Synthesis and structure–activity relationship study of novel 3-diethoxyphosphorylfuroquinoline-4,9-diones with potent antitumor efficacy

Modranka, Jakub; Drogosz-Stachowicz, Joanna; Pietrzak, Anna; Janecka, Anna; Janecki, Tomasz

doi:10.1016/j.ejmech.2021.113429

Cited by 14 publications

(8 citation statements)

References 32 publications

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“…The interaction between 1,4-quinone moiety of hybrid and NQO1 protein leads to reduction in quinone to hydroquinone and production of reactive oxide form (ROS) [ 30 , 31 ]. According to a literature method, the ability of hybrids 11 – 14 and streptonigrin ( ST ) to be a substrate for NQO1 was examined by measuring the oxidation of NADPH to NADP + [ 29 , 32 ].…”

Section: Resultsmentioning

confidence: 99%

Hybrids of 1,4-Quinone with Quinoline Derivatives: Synthesis, Biological Activity, and Molecular Docking with DT-Diaphorase (NQO1)

et al. 2022

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Hybrids 1,4-quinone with quinoline were obtained by connecting two active structures through an oxygen atom. This strategy allows to obtain new compounds with a high biological activity and suitable bioavailability. Newly synthesized compounds were characterized by various spectroscopic methods. The enzymatic assay used showed that these compounds were a suitable DT-diaphorase (NQO1) substrates as evidenced by increasing enzymatic conversion rates relative to that of streptonigrin. Hybrids were tested in vitro against a panel of human cell lines including melanoma, breast, and lung cancers. They showed also a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activity of the studied hybrids was increasing against the cell lines with higher NQO1 protein level, such as breast (MCF-7 and T47D) and lung (A549) cancers. Selected hybrids were tested for the transcriptional activity of the gene encoding a proliferation marker (H3 histone), cell cycle regulators (p53 and p21) and the apoptosis pathway (BCL-2 and BAX). The molecular docking was used to examine the probable interaction between the hybrids and NQO1 protein.

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Section: Resultsmentioning

confidence: 99%

Hybrids of 1,4-Quinone with Quinoline Derivatives: Synthesis, Biological Activity, and Molecular Docking with DT-Diaphorase (NQO1)

et al. 2022

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“…Very recently, Janeka and coworkers have expanded their previous studies on antitumor naphthofurandione–phosphonate hybrids [ 44 , 45 ] from which compound 30 emerged as the most active ( Figure 12 ). By combining the quinolinedionefurandione scaffold with the phosphonate moiety, they obtained a series of new diethoxyphosphorylfuroquinoline-4,9-diones hybrids ( Figure 30 ) [ 71 ]. Starting from 6,7-dichloroquinoline-5,8-dione, the two N ,O- syn and N ,O- anti regioisomers were produced and their stereochemistry was assigned by 13 C- and 31 P-NMR analyses.…”

Section: Design Synthesis and Biological Evaluation Of Antitumor Hybridsmentioning

confidence: 99%

Hybrid Molecules Containing Naphthoquinone and Quinolinedione Scaffolds as Antineoplastic Agents

et al. 2022

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In recent decades, molecular hybridization has proven to be an efficient tool for obtaining new synthetic molecules to treat different diseases. Based on the core idea of covalently combining at least two pharmacophore fragments present in different drugs and/or bioactive molecules, the new hybrids have shown advantages when compared with the compounds of origin. Hybridization could be successfully applied to anticancer drug discovery, where efforts are underway to develop novel therapeutics which are safer and more effective than those currently in use. Molecules presenting naphthoquinone moieties are involved in redox processes and in other molecular mechanisms affecting cancer cells. Naphthoquinones have been shown to inhibit cancer cell growth and are considered privileged structures and useful templates in the design of hybrids. The present work aims at summarizing the current knowledge on antitumor hybrids built using 1,4- and 1,2-naphthoquinone (present in natural compounds as lawsone, napabucasin, plumbagin, lapachol, α-lapachone, and β -lapachone), and the related quinolone- and isoquinolinedione scaffolds reported in the literature up to 2021. In detail, the design and synthetic approaches adopted to produce the reported compounds are highlighted, the structural fragments considered in hybridization and their biological activities are described, and the structure–activity relationships and the computational analyses applied are underlined.

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“…In our previous paper [ 19 ] we reported the synthesis of 3-diethoxyphosphorylfuroquinoline-4,9-diones combining furoquinoline-5,8-dione skeleton with diethoxyphosphoryl moiety. All obtained compounds proved to be highly cytotoxic for breast cancer adenocarcinoma MCF-7 and promyelocytic leukemia HL-60 cells, with IC 50 values in the low µM range.…”

Section: Introductionmentioning

confidence: 99%

Anticancer Properties of 3-Dietoxyphosphorylfuroquinoline-4,9-dione

et al. 2023

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Herein, the antitumor activity of a novel synthetic analog with 5,8-quinolinedione scaffold, diethyl (2-(2-chlorophenyl)-4,9-dioxo-4,9-dihydrofuro [3,2-g]quinolin-3-yl)phosphonate (AJ-418) was investigated on two breast cancer cell lines. This analog was selected from a small library of synthetic quinolinediones on the basis of its strong antiproliferative activity against MCF-7 and MDA-MB-231 cells and 4-5-fold lower cytotoxicity towards healthy MCF-10A cells. The morphology of MCF-7 and MDA-MB-231 cancer cells treated with AJ-418 changed drastically, while non-tumorigenic MCF-10A cells remained unaffected. In MCF-7 cells, after 24 h incubation, the increased number of apoptotic cells coincided with a decrease in proliferation and cell viability. The 24 h treatment of MDA-MB-231 cells with the tested compound reduced their cell viability and proliferation rate; however, a significant pro-apoptotic effect was visible only after longer incubation times (48 h and 72 h). Then, the maximum tolerated dose (MTD) of compound AJ-418 in C3H mice after subcutaneous administration was determined to be 160 mg/kg, showing that this analog was well tolerated and can be further evaluated to assess its potential therapeutic effect in tumor-bearing mice.

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Synthesis and structure–activity relationship study of novel 3-diethoxyphosphorylfuroquinoline-4,9-diones with potent antitumor efficacy

Cited by 14 publications

References 32 publications

Hybrids of 1,4-Quinone with Quinoline Derivatives: Synthesis, Biological Activity, and Molecular Docking with DT-Diaphorase (NQO1)

Hybrids of 1,4-Quinone with Quinoline Derivatives: Synthesis, Biological Activity, and Molecular Docking with DT-Diaphorase (NQO1)

Hybrid Molecules Containing Naphthoquinone and Quinolinedione Scaffolds as Antineoplastic Agents

Anticancer Properties of 3-Dietoxyphosphorylfuroquinoline-4,9-dione

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