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

Abstract

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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“…Recently, as the second-generation PDE-5 inhibitor, tadalafil and analogues as adulterants have been becoming increasingly popular (about one-thirds of illegal PDE-5 inhibitor adulterants) in drinks, function food, and dietary supplements sourced from medicinal and edible food (Bujang et al, 2017;Causanilles et al, 2016;Dong et al, 2020;Guo et al, 2017;Jiru et al, 2019;Kee et al, 2018;Lee et al, 2019;Mandava et al, 2017;Park et al, 2017). These inhibitors have been demonstrated to inhibit not only PDE-5 but also PDE-6 (Maki et al, 2019), which could lead to more serious potential side effects for human health through the interaction with nitrates to increase the work-load of the heart, causing aches and even death (Bakota et al, 2017;Mandava et al, 2017;Moschos & Nitoda, 2016). Though these PDE-5 inhibitors had been forbidden to be added into dietary food products in many countries, since 2003, nearly 100 unapproved analogues or synthetic PDE-5 inhibitors have been found to be adulterated in spirit drinks and dietary supplements to avoid the statutory test and improve performance (Feng et al, 2020;Lee et al, 2019;Mandava et al, 2017).…”

“…These inhibitors have been demonstrated to inhibit not only PDE-5 but also PDE-6 (Maki et al, 2019), which could lead to more serious potential side effects for human health through the interaction with nitrates to increase the work-load of the heart, causing aches and even death (Bakota et al, 2017;Mandava et al, 2017;Moschos & Nitoda, 2016). Though these PDE-5 inhibitors had been forbidden to be added into dietary food products in many countries, since 2003, nearly 100 unapproved analogues or synthetic PDE-5 inhibitors have been found to be adulterated in spirit drinks and dietary supplements to avoid the statutory test and improve performance (Feng et al, 2020;Lee et al, 2019;Mandava et al, 2017). The safety of these derivatives was lack of pharmacological and toxicological profile, and if illegally added to food, the consequences would be disastrous (Causanilles et al, 2016;Patel et al, 2014;Wang et al, 2018).…”

“…PDE-5 inhibitors, including sildenafil, tadalafil and their analogues, are a class of chemical substances that can selectively inhibit the PDE-5 enzyme to achieve the treatment of erectile dysfunction (ED) approved by both Europe and US-FDA (Geerkens et al, 2020;Kuan & Broch, 2002;McCabe et al, 2016). Recently, as the second-generation PDE-5 inhibitor, tadalafil and analogues as adulterants have been becoming increasingly popular (about one-thirds of illegal PDE-5 inhibitor adulterants) in drinks, function food, and dietary supplements sourced from medicinal and edible food (Bujang et al, 2017;Causanilles et al, 2016;Dong et al, 2020;Guo et al, 2017;Jiru et al, 2019;Kee et al, 2018;Lee et al, 2019;Mandava et al, 2017;Park et al, 2017). These inhibitors have been demonstrated to inhibit not only PDE-5 but also PDE-6 (Maki et al, 2019), which could lead to more serious potential side effects for human health through the interaction with nitrates to increase the work-load of the heart, causing aches and even death (Bakota et al, 2017;Mandava et al, 2017;Moschos & Nitoda, 2016).…”