Structural Elucidation of a Tadalafil Analogue Found in a Dietary Supplement

Hasegawa, Takashi; Saijo, Masaaki; Ishii, Toshiyasu; Nagata, Tomoko; Haishima, Yuji; Kawahara, Nobuo; Goda, Yukihiro

doi:10.3358/shokueishi.49.311

Cited by 35 publications

(11 citation statements)

References 13 publications

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“…1), all of which are known as active drug ingredients for the treatment of penile erectile dysfunction (ED). [1][2][3] In our previous paper, we identified a new tadalafil analogue, chloropretadalafil, 4) which had been synthesized as a tadalafil precursor, 5) from a dietary supplement along with hydroxyhomosildenafil and aminotadalafil.…”

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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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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 rapid and quantitative LC-MS/MS screening method for 71 known erectile dysfunction drugs was recently published [16] and new analogs are continuously being discovered in adulterated dietary supplements. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] This article describes the structural characterization of chloropropanoylpretadalafil ("Compound 1"), an analog of chloropretadalafil (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Isolation and structural characterization of a new tadalafil analog (chloropropanoylpretadalafil) found in a dietary supplement

Kern

Lorenz

Lanzarotta

et al. 2016

Journal of Pharmaceutical and Biomedical Analysis

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“…[5][6][7][8][9][10][11][12][13][14] Epimeric tadalafil analogues 5,15) and precursor-related analogues of tadalafil (1) have also been identified. [16][17][18] These analogues were presumably designed for use in adulteration to avoid identification by authorities. Recently, we found a new type of tadalafil analogues in dietary supplements, exemplified by 2a,b and 3, which bear two (pre) tadalafil moieties (Fig.…”

Section: Synthesis and Structure Revision Of Dimeric Tadalafil Analogmentioning

confidence: 99%

Synthesis and Structure Revision of Dimeric Tadalafil Analogue Adulterants in Dietary Supplements

Mandava

Ganganna

Hwang

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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A number of phosphodiesterase 5 (PDE5) inhibitors approved by authorities have been used successfully in the treatment of erectile dysfunction. These medicines must be prescribed carefully due to their adverse effects, but they and their analogues are being illegally added to dietary supplements. These illegal dietary supplements pose a significant risk to public health. Several dimeric tadalafil analogues have been synthesized for use as reference standards in the inspection of functional foods that are mainly advertised as sexual enhancement products. During the course of this synthesis, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) was proven to be the reagent of choice for amide coupling to produce these dimeric tadalafil analogues. Moreover, the trans-isomer structures tentatively assigned for the isolated dimeric tadalafil analogues (bisprehomotadalafil and bisprecyclopentyltadalafil) found in dietary supplements are now revised to cis-isomer structures.Key words phosphodiesterase 5 inhibitor; bisprehomotadalafil; bisprecyclopentyltadalafil; bisprenortadalafil; dietary supplement Tadalafil (1, Cialis ® ), a phosphodiesterase 5 (PDE5) inhibitor, has been widely used for the treatment of erectile dysfunction (ED). In spite of its excellent efficacy and safety profile, the administration of tadalafil (1) to patients who are concurrently using any form of organic nitrates or guanylate cyclase stimulators is contraindicated due to its hypotensive effects. 1-3)Tadalafil (1) should also not be prescribed in patients with Stevens-Johnson syndrome or exfoliative dermatitis because hypersensitivity reactions to this ED drug have been reported in such patients. 4) However, tadalafil (1) and its analogues have been detected in a number of dietary supplements over the last decade. These illegal products are mainly advertised as sexual enhancement products and sold without any declarations on the label of the pharmacological and toxicological effects arising from the PDE5 inhibitory activity. Most of the tadalafil analogues detected in illegal dietary supplements were generated by removal of an N-methyl group or its replacement by another group such as amino, ethyl, butyl, octyl or cyclopentyl.5-14) Epimeric tadalafil analogues 5,15) and precursor-related analogues of tadalafil (1) have also been identified.16-18) These analogues were presumably designed for use in adulteration to avoid identification by authorities. Recently, we found a new type of tadalafil analogues in dietary supplements, exemplified by 2a,b and 3, which bear two (pre) tadalafil moieties (Fig. 1). We have named these trans-bisprehomotadalafil, trans-bisprecyclopentyltadalafil and bisprenortadalafil, respectively. 5,19,20) The relative stereochemistry of these dimeric analogues was tentatively assigned based on no observation of nuclear Overhauser effect (NOE) between the protons at stereogenic centers in the molecules and by comparison of their spectral data with those of monomeric tadalafil der...

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Structural Elucidation of a Tadalafil Analogue Found in a Dietary Supplement

Cited by 35 publications

References 13 publications

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

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

Isolation and structural characterization of a new tadalafil analog (chloropropanoylpretadalafil) found in a dietary supplement

Synthesis and Structure Revision of Dimeric Tadalafil Analogue Adulterants in Dietary Supplements

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