Identification of chalcones as potent and selective PDE5A1 inhibitors

Nam, Ky-Youb; Choi, Nam Song; Han, Cheol; Ahn, Soon Kil

doi:10.1016/j.bmcl.2012.04.094

Cited by 6 publications

(9 citation statements)

References 29 publications

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“…Although these compounds were taken from different sources, the compound 16 [11,13] showed similar values of inhibitory concentration (IC50) with ours, 0.075, 0.010 and 0.014 (our result) μM, respectively.…”

Section: Sar Datasetsupporting

confidence: 83%

“…Moreover, based on PDE5 inhibitory mechanism, the effect and mechanism study on ED could be evaluated using cavernous smooth muscle cells (CSMCs) cellular assay in vitro. In this study, for the first time, 6 main 8-isopentenyl flavonoids, Icariin (1), 2-O"-rhamnosylicaridide II (2), Baohuoside I (3), Epimedin A, B, C (4)(5)(6) were separated from the PFES and identified by 1 H NMR, 13 C NMR and MS, and these compounds were detected PDE5A1 inhibitory activity with the novel HPLC assay. We also adapted a series of PDE5 inhibitors from different reports [11,13] to firstly establish CoMFA and CoMSIA models, aiming at finding the relationship between the biological activity and the key structural factors of 8-isopentenyl flavonoids from the models.…”

Section: Introductionmentioning

confidence: 79%

“…In this study, for the first time, 6 main 8-isopentenyl flavonoids, Icariin (1), 2-O"-rhamnosylicaridide II (2), Baohuoside I (3), Epimedin A, B, C (4)(5)(6) were separated from the PFES and identified by 1 H NMR, 13 C NMR and MS, and these compounds were detected PDE5A1 inhibitory activity with the novel HPLC assay. We also adapted a series of PDE5 inhibitors from different reports [11,13] to firstly establish CoMFA and CoMSIA models, aiming at finding the relationship between the biological activity and the key structural factors of 8-isopentenyl flavonoids from the models. Furthermore, The SAR results were verified by the cellular effects of the cGMP level and cytoplasmic Ca 2+ in CSMCs, and the mechanism on PKG/Ca 2+ signaling pathway was also studied.…”

Section: Introductionmentioning

confidence: 79%

“…The potencies of compounds 1-6 and 16 were obtained by our in vitro activity assay combined with HPLC. The remains were adapted from two literature [11,13].…”

Section: Sar Datasetmentioning

confidence: 99%

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Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum Maxim. as PDE5A inhibitors

Wu²,

et al. 2022

Preprint

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Background: As known, inhibition of phosphodiesterase 5 (PDE5) has the therapeutic effect on male erectile dysfunction (ED), and the processed folium of Epimedium sagittatum Maxim. (PFES) characterized by 8-isopentenyl flavonoids is a famous herb for treating ED. However, the main flavonoids inhibitory activities, structure-activity relationship (SAR) and signaling pathway have been not systematically studied so that its pharmacodynamic mechanism is unclear. Methods: We aimed to initially reveal the PFES efficacy mechanism for treating ED. For the first time, 6 main 8-isopentenyl flavonoids (1-6) from PFES were isolated and identified. Then based on HPLC detection, we proposed a novel method with superior applicability compared to traditional radioisotope assay to screen inhibitors among them. We further established three-dimensional quantitative structure-activity relationship (3D-QSAR) models through CoMFA and CoMSIA to analyze the SAR for those inhibitors. Results: The results were verified by cellular effects of the screened flavonoids. Among 6 compounds, Icariin (1), 2-O"-rhamnosylicaridide II (2) and Baohuoside I (3) were identified with significant activities (IC50 = 8.275, 3.233, 5.473 mM). Then 3D-QSAR studies showed that the replacement of C8 with bulky steric groups as isopentenyl, C3 with positive charge groups and C4' with a hydrogen bond acceptor substituent could increase inhibitory effects. In contrast, the substitution of C7 with bulky steric groups or hydrophilic groups tended to decrease the efficacies. And compounds1, 2, 3 could increase cGMP level and decrease cytoplasmic Ca2+ of rat corpus cavernosum smooth muscle cells (CCSMCs)by activating PKG. Conclusion: 8-isopentenyl flavonoids could be the main pharmacodynamic substances of PFES in the treatment for ED, and some had significant PDE5A1 inhibitory activities so as to activate cGMP/PKG/Ca2+ signaling pathway in CCSMCs, that was related to the substituents at the key sites such as C8, C3, C4' and C7 in the characteristic compounds.

