Design, synthesis and biological activity of 1,4-quinone moiety attached to betulin derivatives as potent DT-diaphorase substrate

Kadela-Tomanek, Monika; Jastrzębska, Maria; Marciniec, Krzysztof; Chrobak, Elwira; Bębenek, Ewa; Latocha, Małgorzata; Kuśmierz, Dariusz; Boryczka, Stanisław

doi:10.1016/j.bioorg.2020.104478

Cited by 18 publications

(13 citation statements)

References 53 publications

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“…1,4-Quinone-based betulin derivatives were synthesized and evaluated for their anticancer effects against seven human cancer cell lines including Caco-2 colorectal cancer cells and HFF1 normal fibroblast cells. 28-(3-(6-chloro-2-methyl-5,8-quinolinedione-7-yloxy)-propyl-1 H -1,2,3-triazol-4-ynoiloxy)-3-oxolup-20(29)-en ( 19b ) ( Figure 11 ) exhibited the most potent anti-colorectal activity compared to cisplatin, whereas 19b also showed cytotoxic effects against HFF1 cells [ 42 ]. Recent study showed that PQ2 displayed notable inhibition against HCT-116 cell line though PQ3 and PQ10 showed no cytotoxicity, indicating more selective anticancer action of PQ2 towards HCT-116 cells compared to PQ3 and PQ10 .…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

et al. 2022

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Plants have paved the way for the attainment of molecules with a wide-range of biological activities. However, plant products occasionally show low biological activities and/or poor pharmacokinetic properties. In that case, development of their derivatives as drugs from the plant world has been actively performed. As plant products, plastoquinones (PQs) have been of high importance in anticancer drug design and discovery; we have previously evaluated and reported the potential cytotoxic effects of a series of PQ analogs. Among these analogs, PQ2, PQ3 and PQ10 were selected for National Cancer Institute (NCI) for in vitro screening of anticancer activity against a wide range of cancer cell lines. The apparent superior anticancer potency of PQ2 on the HCT-116 colorectal cancer cell line than that of PQ3 and PQ10 compared to other tested cell lines has encouraged us to perform further mechanistic studies to enlighten the mode of anti-colorectal cancer action of PQ2. For this purpose, its apoptotic effects on the HCT-116 cell line, DNA binding capacity and several crucial pharmacokinetic properties were investigated. Initially, MTT assay was conducted for PQ2 at different concentrations against HCT-116 cells. Results indicated that PQ2 exhibited significant cytotoxicity in HCT-116 cells with an IC50 value of 4.97 ± 1.93 μM compared to cisplatin (IC50 = 26.65 ± 7.85 μM). Moreover, apoptotic effects of PQ2 on HCT-116 cells were investigated by the annexin V/ethidium homodimer III staining method and PQ2 significantly induced apoptosis in HCT-116 cells compared to cisplatin. Based on the potent DNA cleavage capacity of PQ2, molecular docking studies were conducted in the minor groove of the double helix of DNA and PQ2 presented a key hydrogen bonding through its methoxy moiety. Overall, both in vitro and in silico studies indicated that effective, orally bioavailable drug-like PQ2 attracted attention for colorectal cancer treatment. The most important point to emerge from this study is that appropriate derivatization of a plant product leads to unique biologically active compounds.

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

et al. 2022

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“…In this study, a series of triazole betulin derivatives with attached 1,4-quinone ( 1 – 16 ), as well as triazole betulin derivatives ( 17 – 20 ), were used. According to literature data [ 36 ], the reaction between triazole betulin derivatives ( 17 – 20 ) and 1,4-quinone compounds in the presence of potassium carbonate in tetrahydrofuran lead to the hybrids 1 – 16 . The chemical structures of compounds 1 – 20 are presented in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Lipophilicity, Pharmacokinetic Properties, and Molecular Docking Study on SARS-CoV-2 Target for Betulin Triazole Derivatives with Attached 1,4-Quinone

et al. 2021

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A key parameter in the design of new active compounds is lipophilicity, which influences the solubility and permeability through membranes. Lipophilicity affects the pharmacodynamic and toxicological profiles of compounds. These parameters can be determined experimentally or by using different calculation methods. The aim of the research was to determine the lipophilicity of betulin triazole derivatives with attached 1,4-quinone using thin layer chromatography in a reverse phase system and a computer program to calculate its theoretical model. The physiochemical and pharmacokinetic properties were also determined by computer programs. For all obtained parameters, the similarity analysis and multilinear regression were determined. The analyses showed that there is a relationship between structure and properties under study. The molecular docking study showed that betulin triazole derivatives with attached 1,4-quinone could inhibit selected SARS-CoV-2 proteins. The MLR regression showed that there is a correlation between affinity scoring values (ΔG) and the physicochemical properties of the tested compounds.

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“… 1,4-Naphthoquinone, quinoline 5,8-dione and isoquinoline-5,8-dione scaffolds in hybrids with betulin as reported by Kadela-Tomanek et al [ 73 , 74 , 75 ]. …”

Section: Figurementioning

confidence: 81%

“…Recently, the same authors expanded the study to hybrids presenting the betulin scaffold connected by a triazole linker to the 1,4-quinone unit, also including isoquinoline 5,8-dione [ 75 ]. The tested compounds displayed a higher activity against cancer cell lines characterized by increased levels of the NQO1 protein.…”

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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Design, synthesis and biological activity of 1,4-quinone moiety attached to betulin derivatives as potent DT-diaphorase substrate

Cited by 18 publications

References 53 publications

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

Lipophilicity, Pharmacokinetic Properties, and Molecular Docking Study on SARS-CoV-2 Target for Betulin Triazole Derivatives with Attached 1,4-Quinone

Hybrid Molecules Containing Naphthoquinone and Quinolinedione Scaffolds as Antineoplastic Agents

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