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Isolation and Identification of New Sildenafil Analogues from Dietary Supplements

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Isolation and Identification of New Sildenafil Analogues from Dietary Supplements 40 Journal of Food and Drug Analysis, Vol. 21, No. 1, 2013, Pages 40-49 doi:10.6227/jfda.2013210105 Isolation and Identification of New Sildenafil Analogues from Dietary Supplements YUNG-CHIH LIAO1,2*, KUO-CHIH LAI2, HUI-CHUN LEE2, YI-CHU LIU2, YUN-LIAN LIN3 AND DANIEL YANG-CHIH SHIH2 1. Center for Drug Evaluation, Taiwan, R.O.C. 2. Food and Drug Administration, Department of Health, Executive Yuan, Taiwan, R.O.C. 3. National Research Institute of Chinese Medicine, Taiwan, R.O.C. (Received: March 17, 2012; Accepted: November 13, 2012) ABSTRACT Three derivatized thio-sildenafil compounds were isolated from herbal health supplements. The structures of these three compounds were determined by NMR, high resolution MS, LC/MS/MS, UV and IR spectroscopy. Compound 1 and 2 have been identified as propoxy- phenyl thioaildenafil and propoxyphenyl aildenafil, respectively. Compound 3, named propoxyphenyl hydroxyethylthiosildenafil, is an analogue of thiosildenafil. The major difference between compound 3 and thiosildenafil is that propoxy and hydroxyethyl groups in compound 3 replaced the function groups of ethoxyl and methyl in thiosildenafil. Since their structures were similar to that of sildenafil or thiosildenafil, according to structure-activity relationship, the side effects of these analogues might be also associated with that of sildenafil or thio-sildenafil. Based on this study, these three analogues have been included in the inspection list of illegal adulterants in TFDA. Key words: propoxyphenyl hydroxyethylthiosildenafil, propoxyphenyl aildenafil, propoxyphenyl thioaildenafil, NMR, TFDA INTRODUCTION found for the first time in Taiwan. Compounds 3, named propoxyphenyl hydroxyethylthiosildenafil, has not been In recent years, inhibitors of cyclic nucleotide phospho- reported before. The structures of these analogues are illus- diesterase type 5 (PDE-5) have been used as a therapeutic trated in Figure 1. drug for the treatment of erectile dysfunction (ED)(1). Nowa- days, three PDE-5 inhibitor drugs have been approved by the Food and Drug Administration for the treatment of male ED: MATERIALS AND METHODS sildenafil, vardenafil, and tadalafil. Since then, more PDE-5 inhibitor drugs and their modified analogues have been found I. General in the so-called “natural” herbal health supplements in the market(2-11). Because the structurally modified analogues Melting points were measured on a BŰCHI Melting may pose some unknown adverse effects(12,13), it’s impor- Point B-540 unit; Optical rotations were taken on a JASCO- tant to find the presence of known or unknown analogues of P-1030 polarimeter (cell length 10 mm); UV spectra were PDE-5 inhibitor. Two novel adulterants, thiohomosildenafil acquired on a JASCO CARY 300 Conc UV/Vis spectro- and hydroxythiohomosildenafil, have been found in our photometer; IR spectra were recorded on a JASCO FT-IR laboratory(14). These two sildenafil analogues were modified 480+ spectrophotometer; NMR spectra were recorded on a by replacing a carbonyl group in sildenafil with a thiocar- Bruker AVIII 800MHz NMR spectrometer. Chemical shift bonyl group. Here we have further isolated three sildenafil (δ) values are in ppm (part per million) with CDCl3 as internal analogues from herbal dietary supplements. These three standard and coupling constants (J) are in Hz. High resolu- compounds were all characterized by nuclear magnetic reso- tion ESI-MS (HRESI-MS) measurements were performed nance (NMR), electrospray ionization-mass spectrometry on Agilent 6530 Accurate-Mass Q-TOF LC/MS. Thin layer (ESI-MS), infar-red (IR), ultraviolet (UV) spectroscopy. chromatography (TLC) was performed on Kieselgel 60, F254 Compound 1 and 2 have been identified as propoxyphenyl (0.20 mm, Merck), and spots were observed under UV light at thioaildenafil and propoxyphenyl aildenafil(15), which were 254 and 366 nm, and stained by spraying with Dragendorff’s reagent. For column chromatography, silica gel (Kieselgel 60, * Author for correspondence. Tel: 0937797581 ® Fax: +886-2-8170-6002; Email: [email protected] 70-230, and 230-400 mesh, Merck) and SUPELCO Flash !21卷1期書冊.indb 40 2013/3/19 下午 03:46:55 41 Journal of Food and Drug Analysis, Vol. 21, No. 1, 2013 S 10 CH3 5 4 N HN 9 3 OO 