Extending the use of tadalafil scaffold: Development of novel selective phosphodiesterase 5 inhibitors and histone deacetylase inhibitors

ElHady, Ahmed K.; Shih, Shou-Ping; Chen, Yu-Cheng; Liu, Yi-Chang; Ahmed, Nermin S.; Keeton, Adam B.; Piazza, Gary A.; Engel, Matthias; Abadi, Ashraf H.; Abdel‐Halim, Mohammad

doi:10.1016/j.bioorg.2020.103742

Cited by 15 publications

(11 citation statements)

References 53 publications

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“…However, a further focus on the activities of all isolated stereoisomers would shed light on the real potential of these structures. Besides, a series of isolated stereoisomers of slightly different structure was reported very recently . Interestingly, some compounds managed to efficiently bind to HDACs while incorporating short linkers, an observation that contradicts previously described results.…”

Section: β-Carboline-based Multitarget Strategiesmentioning

confidence: 74%

“…Besides, a series of isolated stereoisomers of slightly different structure was reported very recently. 179 Interestingly, some compounds managed to efficiently bind to HDACs while incorporating short linkers, an observation that contradicts previously described results. Even a four-carbon derivative, compound 149a, was able to inhibit both PDE5 (IC 50 = 12 nM) and HDAC (IC 50 = 131 nM) with decent activity levels; shorter one-, two-, and three-carbons analogues failed to efficiently bind HDAC, although their anti-PDE5 activities were exquisite (IC 50 = 2.0−20 nM for four molecules).…”

Section: ■ Histone Deacetylase (Hdac) Inhibitorsmentioning

confidence: 99%

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β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

et al. 2021

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The natural β-carboline alkaloids display similarities with neurotransmitters that can be favorably exploited to design bioactive and bioavailable drugs for Alzheimer's disease (AD) therapy. Several AD targets are currently and intensively being investigated, divided in different hypotheses: mainly the cholinergic, the amyloid β (Aβ), and the Tau hypotheses. To date, only symptomatic treatments are available involving acetylcholinesterase and NMDA inhibitors. On the basis of plethoric single-target structure−activity relationship studies, the β-carboline scaffold was identified as a powerful tool for fostering activity and molecular interactions with a wide range of AD-related targets. This knowledge can undoubtedly be used to design multitarget-directed ligands, a highly relevant strategy preferred in the context of multifactorial pathology with intricate etiology such as AD. In this review, we first individually discuss the AD targets of the β-carbolines, and then we focus on the multitarget strategies dedicated to the deliberate design of new efficient scaffolds.

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Section: β-Carboline-based Multitarget Strategiesmentioning

confidence: 74%

Section: ■ Histone Deacetylase (Hdac) Inhibitorsmentioning

confidence: 99%

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

et al. 2021

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“…Cells were washed twice with PBS and were treated with RIPA lysis buffer (1% Nonidet P-40, 1× PBS, 0.1% sodium dodecyl sulfate (SDS), 0.5% sodium deoxycholate, 1 mM sodium orthovanadate, 100 μg/mL phenylmethylsulfonyl fluoride, and 30 μg/mL aprotinin) (all chemicals were obtained from Sigma-Aldrich) for 30 min to obtain the cell lysates [ 45 ]. The lysates were collected and centrifuged at 13,000× g for 30 min at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

The Antileukemic and Anti-Prostatic Effect of Aeroplysinin-1 Is Mediated through ROS-Induced Apoptosis via NOX Activation and Inhibition of HIF-1a Activity

Shih

El‐Shazly

et al. 2022

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Aeroplysinin-1 is a brominated isoxazoline alkaloid that has exhibited a potent antitumor cell effect in previous reports. We evaluated the cytotoxicity of aeroplysinin-1 against leukemia and prostate cancer cells in vitro. This marine alkaloid inhibited the cell proliferation of leukemia Molt-4, K562 cells, and prostate cancer cells Du145 and PC-3 with IC50 values of 0.12 ± 0.002, 0.54 ± 0.085, 0.58 ± 0.109 and 0.33 ± 0.042 µM, respectively, as shown by the MTT assay. Furthermore, in the non-malignant cells, CCD966SK and NR8383, its IC50 values were 1.54 ± 0.138 and 6.77 ± 0.190 μM, respectively. In a cell-free system, the thermal shift assay and Western blot assay verified the binding affinity of aeroplysinin-1 to Hsp90 and Topo IIα, which inhibited their activity. Flow cytometry analysis showed that the cytotoxic effect of aeroplysinin-1 is mediated through mitochondria-dependent apoptosis induced by reactive oxygen species (ROS). ROS interrupted the cellular oxidative balance by activating NOX and inhibiting HIF-1α and HO-1 expression. Pretreatment with N-acetylcysteine (NAC) reduced Apl-1-induced mitochondria-dependent apoptosis and preserved the expression of NOX, HO-1, and HIF-1a. Our findings indicated that aeroplysinin-1 targeted leukemia and prostate cancer cells through multiple pathways, suggesting its potential application as an anti-leukemia and prostate cancer drug lead.

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“…System operation and data acquisition were controlled using MassLynx 4.1 software (Waters). HRMS was measured as previously described [ 64 ].…”

Section: Methodsmentioning

confidence: 99%

Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

et al. 2022

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In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common component of these regimens. Food and Drug Administration (FDA)-approved NS5A inhibitors, although very potent, do not have the same potency against all eight genotypes of HCV. Therefore, this study aims to synthesize NS5A inhibitor analogues with high potency pan-genotypic activity and high metabolic stability. Starting from an NS5A inhibitor scaffold previously identified by our research group, we made several modifications. Two series of compounds were created to test the effect of changing the length and spatial conformation (para-para vs. meta-meta-positioned bis-imidazole-proline-carbamate), replacing amide groups in the linker with imidazole groups, as well as different end-cap compositions and sizes. The frontrunner inhibits genotype 1b (Con1) replicon, with an EC50 value in the picomolar range, and showed high genotypic coverage with nanomolar range EC50 values against four more genotypes. This together with its high metabolic stability (t½ > 120 min) makes it a potential preclinical candidate.

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Extending the use of tadalafil scaffold: Development of novel selective phosphodiesterase 5 inhibitors and histone deacetylase inhibitors

Cited by 15 publications

References 53 publications

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

The Antileukemic and Anti-Prostatic Effect of Aeroplysinin-1 Is Mediated through ROS-Induced Apoptosis via NOX Activation and Inhibition of HIF-1a Activity

Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

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