 (t, J = 7.5 Hz, 3H, 82CH3), 0.08 and
‒0.08 (each br s, 1H, 2NH). Anal. calcd for C38H44N6O4: C,
70.35; H, 6.84; N, 12.95. Found: C, 70.47; H, 6.82; N, 12.92.
Purpurin-18-N-(N,N-diethyl)ethylimide 6b. Yield: 95%. mp
125 - 127 oC. UV-vis in CH2Cl2, λmax (nm, rel. intensity log ε),
419.4 (1.02), 481.1 (0.04), 512.5 (0.06), 551.1 (0.19), 651.6
(0.08), 708.3 (0.37). 1H NMR (500 MHz, CDCl3) δ 9.40 (s, 1H,
for 10H), 9.18 (s, 1H, for 5H), 8.55 (s, 1H, for 20H), 7.79 (dd,
J = 17.5, 11.5 Hz, 1H, 31H), 6.23 (d, J = 18.0 Hz, 1H, trans-32H),
6.10 (d, J = 11.5 Hz, 1H, cis-32H), 5.37 (m, 1H for 17H), 4.59 (t,
2H, J = 7.0 Hz, N-CH2-CH2-N-(CH2CH3)), 4.36 (q, J = 7.5 Hz,
1H, 18H), 3.71 (s, 3H, 12-CH3), 3.48 (q, J = 8.0 Hz, 2H, 81CH2),
3.58 (s, 3H, 172CO2CH3), 3.30 (s, 3H, 2CH3), 3.09 (s, 3H,
7CH3), 2.90 (q, 4H, N-(CH2CH3)2), 2.73-2.68, 2.44-2.37 and
2.10-1.97 (m, 6H, N-CH2-CH2-N-(CH2CH3)2, 2 × 171H and 2 ×
172H), 1.78 (d, J = 7.5 Hz, 3H, 18CH3), 1.57 (t, J = 7.5 Hz, 3H,
82CH3), 1.27 (t, J = 7.0 Hz, 6H, N-(CH2-CH3)2), 0.25 and ‒0.02
(each br s, 1H, 2NH). Anal. calcd for C40H48N6O4: C, 70.98; H,
7.15; N, 12.42. Found: C, 70.93; H, 7.20; N, 12.48.
Purpurin-18-N-(N-isopropylamino)ethylimide 6c. Yield:
94%. mp 116 - 118 oC. UV-vis in CH2Cl2, λmax (nm, rel. intensity
log ε), 419.8 (0.97), 480.9 (0.05), 512.5 (0.06), 552.6 (0.20),
661.4 (0.09), 710.6 (0.35). 1H NMR (500 MHz, CDCl3) δ 9.94 (s,
1H, for 10H), 8.97 (s, 1H, for 5H), 8.52 (s, 1H, for 20H), 7.80
(dd, J = 19.5, 11.5 Hz, 1H, 31H), 6.27 (d, J = 17.5 Hz, 1H, trans-
32H), 6.15 (d, J = 11.5 Hz, 1H, cis-32H), 5.27 (m, 1H for 17H),
4.84 (m, 2H, N-CH2-CH2-NH-), 4.34 (q, J = 7.5 Hz, 1H, 18H),
3.59 (s, 3H, 12-CH3), 3.60 (q, J = 6.5 Hz, 2H, 81CH2), 3.57 (s,
3H, 172CO2CH3), 3.24 (s, 3H, 2CH3), 2.82 (s, 3H, 7CH3), 2.92
(m, 1H, NH-CH-(CH3)2), 2.75-2.68, 2.43-2.35 and 2.06-1.91
(m, 6H, N-CH2-CH2-NH-, 2 × 171H and 2 × 172H), 2.04 (br, 1H,
NH), 1.86 (d, J = 8.0 Hz, 3H, 18CH3), 1.54 (t, J = 7.0 Hz, 3H, 82-
CH3), 1.25 (d, J = 6.5 Hz, 6H, NH-CH-(CH3)2), 0.09 and ‒0.62
(each br s, 1H, 2NH). Anal. calcd for C39H46N6O4: C, 70.67; H,
General method: A549 cells were cultured at 37 oC in a humi-
dified 5% CO2 incubator using RFMI 1640 growth medium
supplemented with 10% fetal bovine serum and 1% penicillin/
streptomycin. For phototoxicity studies, A549 cells were plated
in 96-well plates at a density of 10 × 104 cells well. After 24 h of
incubation, 100 µL of 1 µM, 2 µM, 5 µM, 10 µM and 15 µM pur-
purin-18-N-aminoimides were added, respectively. Plates were
returned to the incubator for 24 h. And then the cells were
replaced with fresh media and exposed to light (BioSpec LED,
670 - 700 nm, 2.0 J/cm2) for 15 min. Following illumination,
the plates were incubated at 37 oC in the dark. Every 3, 24, 48
hours later, WST-1 was put into each well and measure the absor-
bance on 450 nm wavelength after photoirradiation or without
light, respectively. Each experiment was done with three repli-
cate wells. The percentage cell survival was calculated by nor-
malization with respect to the value for no photosensitizer treat-
ment.
