Evaluation of (2S,3R)-2-(amino)-[4-(N-benzylarenesulfonamido)-3-hydroxy-1-phenylbutane derivatives: a promising class of anticancer agents

Here, we report the synthesis, enzyme inhibition and structure–activity relationship studies of a new potent class of HIV-1 protease inhibitors, which contain a pseudo-symmetric hydroxyethylamine core and heteroarylcarboxyamide moieties. The simple synthetic pathway furnished nine compounds in a few steps with high yields. The compounds were designed taking into account our previous results on other series of inhibitors with different substituents at P’ and P’’ and different ways of linking them to the inhibitor core. Potent inhibitory activity was obtained with nanomolar IC50 values measured with a standard fluorimetric test in 100 mM MES buffer, pH 5.5, containing 400 mM NaCl, 1 mM EDTA, 1 mM DTT and 1 mg/ml BSA. Compounds 9a–c, containing the indole ring in P1, exhibited an HIV-1 protease inhibitory activity more powerful than darunavir in the same assay. To obtain molecular insight into the binding properties of these compounds, docking analysis was performed, and their binding properties were also compared.

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“…Compound 4 was obtained as a white solid, yield 88%. 1 H and 13 C NMR spectra were consistent with the data in the literature [25].…”

Section: Chemistrysupporting

confidence: 89%

The Pseudo-Symmetric N-benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

et al. 2021

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“…Compound 4 was obtained as a white solid, yield 88%. 1 H and 13 C NMR spectra were consistent to literature data [25]. (s, 9H).…”

Section: Tert-butyl (2s3r)-4-(benzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate (4) Compoundsupporting

confidence: 87%

The Pseudo-Symmetric N-benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

D’Orsi¹,

Funicello²,

Lupattelli³

et al. 2021

Preprint

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New series of compounds containing both heterocycle moieties and pseudo-symmetric hydroxyethylamine core were obtained using a simple synthetic path that can provide a library of compounds in few steps and high yields. Furthermore, diversity-oriented synthesis was studied to change different functionalities according to needs. The in vitro inhibition activity against recombinant HIV-1 protease was evaluated. A beneficial effect of this class of compounds can be obtained either for the presence of a bis-benzyl group into the core and for the heterocyclic moiety in P1, specifically the indole ring. Docking analysis was also reported.

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“…N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-methoxybenzenesulfonamide and N-((2R,3S) -3-amino-2-hydroxy-4-phenylbutyl)-N-benzyl-4-methoxybenzenesulfonamide, indicated respectively with the abbreviations RDD-19 and RDD-142, were synthetized, purified, and finally characterized by NMR [19,20]. Dulbecco's Modification of Eagle's Medium was purchased from Corning.…”

Section: Chemicals and Antibodiesmentioning

confidence: 99%

“…Many mechanisms of action of HIV-PI in tumor cells have been proposed: interference with the cell cycle, triggering of both caspase-dependent and caspase-independent apoptotic pathways, causing oxidative stress and mitochondrial damage, inhibition of angiogenesis and tumor cell invasion [5]. In this study, we preliminarily performed viability assays on tumor and non-pathological cell lines to evaluate the cytotoxicity of a series of hydroxyethylamine derivatives, used as precursors of HIV-1 protease inhibitors and previously evaluated for their antiviral activity [19][20][21][22]. Subsequently, the two compounds most active on the hepatoma cell lines, RDD-19 and RDD-142, were used for more in-depth biological evaluations.…”

Section: Introductionmentioning

confidence: 99%

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Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2

Rinaldi

Miglionico

Nigro

et al. 2021

Cells

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Background: Several pre-clinical and clinical reports suggest that HIV-1 protease inhibitors, in addition to the antiretroviral properties, possess pleiotropic pharmacological effects including anticancer action. Therefore, we investigated the pro-apoptotic activity in tumor cells of two molecules, RDD-19 and RDD-142, which are hydroxyethylamine derivatives’ precursors of darunavir and several HIV-1 protease inhibitors. Methods: Three hepatoma cell lines and one non-pathological cell line were treated with RDD-19 and RDD-142, and cell viability was assessed. The expression levels of several markers for ER stress, autophagy, cellular ubiquitination, and Akt activation were quantified in HepG2 cells treated with RDD-19 and RDD-142 to evaluate apoptotic and non-apoptotic cell death. Results: RDD-19 and RDD-142 showed a greater dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-pathological hepatic cell line IHH. Both molecules caused two types of cell death, a caspase-dependent apoptosis, which was ascertained by a series of biochemical and morphological assays, and a caspase-independent death that was characterized by the induction of ER stress and autophagy. The strong increase of ubiquitinated proteins inside the cells suggested that the target of these molecules could be the proteasome and in silico molecular docking analysis that was used to support the plausibility of this hypothesis. Furthermore, cells treated with the two compounds displayed decreased levels of p-AKT, which interferes with cell survival and proliferation. Conclusions: These findings demonstrate that two compounds, RDD-19 and RDD-142, have pleiotropic effects and that they may represent promising anticancer candidates.

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Evaluation of (2S,3R)-2-(amino)-[4-(N-benzylarenesulfonamido)-3-hydroxy-1-phenylbutane derivatives: a promising class of anticancer agents

Cited by 7 publications

References 14 publications

The Pseudo-Symmetric N-benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

The Pseudo-Symmetric N-benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

The Pseudo-Symmetric N-benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2

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