October 2011
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Table 1. 1H- and 13C-NMR Data of Isolated Aildenafil Derivative in Chlo-
roform-d
Mutaprodenafil (1)
Atom
dC
d
H (J in Hz)
1ꢂ
4ꢂ
6ꢂ
8ꢂ
9ꢂ
146.7
149.0
154.6
143.5
128.2
39.1
—
—
—
—
—
10ꢂ
11ꢂ
12ꢂ
13ꢂ
14ꢂ
15ꢂ
16ꢂ
17ꢂ
18ꢂ
19ꢂ
20ꢂ
21ꢂ
24ꢂ/28ꢂ
25ꢂ/27ꢂ
29ꢂ/30ꢂ
32ꢂ
34ꢂ
36ꢂ
38ꢂ
4.37 s
27.7
21.9
13.8
127.3
131.5
126.6
130.0
113.1
160.7
64.7
14.3
51.7
50.1
19.2
115.2
139.2
150.1
33.0
2.94 t (7.6)
1.84 m
0.95 t (7.3)
—
—
7.79 d (2.7)
7.60 dd (2.7, 9.2)
6.99 d (9.2)
—
4.06 q (6.9)
1.32 t (6.9)
1.71 t (11.0), 3.47 dd (2.8, 11.0)
2.88 m
0.96 d (6.3)
—
7.86 s
—
Fig. 3. LC-MS Spectra of the Isolated and Synthesized Compounds
named mutaprodenafil from a dietary supplement for ED and
proposed that it is an aildenafil derivative with an imidazole
moiety. Furthermore, we synthesized mutaprodenafil (1)
from thioaildenafil to confirm its structure. We found that
mutaprodenafil could be synthesized from thioaildenafil and
commercially available 5-chloro-1-methyl-4-nitroimidazole.
Mutaprodenafil is the first prodrug type analogue of the legal
drugs used for the treatment of penile ED. In order to avoid
illegal compounds being detected by routine inspections,
counterfeit drug manufacturers synthesize new types of ille-
gal compounds whenever possible. Normally, their detailed
pharmacological activities are not examined. Thus, patients
who unknowingly take dietary supplements adulterated with
such compounds are at risk of suffering harmful side effects.
Therefore, we must continuously monitor and prevent illegal
drug manufacturing.
3.78 s
Acknowledgements This work was partly supported by a Health and
Labour Science Research Grant from the Ministry of Health, Labour, and
Welfare of Japan.
Fig. 2. HMBC, 1H–15N HMBC, and INADEQUATE Correlations for
Compound 1
References and Notes
over anhydrous sodium sulfate. Evaporation of the solvent
gave an oily residue, which was purified by gel permeation
chromatography (GPC) to give 1 (15 mg, 48%) as a white
solid.19)
1) Venhuis B. J., Barends D. M., Zwaagstra M. E., de Kaste D., “RIVM
Report 370030001/2007,” National Institute for Public Health and the
Environment, the Netherlands, 2007, and references cited therein.
2) Hou P., Zou P., Low M. Y., Chan E., Koh H. L., Food Addit. Contam.,
23, 870—875 (2006).
3) Park H. J., Jeong H. K., Chang M. I., Im M. H., Jeong J. Y., Choi D.
M., Park K., Hong M. K., Youm J., Han S. B., Kim D. J., Park J. H.,
Kwon S. W., Food Addit. Contam., 24, 122—129 (2007).
4) Hasegawa T., Saijo M., Ishii T., Nagata T., Haishima Y., Kawahara N.,
Goda Y., J. Food Hyg. Soc. Jpn., 49, 311—315 (2008).
5) Lam Y. H., Poon W. T., Lai C. K., Chan A. Y. W., Mak T. W. L., J.
Pharm. Biomed. Anal., 46, 804—807 (2008).
6) Uchiyama N., Saisho K., Kikura-Hanajiri R., Haishima Y., Goda Y.,
Chem. Pharm. Bull., 56, 1331—1334 (2008).
7) Kumasaka K., Kawahara N., Doi K., Kojima T., Goda Y., Chem.
Pharm. Bull., 56, 227—230 (2008).
8) Goda Y., Kamakura H., Functional Food, 2, 198—202 (2008).
9) Zou P., Hou P., Oh S. S., Chong Y. M., Bloodworth B. C., Low M. Y.,
Koh H. L., J. Pharm. Biomed. Anal., 47, 279—284 (2008).
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814—817 (2008).
1
Then, we measured the H- and 13C-NMR spectra of the
synthesized 1 and found that the data were almost identical
to those of the isolated molecule. Furthermore, the retention
time of the LC-MS spectrum of the synthesized 1 was the
same as that of the isolated molecule (Fig. 3).20) These results
indicate that the structure of the isolated aildenafil derivative
can not be a nitrosated prodrug A, but rather that compound
1 contains an imidazole moiety. Since compound 1 can be
converted to aildenafil by acidic treatment and we revised the
structure proposed by Venhuis’s group (nitrosoꢀprodenafil),
we named it mutaprodenafil (mutatisꢁprodenafil). In this
communication, we have synthesized mutaprodenafil 1 and
authenticated its veridical structure.
In conclusion, we isolated a new illegal sildenafil analogue