Results and Discussion
For our study, methyl pheophorbide-a (MPa) 4 was extracted
from chlorophyll paste (excrementum bombycis) by slight modi-
fications of the previously reported procedure in 5.1% yield.20
MPa 4 was transformed into purpurin-18 methyl ester 56 by

PDT Effect of Purpurin-18-N-Aminoimides
Bull. Korean Chem. Soc. 2010, Vol. 31, No. 11 3315
1.2
1.1
1.0
0.9
0.8
0.7
0.6
0.5
NH
N
N
NH
N
N
NH
N
N
c
b
HN
HN
HN
Purpurin-18
6a
6b
6c
6d
6e
O
O
O
N
R
O
O
O
O
O
O
O
OCH3
OCH3
OCH3
OCH3
4
5
6
0.4
0.3
0.2
0.1
0.0
6a. R=(CH2)2N(CH3)2
6d. R=(CH2)3NH(CH2)3N(CH3)2
a
6b. R=(CH2)2N(CH2CH3)2
6c. R=(CH2)2NHCH(CH3)2
6e. R=(CH2)3
N
Chlorophyll Paste
(excrementum bombycis)
N
400
500
600
700
Scheme 1. Synthesis of purpurin-18-N-aminoimides. Reagents and
conditions: a. 5% H2SO4/Methanol, rt; b. KOH/1-propanol/air, rt; c.
Corresponding amines/toluene, reflux
Wavelength (nm)
Figure 2. Electronic absorption spectra of 6a-6e in dichloromethane.
Table 1. Absorption maxima of 6a-6e in dichloromethane and their red-
shift values of the redmost Qy band
air oxidation in n-propanol containing KOH and was used as
a substrate. As shown in Scheme 1, reaction of 5 with various
amines with reflux gave the desired purpurin-18-aminoimides
6a, 6b, 6c, 6d and 6e in 97%, 95%, 94%, 97% and 96% yield,
respectively. Thus, this method appeared to be an efficient app-
roach for preparing photosensitizers with N-amino-imide sub-
stituents that can be prepared in excellent yield directly from
purpurin-18 methyl ester via one-pot synthesis.
Absorption maxima, nm
compound
∆Qy (nm)
Soret
Redmost Qy
6
411.4
419.2
419.4
419.8
419.1
418.9
699.9
706.7
708.3
710.6
706.9
707.6
0
6.8
8.4
10.7
7.0
7.7
6a
6b
6c
6d
6e
The structures of the final products were confirmed by 1H-
NMR spectroscopy and mass spectrometry. Compared to the
purpurin-18 methyl ester 5 the 1H-NMR spectra of 6a-6e showed
each triplet at δ 4.74, 4.59, 4.84, 4.56 and 4.55 ppm for the pro-
tons of CO-N-CH2-, respectively. In compounds 6a and 6d,
N-(CH3)2 appears as a singlet at δ 2.76 and 2.05 ppm, respective-
ly. And compound 6b shows a triplet at δ 1.27 ppm for the pro-
tons of N-(CH2CH3)2. Compound 6c showed the appearance of
a doublet at δ 1.25 ppm assigned to NH-CH-(CH3)2 protons. The
imidazole protons of compound 6e gave two singlet at δ 7.15 and
7.08 ppm.
