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Identification of a new tadalafil analogue, N-3-hydroxypropylnortadalafil, in a supplement product

https://doi.org/10.1016/j.jpba.2018.05.049Get rights and content

Highlights

  • A new tadalafil analogue, N-3-hydroxypropylnortadalafil, was identified by NMR.

  • This analogue was adulterated in several supplement products from market.

  • This analogue can be distinguished with other isomers by different retention time.

Abstract

A novel tadalafil analogue, which exhibits similarity to 2-hydroxypropylnortadalafil, was found in dietary supplements using adulterants screening and isolated using column chromatography. By using extensive 1D- and 2D-NMR and MS spectral analyses, the structure was determined as 6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-(3-hydroxypropyl)pyrazino(1′,2′:1,6)pyrido(3,4-b)indole-1,4-dione, and the analogue was named N-3-hydroxypropylnortadalafil.

Introduction

Several phosphodiesterase type 5 (PDE-5) inhibitors are used as prescription drugs to treat erectile dysfunction (ED). PDE-5 inhibitors and their analogues are found illegally adulterated in some “natural” herbal supplements to enhance sexual performance, which threaten consumer safety because of a lack of awareness. Analogues are more dangerous because the health risks after structural modifications are uncertified. Until 2017, 80 synthetic PDE-5 inhibitor analogues had been reported [1]. Tadalafil, which was approved by the European Union in 2002 and the Food and Drug Administration in 2003, is a prominent PDE-5 inhibitor drug [2], [3], [4], [5]. The first analogue of tadalafil, aminotadalafil [6], was reported in 2006, and the number of tadalafil analogues rose to 21 in 2017 [1]. Initially, most tadalafil analogues were found with only substitutions on the N-methyl group of the piperazinedione ring like that of aminotadalafil. Since then, more analogues with the main structure of pretadalafil (cleaved piperazinedione ring) such as that of dipropylaminopretadalafil [7] have been reported.

2-hydroxypropylnortadalafil, which was isolated from a dietary supplement named “libido enhancer” and reported in 2012, is a tadalafil analogue with N-methyl group substitution. It contains a hydroxypropyl group substitution for the N-methyl group and the hydroxylation site is at the secondary carbon of the propyl group, as determined using NMR data [8]. This compound added to our screening target list soon after publication, but recently a novel tadalafil analogue was confused with 2-hydroxypropylnortadalafil. This study reports the isolation and structure determination of this novel analogue compound HC-03 (Fig. 1). Compound HC-03 was detected in three different food supplement samples that we analyzed during a routine screening of adulterants. In these samples, HC-03 exhibited 2-hydroxypropylnortadalafil-matched MS2 signals but different Rf values compared with the 2-hydroxypropylnortadalafil standard on the TLC plates after visualization, and its structure was further elucidated using accurate mass and NMR.

Section snippets

Samples and chemicals

Three supplement products from market were analyzed for adulterants using the Taiwan Food and Drug Administration suggested method and were found to contain unknown compound HC-03. Among them, a product in foil packaging without labels was used in further isolation. This product was white capsules containing a white powder, with the average weight for each capsule being 585.1 mg.

A 2-hydroxypropylnortadalafil (mixture of diastereomers) standard was purchased from TLC Pharmaceutical Standards

Mass spectrometry

The accurate mass of the purified HC-03 compound was determined as m/z 434.1710 for [M + H]+(error-1.4 ppm) using Q-TOF/MS. This corresponds to a molecular formula of C24H24N3O5, which was the same as that for 2-hydroxypropylnortadalafil. However, the retention time of HC-03 (5.87 min) differed entirely from that of the 2-hydroxypropylnortadalafil diastereomer mixture (6.57 and 6.76 min), which suggested that compound HC-03 may be an isomer of 2-hydroxypropylnortadalafil and was more

Conclusion

In this study, a new tadalafil analogue was isolated from a commercial food supplement and its structure was determined using Q-TOF/MS and NMR. This novel analogue has a 3-hydroxypropyl group instead of the N-methyl group of tadalafil on the piperazinedione ring, and it was named N-3-hydroxypropylnortadalafil.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

The authors thank the Instrumentation Center, National Taiwan University for technical assistance with NMR data acquisition.

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