Structure determination of a sildenafil analogue contained in commercial herb drinks

Shin, Choonshik; Hong, Moo-Ki; Kim, Daibyung; Lim, Yoongho

doi:10.1002/mrc.1467

Cited by 42 publications

(17 citation statements)

References 5 publications

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“…Today, there are three such drugs approved by the U.S. Food and Drug Administration: sildenafil citrate (Viagra ® , manufactured by Pfizer), vardenafil hydrochloride (Levitra ® , manufactured by Bayer), and tadalafil (Cialis ® , manufactured by Lilly). In the last few years, these ED drugs and structurally modified synthetic analogues have been found in "natural" herbal health supplements marketed as aphrodisiacs [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Most sildenafil analogues found as adulterants have been modified in the piperazine portion of the molecule, but recently, herbal dietary supplements were found to contain thiosildenafil [17] and thiohomosildenafil [16,17], two novel sildenafil analogues modified by replacing a carbonyl group in sildenafil with a thiocarbonyl group.…”

Section: Introductionmentioning

confidence: 99%

Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs

Reepmeyer

d’Avignon

2009

Journal of Pharmaceutical and Biomedical Analysis

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a b s t r a c tTwo analogues of sildenafil were detected in herbal dietary supplements marketed as aphrodisiacs. Both compounds were identified as thioketone analogues of sildenafil in which the carbonyl group in the pyrimidine ring of sildenafil was substituted with a thiocarbonyl group. The first compound was identified as thiosildenafil, a compound that has recently been reported as an adulterant in health supplements. The structure of the second compound was established using LC-MS, UV spectroscopy, ESI-MS n , NMR and a hydrolytic process. A detailed study of the hydrolysis products of sildenafil, thiosildenafil, and the second unknown compound proved that the second compound, named thiomethisosildenafil, had a structure analogous to sildenafil in which the N-methylpiperazine moiety had been replaced with 2,6-dimethylpiperazine and the oxygen atom of the carbonyl group in the heterocyclic ring had been replaced with a sulfur atom. Under the hydrolytic reaction conditions employed in this study, thioketones hydrolyze to ketones (e.g., thiosildenafil → sildenafil), making this a valuable technique for the structure elucidation of thiosildenafil analogues. Ten herbal dietary supplements, each as a capsule dosage form, were found to contain 8-151 mg of thiomethisosildenafil per capsule, and one herbal dietary supplement was found to contain 35 mg of thiosildenafil per capsule. Published by Elsevier B.V.

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Section: Introductionmentioning

confidence: 99%

Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs

Reepmeyer

d’Avignon

2009

Journal of Pharmaceutical and Biomedical Analysis

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“…Thus far, a large number of analogues of sildenafil, tadarafil and vardenafil have been reported, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] while a new type of phosphodiesterase-5 (PDE-5) inhibitor, (R)-xanthoanthrafil, an anthranilic acid derivative, has been found in a dietary supplement advertising sexual enhancement for men. 24) (R)-Xanthoanthrafil was first synthesized as a candidate compound for the treatment of ED by Fujisawa Pharmaceutical Co., Ltd. (currently Astellas Pharma Inc., Tokyo, Japan), 25) and was reported as a PDE-5 inhibitor, FR226807, after the manufacturer discontinued the process of developing the drug for approval.…”

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confidence: 99%

Isolation and Structural Elucidation of Cyclopentynafil and N-Octylnortadalafil Found in a Dietary Supplement

