Design, synthesis and biological evaluation of novel naphthoquinone-4-aminobenzensulfonamide/carboxamide derivatives as proteasome inhibitors

Uysal, Şirin; Soyer, Zeynep; Saylam, Merve; Tarikogullari, Ayse H.; Yılmaz, Sinem; Ballar, Petek

doi:10.1016/j.ejmech.2020.112890

Cited by 12 publications

(10 citation statements)

References 40 publications

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“…To assess the potential of the two selected compounds from the molecular docking simulations we identified for each of these compounds the specific interactions that they established with each of the proteins. We compared these data with information obtained from X-ray cocrystallised structures with known inhibitors as well as with results already gathered from the several molecular docking simulations performed by other groups to gain insight into EZH2 [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ] and P20S inhibition [ 32 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

et al. 2021

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Multiple myeloma is an incurable plasma cell neoplastic disease representing about 10–15% of all haematological malignancies diagnosed in developed countries. Proteasome is a key player in multiple myeloma and proteasome inhibitors are the current first-line of treatment. However, these are associated with limited clinical efficacy due to acquired resistance. One of the solutions to overcome this problem is a polypharmacology approach, namely combination therapy and multitargeting drugs. Several polypharmacology avenues are currently being explored. The simultaneous inhibition of EZH2 and Proteasome 20S remains to be investigated, despite the encouraging evidence of therapeutic synergy between the two. Therefore, we sought to bridge this gap by proposing a holistic in silico strategy to find new dual-target inhibitors. First, we assessed the characteristics of both pockets and compared the chemical space of EZH2 and Proteasome 20S inhibitors, to establish the feasibility of dual targeting. This was followed by molecular docking calculations performed on EZH2 and Proteasome 20S inhibitors from ChEMBL 25, from which we derived a predictive model to propose new EZH2 inhibitors among Proteasome 20S compounds, and vice versa, which yielded two dual-inhibitor hits. Complementarily, we built a machine learning QSAR model for each target but realised their application to our data is very limited as each dataset occupies a different region of chemical space. We finally proceeded with molecular dynamics simulations of the two docking hits against the two targets. Overall, we concluded that one of the hit compounds is particularly promising as a dual-inhibitor candidate exhibiting extensive hydrogen bonding with both targets. Furthermore, this work serves as a framework for how to rationally approach a dual-targeting drug discovery project, from the selection of the targets to the prediction of new hit compounds.

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Section: Resultsmentioning

confidence: 99%

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

et al. 2021

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“…Then, these intermediates were converted into final amide derivative compounds by interacting with appropriate anilines (Uysal et al, 2012). PI-083 lead compound, which was used to compare antiproteasomal activity, was synthesized, and the synthesis procedure and spectral data of this compound were described in our previous work (Uysal et al, 2021).…”

Section: Chemistrymentioning

confidence: 99%

“…The proteasome inhibitory activity of compounds in crude extracts was analyzed on MCF-7 cells as previously reported (Sirin Uysal et al, 2021). Briefly, cells were lysed with a lysis buffer composed of 8.56 g sucrose, 0.6 g HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfon ic acid), 0.2 g MgCl 2 , 0.037 g EDTA (ethylenediaminetetraacetic acid) prepared in 100 mL.…”

Section: Cell-based Proteasome Inhibition Assaymentioning

confidence: 99%

“…Furthermore, studies regarding PI‐083 and its analogs demonstrated that 2‐chloronaphthoquinone scaffold presented in PI‐083 was a favorable structural phenotype for novel proteasome inhibitor development studies (Lawrence et al, 2010). Recently, we have reported some novel naphthoquinone‐4‐aminobenzensulfonamide/carboxamide derivatives that exhibit proteasome inhibitory activity (Uysal et al, 2021). In this study, a series of novel naphthoquinone‐glycine/β‐alanine anilide derivatives were designed by applying molecular modification method to the structure of PI‐083 lead compound.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of some novel naphthoquinone‐glycine/β‐alanine anilide derivatives as noncovalent proteasome inhibitors

et al. 2023

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A series of novel noncovalent glycine/β‐alanine anilide derivatives possessing 2‐chloronaphthoquinone structure as a pharmacophoric unit were designed, synthesized, and evaluated for their antiproliferative and antiproteasomal activities against MCF‐7 cell line, in vitro. According to biological activity results, all the target compounds showed antiproliferative activity in the range of IC50 = 7.10 ± 0.10–41.08 ± 0.14 μM and most of them exhibited inhibitory efficacy with varying ratios against the three catalytic subunits (β1, β2, and β5) presenting caspase‐like (C‐L), trypsin‐like (T‐L) and chymotrypsin‐like (ChT‐L) activities of proteasome. The antiproteasomal activity evaluations revealed that compounds preferentially inhibited the β5 subunit compared with β1 and β2 subunits of the proteasome. Among the compounds, compounds 7 and 9 showed the highest antiproliferative activity with an IC50 value of 7.10 ± 0.10 and 7.43 ± 0.25 μM, respectively. Additionally, compound 7 displayed comparable potency to PI‐083 lead compound in terms of β5 antiproteasomal activity with an inhibition percentage of 34.67 at 10 μM. This compound showed an IC50 value of 32.30 ± 0.45 μM against β5 subunit. Furthermore, molecular modeling studies of the most active compound 7 revealed key interactions with β5 subunit. The results suggest that this class of compounds may be beneficial for the development of new potent proteasome inhibitors.

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“…The changes in the cell cycle and cell necrosis with increased concentrations of BrPQ5 contributed to the dose-dependent antiproliferative effects in MCF7 cells. In the anticancer research associated with quinone chemistry, several 1,4-quinone molecules were developed and have demonstrated proteasome inhibition [48][49][50]. In light of these papers and our in silico study results that indicated BrPQ5's interaction with proteasome catalytic subunits, we focused on further investigating the BrPQ5 effects on the catalytic activity of the proteasome.…”

Section: Cellmentioning

confidence: 99%

Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction

et al. 2022

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Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog (BrPQ5) was selected for a full panel five-dose in vitro assay by the NCI’s Development Therapeutic Program (DTP) division to determine GI50, TGI, and LC50 parameters. The brominated PQ analog (BrPQ5) displayed remarkable activity against most tested cell lines, with GI50 values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possible BrPQ5 interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity of BrPQ5 was assessed, and IC50 values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects of BrPQ5 on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed that BrPQ5 caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However, BrPQ5 did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents.

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Design, synthesis and biological evaluation of novel naphthoquinone-4-aminobenzensulfonamide/carboxamide derivatives as proteasome inhibitors

Cited by 12 publications

References 40 publications

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

Design, synthesis, and biological evaluation of some novel naphthoquinone‐glycine/β‐alanine anilide derivatives as noncovalent proteasome inhibitors

Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction

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