The electronic absorption spectra of purpurin-18-N-amino-
imides were compared with purpurin-18 methyl ester. All com-
pounds showed the same pyrrole-type visible spectra in dichlo-
romethane, but the peaks in max of Qy and Soret bands are diff-
erent. As can be seen from Figure 2, all the chlorins showed
similar characteristics. The Soret band was observed near 419
nm, and the long-wavelength absorption bands were observed
at λmax = 706.7, 708.3, 710.6, 706.9 and 707.6 nm for 6a, 6b,
6c, 6dand 6e, respectively. Thus comparing with purpurin-18
methyl ester 5 (λmax = 699.9 nm), the purpurin-18-aminoimides
6a, 6b, 6c, 6d and 6e, showed a red-shift of 6.8, 8.4, 10.7, 7.0,
7.7 nm, respectively (Table 1). In other words the use of pho-
tosensitizer having long-wavelength band is desirable for better
tissue penetration of excitied light in vivo, the purpurin-18-N-
aminoimides may be considered as promising candidates.19, 21
The in vitro activities of purpurin-18 methyl ester 5 and the
corresponding purpurin-18-N-aminoimides were determined
with A549 cells. A549 cells with each compound at variable
concentrations were incubated in A549 cells at 37 oC for 3 h,
24 h and 48 h respectively. As shown in Figure 3, none of the
compounds up to 15 µM concentration have any significant
dark cytotoxicity at 3h and 24h. But the compounds showed little
dark cytotoxicity at 48 h, presumably by light penetration errors
during long time incubation. The higher concentration of the
photosensitizer the more dark cytotoxicity was shown. Among
the compounds investigated, compound 6bshowed the best effi-
cacy at 3 h with 16.1% cell survival at 2 µM. After 24 h incuba-
tion in the dark, all the purpurin-18-N-aminoimides exhibited
similar PDT efficacy. However, compared to the standard pur-
purin-18 methyl ester 5, all the purpurin-18-N-aminoimides
showed higher PDT efficacy. The in vitro efficacy after 24 h
incubation was observed in the following order: 6c > 6e > 6a>
6d > 6b > 5. And the dark cytotoxicity was 3%, 5%, 3%, 3%
and 5% for compounds 6a, 6b, 6c, 6dand 6e at 2 µM after 24 h,
respectively.
Conclusions
We have developed a simple and efficient synthetic route for
preparing the purpurin 18-N-aminoimides. Reaction of 5 with
various amines at reflux gave the corresponding imides in ex-
cellent yield (> 94%). On the basis of the preliminary in vitro
studies, it is clearly indicated that the purpurin-18-N-aminoimid-
es exhibit better PDT efficacy than the standard purpurin-18
methyl ester 5.

3316 Bull. Korean Chem. Soc. 2010, Vol. 31, No. 11
Bing Cun Cui et al.
PDT, 3 h
Dark, 3 h
140
120
100
80
60
40
20
0
120
6a
6b
6c
6d
6e
5
100
80
60
40
20
0
6b
6c
5
6a
6d
6e
0
0
0
1
1
1
2
5
10
10
10
15
15
15
0
0
0
1
1
1
2
5
10
10
10
15
15
15
Drug Dose (μM)
Drug Dose (μM)
PDT, 24 h
Dark, 24 h
120
120
100
80
60
40
20
0
100
80
60
40
20
0
6a
6b
6c
6b
6e
5
6c
5
6a
6d
6d
6e
5
2
5
2
Drug Dose (μM)
Drug Dose (μM)
PDT, 48 h
Dark, 48 h
120
120
100
80
60
40
20
0
6a
100
80
6b
6c
60
6d
6a
6b
6e
6c
5
6e
5
40
20
0
6d
2
5
2
5
Drug Dose (μM)
Drug Dose (μM)
Figure 3. Cell viability results of the photosensitizers on A549 cells. The cell viability of 6a-6e was assigned for PDT in the concentration ranges
of 1 µM, 2 µM, 5 µM, 10 µM and 15 µM after 3 h, 24 h, and 48 h by comparing with those of purpurin-18 methyl ester.

PDT Effect of Purpurin-18-N-Aminoimides
Bull. Korean Chem. Soc. 2010, Vol. 31, No. 11 3317
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Acknowledgments. This work was supported by Inje-Uni-
versity Research Grant in 2010.
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