Hasegawa

Takahashi

Saijo

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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A new sildenafil analogue, cyclopentynafil (1) and a new tadalafil analogue, N-octylnortadalafil (2) were isolated from a dietary supplement illegally marketed for erectile dysfunction. The structures of the sildenafil and tadalafil analogues were elucidated by using HPLC-photodiode array (PDA), LC-MS, high-resolution MS, NMR and circular dichroism (CD). These compounds were determined to be 5- In this paper, we report the analysis and structural elucidation of a new sildenafil analogue, cyclopentynafil and a new tadalafil analogue, N-octylnortadalafil, that were isolated from a dietary supplement illegally marketed for erectile dysfunction. ExperimentalChemicals and Reagents HPLC-grade acetonitrile and all other reagents (analytical grade) were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan).Sample The examined product was purchased as a processed food composed mainly of walnuts through the Internet and was composed of four pieces of ivory tablets (400 mg). The product properties were as follows: product name; Highperwalnup 2, producing company; Art Creation Co., Ltd., sales company; Ogawa Planning Co., Ltd., date of purchase; December 28, 2007.Preparation of Sample Solution One tablet was finely powdered, and 100 mg of the powder was ultrasonically extracted in 10 ml of 70% methanol for 15 min. The extract was centrifuged at 1700ϫg. The supernatant was filtered through a 0.45 mm filter. The filtrate was used for HPLC, and a portion of it was diluted 10-fold with methanol for liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) analysis.HPLC Analysis HPLC analysis was performed using a JASCO PU-2089 apparatus equipped with a photodiode array (PDA) detector model MD-2015 (JASCO Corporation, Tokyo, Japan). The sample solution was separated by using a TSK-GEL ODS-80Ts column (150ϫ4.6 mm i.d., 5 mm, Tosoh Co., Tokyo, Japan). The mobile phase was an acetonitrile/water/phosphoric acid (100 : 900 : 1) mixture solution containing 5 mmol/l sodium hexanesulfonate (eluent A) and an acetonitrile/water/phosphoric acid (900 : 100 : 1) mixture solution containing 5 mmol/l sodium hexanesulfonate (eluent B). The gradient elution was started at 90% eluent A, and was linearly decreased to 55% A in 25 min and to 10% A in 44-49 min. The flow rate of the mobile phase was set at 1.0 ml/min, and the injection volume was 20 ml. The column temperature was maintained at 40°C. The PDA detection wavelength was set from ultraviolet (UV) 200 to 400 nm, and max-plot chromatographic monitoring was performed (200-400 nm).LC-ESI-MS Analysis LC-ESI-MS analysis was performed using a Waters alliance 2695 separation module and ZQ mass spectrometer (Waters Corporation, Milford, MA, U.S.A.). The sample solution was separated by using an Atlantis dC18 column (150ϫ2.1 mm i.d., 3 mm, Waters Corporation). The mobile phase was 0.1% formic acid aqueous solution (eluent A) and acetonitrile containing 0.1% formic acid (eluent B). The gradient elution began at 95% eluent A, and linearly decreased to 80% A in 15 min and ...

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“…Detailed 13 C and 1 H NMR data have been reported for sildenafil and three sildenafil analogues using either CDCl 3 , DMSO-d 6 , or D 2 O/acetone-d 6 as solvent [3,4,14,15]. The NMR data for methisosildenafil (Table 1), sildenafil [14] and homosildenafil [4], all in a solvent of CDCl 3 , are consistent in their molecular assignments except for the piperazine portion of the molecule where the structures of the compounds differ.…”

Section: Nmrmentioning

confidence: 99%

Structure elucidation of a novel analogue of sildenafil detected as an adulterant in an herbal dietary supplement

Reepmeyer

Woodruff

d’Avignon

2007

Journal of Pharmaceutical and Biomedical Analysis

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A new analogue of sildenafil was detected in an herbal dietary supplement, which was sold over the internet and promoted as a product for the enhancement of sexual performance. The structure of the compound was established using LC-MS, UV spectroscopy, MS-MS, and NMR. In addition, the compound was cleaved at its sulfonamide S-N bond yielding a sulfonic acid and an amine, which were independently characterized using LC-MS, GC-MS, and derivatization. The compound, named methisosildenafil, is a novel synthetic analogue of sildenafil in which the N-methylpiperazine moiety has been replaced with 2,6-dimethylpiperazine.

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Structure determination of a sildenafil analogue contained in commercial herb drinks

Cited by 42 publications

References 5 publications

Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs

Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs

Isolation and Structural Elucidation of Cyclopentynafil and N-Octylnortadalafil Found in a Dietary Supplement

Structure elucidation of a novel analogue of sildenafil detected as an adulterant in an herbal dietary supplement

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