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Prof. Dell'Agli and his colleagues tested the four plants in vitro to see how efficient they were at inhibiting PDE5. Just one - Epimedium brevicornum, also known as horny goat weed - had an effect. This confirmed previous studies showing that icariin, a compound found inside the horny goat weed, is a PDE5 inhibitor boosting libido, increase sexual desire, and treat erectile dysfunction.

The activity of plant extracts and individual compounds against human recombinant PDE5A1 is shown in Figure S1 (Supporting Information). Cinnamaldehyde, icariin (1), and ferutinin were considered as the putative active principles of C. cassia, E. breVicornum, and F. hermonis, respectively, since the compounds represent the most abundant secondary metabolites of those species. Only E. breVicornum and icariin (1) strongly inhibited PDE5A1 (-80% and -72%, respectively), whereas the other test materials were much less active (-15 to -23%). Inhibition by cinnamalde-hyde (-16%) and ferutinin (-7%) was not significant.


The medicinal plants tested in the present study had a reputation for aphrodisiac effects and therefore represented the start of a screening program to search for compounds to be developed as a new natural drug alternative to sildenafil. The observation that only E. breVi-cornum and its active principle 1 inhibited PDE5 in a significant manner, in agreement with previous results,17-20 suggests that the other plant extracts may interfere with erectile function through mechanisms other than PDE5 inhibition.


Compound 1 was a good PDE5 inhibitor (IC50 of 5.9 μM), but required improvement in order to have equivalent potency to sildenafil, which gave an IC50 of 75 nM. The inhibitory effects of icariin derivatives 2-6 on


PDE5A1 is shown. Since aglycons might be expected to possess higher activity than the corresponding glycosides, the first general structural modification to 1 was the removal of one or both of the sugar moieties at the hydroxyl groups at positions C-3 and C-7 of the flavone scaffold.
Enzymatic hydrolysis of 1 with cellulase and naringinase allowed the partial or total removal of the sugar moieties, respectively.

The last modification to 1 was the replacement of one or both sugar moieties with the hydroxyethyl side chain, representing a simplification of the sugar residue. The substitution for Glc by a hydroxyethyl group at C-7 gave 7-(2-hydroxyethyl)-3-O-rhamno-sylicariin (4), which was less potent than 2 (IC50 363 vs 156 nM, respectively). When both hydroxyls at C-3 and C-7 were derivatized with hydroxyethyl moieties, as in 3,7-bis(2-hydroxyethyl)icaritin (5), PDE5A1 was potently inhibited, with an IC50 of 74 nM, almost identical to that of sildenafil (75 nM).

The selectivity against human PDE5A1 was investigated by testing all compounds against human PDE6C, at concentrations 10-fold higher than their PDE5A1 IC50 values. Compounds 1 and 4 inhibited PDE6 activity (45% and 86%, respectively), while 2, 3, 5, and 6 were inactive.
For 5, the best PDE5 inhibitor among the icariin derivatives tested, concentration inhibition curves for PDE6 and cAMP-PDE were performed.  The PDE6C/PDE5 IC50 ratio was 418 for 5 and 2.2 for sildenafil, while the cAMP-PDE/PDE5 IC50 ratio was 1300 for 5 and 367 for sildenafil. These results indicate that the selectivity of 5 for PDE5 was improved with respect to that of sildenafil. Compound 5 was not cytotoxic for human fibroblasts even at the highest concentration tested (100 μM). Thus, the inhibitory potency of 5 was 80-fold higher that of the parent compound icariin.

Preparation of Icariin
A solution of icariin (1) (526 mg) in DMSO (1 mL) was added dropwise for 72 h to a Na acetate-buffered hydroalcoholic solution at 37 °C (0.25 M, pH 5.0, in EtOH/H2O, 30: 70) (50 mL) containing naringinase (207 mg). The obtained suspension was allowed to stir at 37 °C for 7 days.
Then, a further amount of naringinase (97 mg) was added and the mixture was stirred under the same conditions for a further day. EtOH was removed by evaporation and the aqueous suspension was filtered under vacuum and dried.
The residue obtained was washed with H2O and dried to give icaritin (3, 290 mg; purity 95%) as a yellow powder. The mother liquors were diluted with H2O and extracted with EtOAc (2 × 200 mL). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford an additional amount of 3 (20 mg); quantitative yield, mp 232-233 °C;24 1H NMR (CDCl3, 300 MHz, 30 °C) δ 1.78 (3H, s,
CH3-14), 1.87 (3H, s, CH3-15), 2.70 (2H, s, OH), 3.61 (2H, d, J ) 6.8 Hz, H-11), 3.89 (3H, s, OCH3), 5.36 (1H, t, J ) 6.8 Hz, H-12), 6.32 (1H, s, H-6), 7.04 (2H, d, J ) 8.4 Hz, H-3′, H-5′), 8.16 (2H, d, J ) 8.4 Hz, H-2′, H-6′); ESIMS (positive-ion mode) m/z 369 [M + H]+.
Supporting Information Available: Figures showing the HPLC traces of the extracts under study and the effects of plant extracts and pure compounds on the inhibition of PDE5A1. This information is available free of charge via the Internet at http://pubs.acs.org.
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NP800049Y
10.1021/np800049y CCC: $40.75 2008 American Chemical Society and American Society of Pharmacognosy Published on Web 09/09/2008

Department of Pharmacological Sciences, UniVersity of Milan, Via Balzaretti 9, 20133, Milan, Italy, Department of Pharmaceutical Sciences, UniVersity of
Bologna, Via Belmeloro 6, 40126, Bologna, Italy, and Department of Veterinary Public Health and Animal Pathology, UniVersity of Bologna, Via Tolara di
Sopra 30, 40064 Ozzano Emilia (BO), Italy

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