The identification of (−)-trans-tadalafil, tadalafil, and sildenafil in counterfeit Cialis® and the optical purity of tadalafil stereoisomers

Venhuis, Bastiaan J.; Zomer, G; Vredenbregt, M.J.; Kaste, D. de

doi:10.1016/j.jpba.2009.08.010

Cited by 39 publications

(19 citation statements)

References 8 publications

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“…16) We have also independently isolated the same compound from a dietary supplement and analyzed its structure. Most of our analytical data (1D-, 1 H-, 13 C-NMR, and LC-MS spectra) matched Venhuis's data, and we predicted the structure to be an aildenafil derivative (Table 1). However, our proposed structure ( Considering these results, we firmly believe that the structure of the isolated aildenafil derivative is as illustrated in Fig.…”

supporting

confidence: 80%

“…Among these products, most are adulterated with synthetic compounds, such as sildenafil, vardenafil, and tadalafil, which are active ingredients used for the treatment of penile erectile dysfunction (ED), and their analogs or other unapproved phosphodiesterase-5 (PDE-5) inhibitors. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] In the last year, a new illegal sildenafil analogue was isolated from a dietary supplement for ED. It was reported that the compound is converted to aildenafil, a structural analogue of sildenafil, 15) under physiological acidic conditions.…”

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confidence: 99%

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Identification of Mutaprodenafil in a Dietary Supplement and Its Subsequent Synthesis

Demizu¹,

Wakana²,

Kamakura³

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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confidence: 80%

mentioning

confidence: 99%

Identification of Mutaprodenafil in a Dietary Supplement and Its Subsequent Synthesis

Demizu¹,

Wakana²,

Kamakura³

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…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][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.…”

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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“…Most of the uncovering the adulteration studies focused on both drugs Viagra and Cialis. For this purpose XRD, Raman spectroscopy, NIR, FT-IR, DOSY 1 HNMR and other analytical methods were reported in literature for detecting the illegally manufactured drugs especially Viagra and Cialis [4][5][6][7][8][9][10][11] . In this study Cipram ® , Panadol extra ® , Xenical ® will be investigated.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic and Chemometric Analysis of Illegally Manufactured Formulations of Selected Medicines

Obeidat¹,

Al-Tayyem²

2012

Orientjchem.

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In this study, three common drugs (Cipram ® , Panadol extra ® , Xenical ® ) were investigated. The study involved analyzing the above drugs using the portable NIR spectroscopy. Ten adulterated tablets of each of the above drugs were tested along with ten genuine tablets and other ten placebo tablets which represents another adulterated source for all drugs. Chemometrical Algorithms like Principal Components Analysis (PCA) and Cluster Analysis (CA) were used to extract the useful information from the collected data. Differentiating among original and the counterfeit drugs was successfully demonstrated with no chemical pretreatment. Identifying adulteration source was also possible using the above algorithms.

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The identification of (−)-trans-tadalafil, tadalafil, and sildenafil in counterfeit Cialis® and the optical purity of tadalafil stereoisomers

Cited by 39 publications

References 8 publications

Identification of Mutaprodenafil in a Dietary Supplement and Its Subsequent Synthesis

Identification of Mutaprodenafil in a Dietary Supplement and Its Subsequent Synthesis

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

Spectroscopic and Chemometric Analysis of Illegally Manufactured Formulations of Selected Medicines

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