Potent Inhibition of Human Phosphodiesterase-5 by Icariin Derivatives

Abstract

Plant extracts traditionally used for male impotence (Tribulus terrestris, Ferula hermonis, Epimedium breVicornum, Cinnamomum cassia), and the individual compounds cinnamaldehyde, ferutinin, and icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Human recombinant PDE5A1 was used as the enzyme source. Only E. breVicornum extract (80% inhibition at 50 µg/mL) and its active principle icariin (1) (IC 50 5.9 µM) were active. To improve its inhibitory activity, 1 was subjected to various structural modifications. Thus, 3,7-bis(2-hydroxyethyl)icaritin (5), where both sugars in 1 were replaced with hydroxyethyl residues, potently inhibited PDE5A1 with an IC 50 very close to that of sildenafil (IC 50 75 vs 74 nM). Thus, 5 was 80 times more potent than 1, and its selectivity versus phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) was much higher in comparison with sildenafil. The improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make compound 5 a promising candidate for further development.The inability to achieve or maintain an erection sufficient for satisfactory sexual function is an increasing problem with a considerable impact on interpersonal relationships and quality of life for men.1 During erection, nitric oxide is released from the axon terminals of the parasympathetic nerves and diffuses into smooth muscle cells of the arterial walls of the corpus cavernosum. The consequent activation of guanyl cyclase, converting guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), causes smooth muscle relaxation, leading to dilation and increased influx of blood into the penile tissue. The trapping of blood in the penis results in an erection.2 Selective inhibitors of cGMPphosphodiesterase-5 (PDE5) such as sildenafil (Viagra), tadalafil, and vardenafil are currently used for erectile dysfunction (ED). However, several adverse effects have been recorded in clinical trials, including priapism and visual disturbances.3 Furthermore, therapy with PDE5 inhibitors is cost-effective. Thus, the search for new compounds of this type for drug development could be worthwhile. A variety of natural plant products, including berberine, forskolin, papaverine, and yohimbine, are claimed to be useful for improving sexual performance. Extracts from Lepidium meyenii Walp. (maca), Panax ginseng C.A. Meyer, Ginkgo biloba L., Ferula hermonis Boiss., and many other herbal remedies, alone or in combination, have been promoted for the treatment of sexual problems. 4,5 With the aim of looking for new leads for selective PDE5 inhibitors, plant extracts and their putative active principles were selected for screening against human PDE5 activity in vitro. Our attention focused on Tribulus terrestris L., Ferula hermonis, Epimedium breVicornum Maxim., and Cinnamomum cassia L., since these extracts are claimed traditionally to improve sexual performance. T. terrestris caused vasodilating and antihypertensive effects in rats 6 and a pro-erectile eff...

Modulation of some markers of erectile dysfunction and malonaldehyde levels in isolated rat penile tissue with unripe and ripe plantain peels: identification of the constituents of the plants using HPLC

“…The result revealed that PDE-5 activity was inhibited by the extracts concentration dependently. This finding is in line with previous reports that medicinal plant extracts can inhibit PDE-5 activity, especially plants rich in flavonoids (Dell'Agli et al 2008;Shin et al 2015;Kotirum et al 2015;Pavan et al 2015). The PDE-5 inhibitory potentials of the studied peels could be linked to their rich flavonoid.…”

Effect of icarisid II on diabetic rats with erectile dysfunction and its potential mechanism via assessment of AGEs, autophagy, mTOR and the NO–cGMP pathway

“…9 Icarisid II has also been successfully isolated and assessed its PDE5 inhibitory effect. 11,12 This study investigates the effect of icarisid II on diabetic rats with ED and its potential mechanism via assessment of advanced glycosylation end products (AGEs), autophagy, mTOR and the NO-cGMP pathway.…”

Induction of Apoptosis by Icariside II through Extrinsic and Intrinsic Signaling Pathways in Human Breast Cancer MCF7 Cells

“…1A). Recent studies have demonstrated that IcaS possessed a variety of pharmacological activities as a melanogenesis inhibitor, 9) phosphodiesterase-5 inhibitor, 10) and with anti-hepatotoxic, 11) anti-osteoporosis, 12) neurite outgrowth, 13) and lifespan extension activities. 14) We have previously reported that IcaS possessed anticancer activity.…”