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

Kern, Sara E.; Lorenz, Lisa; Lanzarotta, Adam; Nickum, Elisa A; Litzau, Jonathan J.

doi:10.1016/j.jpba.2016.05.038

Cited by 9 publications

(4 citation statements)

References 31 publications

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“…More recently, Kern et al employed a GC/FT-IR/MS to help elucidate the structure of a new tadalafil analog. 45 However, few studies have explored the potential of using a fully integrated GC/FT-IR/ MS instrument based on a direct deposit IR interface for high confidence identification of compounds of forensic interest that yield ambiguous results using GC/MS alone. To this end, it was the goal of this manuscript to demonstrate the advantages of this instrument to simultaneously provide identification and confirmation for these types of compounds.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Orthogonal Drug Detection Using Fully Integrated Gas Chromatography with Fourier Transform Infrared Detection and Mass Spectrometric Detection

Lanzarotta¹,

Falconer²,

McCauley³

et al. 2016

Appl Spectrosc

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Analytes that co-elute and yield nearly identical electron ionization (EI) mass spectra, as well as analytes that yield non-specific EI fragmentation patterns, have been identified using fully integrated gas chromatography with direct deposit Fourier transform infrared detection and mass spectrometric detection (GC/FT-IR/MS). While the IR detector proved to be more selective for identifying analytes such as synthetic cannabinoids and weight loss drugs, it was limited by a relatively high detection limit of 8.4 parts per million (ppm) for non-targeted identification of sibutramine based on a single injection but was reduced to 840 parts per billion (ppb) for targeted identification of sibutramine by redepositing ten injections along the same track. The MS detector was less selective for identifying these analytes but yielded non-targeted and targeted detection limits of approximately 84 ppb and 8.4 ppb, respectively, which corresponded to a 100-fold advantage compared to the IR detector. Overall, the results of this study demonstrate that the advantages of each detector compensate for the limitations of the other, which allows a wider range of analytes and concentrations to be examined using a fully integrated GC/FT-IR/MS instrument compared to what can be examined using GC/IR or GC/MS independently. Not only does this approach reduce consumption of laboratory resources and time, it provides IR and MS information on the same sample, which is important for forensic analyses that require data from two or more orthogonal techniques to make an identification.

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Section: Introductionmentioning

confidence: 99%

Simultaneous Orthogonal Drug Detection Using Fully Integrated Gas Chromatography with Fourier Transform Infrared Detection and Mass Spectrometric Detection

Lanzarotta¹,

Falconer²,

McCauley³

et al. 2016

Appl Spectrosc

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“…Phosphodiestrase-5 Inhibitors (PDE—5) – Cialis (tadalafil), Levitra (vardenafil), Viagra(sildenafil), and similar drugs: 2016 spectrofluorimetric method for determination of both tadalafil (TAD) and vardenafil (VAR) in pure and tablet dosage forms [ 1102 ]; HPLC-DAD method for the simultaneous determination of seven drugs including the phosphodiesterase-5 inhibitors: sildenafil, tadalafil, and vardenafil, and selective serotonin reuptake inhibitors: dapoxetine, duloxetine, fluoxetine, and paroxetine [ 1103 ]; HPLC-PDA and HPLC-MS methods for the analysis of genuine ViagraA (R), generic products of ViagraA (R), and counterfeit samples [ 1104 ]; immunochromatographic (IC) assay was developed based on polyclonal antibodies for determination of sildenafil and major analogues in herbal samples [ 1105 ]; LC-ESI-MS/MS method to identify phosphodiesterase-5 (PDE-5) inhibitors and their analogues in dietary supplements and food [ 1106 ]; HPLC-UV, GC/FT-IR/MS and HRMS for the isolation and structural characterization of a tadalafil analog (chloropropanoylpretadalafil) in dietary supplements [ 1107 ]; HPLC, QTOF- MS and NMR spectroscopy for identification and structural elucidation of three new tadalafil analogues found in a dietary supplements [ 1108 ]; GC-MS/MS mass for identification, confirmation and quantification of 6 phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, dimethylsildenafil, homosildenafil, thiosildenafil, thiodimethylsildenafil and thiohomosildenafil) in dietary supplements [ 1109 ]; disposable potentiometric sensor for determination of sildenafil [ 1110 ]; UPLC-MS/UV method for simultaneous determination of sildenafil citrate and dapoxetine hydrochloride [ 1111 ]; 2017 colorimetry in identifying imitator products by comparing the color signatures of Viagra tablets with imitator sildenafil tablet [ 1112 ]; ultrasound-assisted (UA) dispersive nanocomposite solid-phase micro-extraction (UA-DNSPME) to determine trace levels of Sildenafil Citrate in water [ 1113 ]; pencil graphite electrode (PGE) system for the trace-level determination of vardenafil hydrochloride [ 1114 ]; two amperometric methods to determine Sildenafil Citrate in Viagra (R) and Generics, using Batch Injection Analysis (BIA) and Flow Injection Analysis (FIA) systems with a cell for Screen Printed Electrodes [ 1115 ]; LC-ESI-MS/MS for determining the synthetic phosphodiesterase-5 inhibitors, sildenafil, tadalafil and vardenafil, and the active metabolite N-desmethyl sildenafil in water matrices [ 1116 ]; batch injection analysis with multiple pulse amperometric detection (BIA-MPA) used as a screening method on tablets containing sildenafil [ 1117 ]; analysis of Voriconazole and Tadalafil by HPLC [ 1118 ]; immunochromatographic strip for screening of tadalafil and its analogues in herbal samples [ 1119 ]; TLC and Raman for detection of PDE-5 inhibitors [ 1120 ]; SPE assisted reversed-phase dispersive liquid-liquid microextraction followed by LC-UV to simultaneously determine the concentration ...…”

Section: Routine and Improved Analyses Of Abused Substancesmentioning

confidence: 99%

Interpol review of controlled substances 2016–2019

Jones

Comparin

2020

Forensic Science International: Synergy

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

Cited by 9 publications

References 31 publications

Simultaneous Orthogonal Drug Detection Using Fully Integrated Gas Chromatography with Fourier Transform Infrared Detection and Mass Spectrometric Detection

Simultaneous Orthogonal Drug Detection Using Fully Integrated Gas Chromatography with Fourier Transform Infrared Detection and Mass Spectrometric Detection

Interpol review of controlled substances 2016–2019

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

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