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Section: Sar Datasetsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 79%

“…The potencies of compounds 1-6 and 16 were obtained by our in vitro activity assay combined with HPLC. The remains were adapted from two literature [11,13].…”

Section: Sar Datasetmentioning

confidence: 99%

See 2 more Smart Citations

Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum Maxim. as PDE5A inhibitors

Wu²,

et al. 2022

Preprint

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“…The Furano chalcones and flavones showed PTP‐1B inhibitory potential . The chalcone derivatives were also used for inhibiting phosphodiesterase (PDE), the enzyme responsible for the hydrolysis of cyclic adenosine 3′, 5′‐monophosphate (cAMP) and cyclic guanosine 3′,5′‐monophosphate (cGMP) . Some chalcones isolated from different plants were already reported to have a vasorelaxation effect on different animal models …”

Section: Introductionmentioning

confidence: 99%

Investigation of anti‐inflammatory, nitric oxide donating, vasorelaxation and ulcerogenic activities of 1, 3‐diphenylprop‐2‐en‐1‐one derivatives in animal models

Sherikar

Dhavale

Bhatia

2019

Clin Exp Pharma Physio

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Summary The main aim of this work is to find out novel chemical moieties with potent anti‐inflammatory and vasorelaxant activities with reduced gastric toxicities. For fulfilling the above aim, here we investigated novel chalcones (1, 3‐diphenylprop‐2‐en‐1‐one derivatives) with nitric oxide (NO) and hydrogen sulphide (H2S) donating potency for anti‐inflammatory activity by carrageenan‐induced rat paw oedema. These molecules then further evaluated for in‐vitro NO‐releasing potency and vasorelaxation effect on isolated adult goat aortic tissue. The promising molecules were further screened for ulcerogenic activity in the rat model. The tested compounds produced % inhibition in paw oedema ranging from 29.16% to 79.69% and standard drug Diclofenac sodium produced 85.30% reduction in paw oedema after 5 hours. Out of this dataset, compounds AI1, AI7, Ca1, B2, B10, D2, and E8 showed 73.01%, 79.69%, 75.02%, 75.46%, 74.35%, 73.9% and 74.35% reduction in paw oedema respectively, which is approximately 80%–90% to that of standard Diclofenac sodium. The compound Ca1 was found to release 0.870 ± 0.025 mol/mol of NO and standard Glyceryl trinitrate (GTN) was found to release 0.983 ± 0.063 mol/mol of NO. The compound Ca1 produced 950.2 μmol/L of EC50 whereas standard GTN produced 975.8 μmol/L of EC50 for aortic smooth relaxation. The compounds Ca1 produced 0.1117 of ulcer index which is far less than that of standard Diclofenac sodium (1.148). The potent lead molecules were further evaluated to understand the mechanism of vasorelaxation by using specific antagonists or blockers of NO and H2S.

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Synthesis, docking studies andin vitroevaluation of novel chalcones as potent inhibitors of phosphodiesterase 5 from human platelets and 5A from bovine recombinant

2018

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Identification of chalcones as potent and selective PDE5A1 inhibitors

Cited by 6 publications

References 29 publications

Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum Maxim. as PDE5A inhibitors

Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum Maxim. as PDE5A inhibitors

Investigation of anti‐inflammatory, nitric oxide donating, vasorelaxation and ulcerogenic activities of 1, 3‐diphenylprop‐2‐en‐1‐one derivatives in animal models

Synthesis, docking studies andin vitroevaluation of novel chalcones as potent inhibitors of phosphodiesterase 5 from human platelets and 5A from bovine recombinant

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