2 15 N 28 23 S 8 30 14 6 7 N N 1 S CH3 16 27 11 10 24 12 3 17 20 N NH 19 HN 4 25 18 O 5 9 26 22 CH OO 2 N 3 15 6 8 CH3 13 27 S 7 1 29 CH3 21 Compound 1 N 16 14 N 26 22 11 propoxyphenyl thioaildenafil 12 23 19 20 O 10 N 17 O 13 CH3 25 24 18 H3C 3 28 4 N Thiosildenafil 21 HN 5 9 OO 2N 28 15 6 8 S 7 1 30 O 10 CH N 16 14 N 3 11 23 3 27 24 19 12 4 N HN 17 O 20 13 HN 5 9 25 OO 2 N 26 18 22 CH3 15 6 8 CH 27 S 7 1 CH 21 3 29 29 3 N 16 14 N Compound 2 22 11 26 12 propoxyphenyl aildenafil 23 19 NH 17 O 20 24 18 13 S 10 28 21 9 N HN 4 OO 15 N S 6 Dimethylsildenafil 8 24 N 16 14 N 1 25 19 12 28 11 N 17 20 30 O 27 18 13 HO 29 22 21 Compound 3 Figure 1. Structures of compounds 1-3 and sildenafil analogues. Chromatography Starter Kit (Verspak silica gel column) were with 95% ethanol (300 mL × 4). The crude extract (3.9 g) used. was partitioned with CH2Cl2/MeOH/Water (20:10:10), and 2 fractions consisting of organic layer (2.0 g) and water layer II. Materials were obtained. The organic layer was chromatographed over a Verspak silica gel column, using SUPELCO® Flash Chro- Two herbal health supplements (samples 1 and 2) claimed matography Starter Kit, with CH2Cl2/MeOH (50:1) to yield for improving erectile function were randomly collected by 3 fractions. the health officers from local markets in 2011. Fraction 3 (124.8 mg) was further purified to afford compound 2 (67.3 mg) by recrystallization with CH2Cl2 and III. Extraction & Isolation compound 3 (33.1 mg) was obtained from fraction 1 (44.2 mg) after washing with n-hexane. (I) Compound 1 IV. Physical Data Sample 1, a dried brown powder (22.1 g), was extracted with 95% ethanol (300 mL × 4). The crude extract (4.8 g) (I) Compound 1 was dissolved with ethyl acetate (EtOAc). The EtOAc soluble layer (3.3 g) was chromatographed on an open silica gel Common name: propoxyphenyl thio-aildenafil; IUPAC column (packaged by Kieselgel 60, 70-230 mash, Merck) name: 5-[2-propoxy-5-((3R,5S)-3,5-dimethylpiperazin- with EtOAc/methanol (MeOH) (10:1) to yield 3 fractions. 1-ylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1, 6-di-hydro- Fraction 2 (344.2 mg) was recrystallized in the solvent system 7H-pyrazolo [4,3-d] pyrimidin-7-thione; formula: of CH2Cl2/MeOH (1:1) to give compound 1 (61.8 mg). C24H34N6O3S2; molecular mass (LC/MS/MS): 519.19 (M+H)+; exacted mass (HRESI-MS): 519.2224 (M+H)+; (II) Compound 2 & 3 m.p.: 189~191°C; [α]25D : +46.3° (c1.1, CH2Cl2); IR (KBr) υmax: 3265 cm-1 (N-H), 1572 cm-1(aromatic ring), 1257 cm-1 Sample 2, a dried brown powder (12.6 g), was extracted (thioketone group). !21卷1期書冊.indb 41 2013/3/19 下午 03:46:55 42 Journal of Food and Drug Analysis, Vol. 21, No. 1, 2013 + 25 (II) Compound 2 (HRESI-MS): 503.2440 (M+H) ; m.p.: 181~183°C; [α] D -1 : +50.2° (c0.3, CH2Cl2); IR (KBr) υmax: 3312 cm (N-H), Common name: propoxyphenyl aildenafil; IUPAC 1690 cm-1 (carbonyl group). name: 5-[2-propoxy-5-((3R,5S)-3,5-dimethylpiperazin-1- ylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-di-hydro-7H- (III) Compound 3 pyrazolo[4,3-d] pyrimidin-7-one.; formula: C24H34N6O4S; molecular mass (LC/MS/MS): 503.25 (M+H)+; exacted mass Common name: propoxyphenyl hydroxyethylthiosildenafil; Compound 1 3: Daughters of 519ES+ 100 1.85e7 % 0 m/z 50 75 100 125 150 175 200 225 250 275 300 325 350 375 400 425 450 475 500 525 550 Compound 2 3: Daughters of 503ES+ 100 1.36e7 % 0 m/z 50 75 100 125 150 175 200 225 250 275 300 325 350 375 400 425 450 475 500 525 550 Compound 3 1: Daughters of 535ES+ 100 8.07e7 % 0 m/z 50 75 100 125 150 175 200 225 250 275 300 325 350 375 400 425 450 475 500 525 550 Figure 2. LC/MS/MS spectra of compounds 1, 2 and 3. !21卷1期書冊.indb 42 2013/3/19 下午 03:47:03 43 Journal of Food and Drug Analysis, Vol. 21, No. 1, 2013 IUPAC name: 5-[2-propoxy-5-(4-hydroxyethylpiperazin-1- The compound 1 was purified and recrystalized as yellow ylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-di-hydro-7H- powder from CH2Cl2. The melting point was between 189 + pyrazolo[4,3-d] pyrimidin-7-thione.; formula: C24H34N6O4S2; and 191°C. Compound 1 showed [M+H] ion at m/z 519.19, + molecular mass (LC/MS/MS): 535.28 (M+H) ; exacted mass corresponding to the molecular formula C24H34N6O3S2 + 25 + (HRESI-MS): 535.2166 (M+H) ; m.p.: 158~160°C; [α] D : (Figure 2) and was reconfirmed by HRESIMS with [M+H] -1 +33.8° (c0.2, CH2Cl2); IR (KBr) υmax: 3448 cm (N-H), 1571 ion 519.2224. The UV spectrum of compound 1 showed λ cm-1 (aromatic ring), 1245 cm-1 (thioketone group).
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