Design, synthesis and investigation of the mechanism of action underlying anti-leukemic effects of the quinolinequinones as LY83583 analogs

Çiftçi, Halil; Bayrak, Nilüfer; Yıldız, Mahmut; Yıldırım, Hatice; Sever, Belgin; Tateishi, Hiroshi; Otsuka, Masami; Fujita, Mikako; Tuyun, Amaç Fatih

doi:10.1016/j.bioorg.2021.105160

Cited by 24 publications

(19 citation statements)

References 77 publications

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“…In our previous studies, we also performed molecular docking studies for quinone-based compounds with the most significant DNA cleaving abilities. 7-Chloro-6-(3,5-dimethylphenyl)amino-5,8-quinolinequinone ( AQQ15 ) [ 47 ] and 6-(benzo[ d ][1,3]dioxol-5-ylamino)-7-chloro-5,8-quinolinequinone ( AQQ13 ) [ 48 ] formed important interactions with DNA. In the current work, PQ2 also formed a key hydrogen bonding through its methoxy moiety in the minor groove of the double helix of DNA.…”

Section: Discussionmentioning

confidence: 99%

“…The X-ray crystallographic structure of DNA was acquired from the PDB server (PDB ID: 2GWA) [ 37 ] and optimized for docking analysis in protein preparation module of Schrödinger software. In molecular docking simulations, Grid Generation and Glide/ XP docking protocols were implemented [ 47 , 48 ].…”

Section: Methodsmentioning

confidence: 99%

“…Some pharmacokinetic characteristics of PQ2 were calculated by the QikProp module of Schrödinger software (Schrödinger Release 2016-2: QikProp, Schrödinger, LLC, New York, NY, USA, 2016) [ 47 , 48 ].…”

Section: Methodsmentioning

confidence: 99%

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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%

Section: Methodsmentioning

confidence: 99%

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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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“…The central nervous system (CNS) activity values of compounds 1-13 (−2 to 0) were in agreement within the range (−2 to 2). The QPlogPo/w value, which is a crucial parameter for membrane permeability, metabolism, bioavailability, the toxicity of molecules, and a ligand binding to the receptor [41], was determined as 5.744, 5.453, and 5.745 for compounds 10, 11, and 12, respectively within the specified range (−2 to 6.5). The QPlogPo/w values of other compounds were detected out of limit.…”

Section: Resultsmentioning

confidence: 99%

EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy

Çi̇ftçi̇

Radwan

Sever

et al. 2021

IJMS

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Glioma, particularly its most malignant form, glioblastoma multiforme (GBM), is the most common and aggressive malignant central nervous system tumor. The drawbacks of the current chemotherapy for GBM have aroused curiosity in the search for targeted therapies. Aberrantly overexpressed epidermal growth factor receptor (EGFR) in GBM results in poor prognosis, low survival rates, poor responses to therapy and recurrence, and therefore EGFR-targeted therapy stands out as a promising approach for the treatment of gliomas. In this context, a series of pentacyclic triterpene analogues were subjected to in vitro and in silico assays, which were conducted to assess their potency as EGFR-targeted anti-glioma agents. In particular, compound 10 was the most potent anti-glioma agent with an IC50 value of 5.82 µM towards U251 human glioblastoma cells. Taking into account its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), compound 10 exerts selective antitumor action towards Jurkat human leukemic T-cells. This compound also induced apoptosis and inhibited EGFR with an IC50 value of 9.43 µM compared to erlotinib (IC50 = 0.06 µM). Based on in vitro and in silico data, compound 10 stands out as a potential orally bioavailable EGFR-targeted anti-glioma agent endowed with the ability to cross the blood–brain barrier (BBB).

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“…In recent years, many new classes of antitumour compounds with a significant effect on the signalling pathways in tumour cells have been developed [1][2][3][4][5][6]. Along with the new classes, antihormonal drugs-SERMs (selective oestrogen receptor modulators) and SERDs (selective oestrogen receptor degraders)-remain highly relevant as an antitumour therapy [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Towards Unravelling the Role of ERα-Targeting miRNAs in the Exosome-Mediated Transferring of the Hormone Resistance

et al. 2021

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Hormone therapy is one of the most effective breast cancer treatments, however, its application is limited by the progression of hormonal resistance, both primary or acquired. The development of hormonal resistance is caused either by an irreversible block of hormonal signalling (suppression of the activity or synthesis of hormone receptors), or by activation of oestrogen-independent signalling pathways. Recently the effect of exosome-mediated intercellular transfer of hormonal resistance was revealed, however, the molecular mechanism of this effect is still unknown. Here, the role of exosomal miRNAs (microRNAs) in the transferring of hormonal resistance in breast cancer cells has been studied. The methods used in the work include extraction, purification and RNAseq of miRNAs, transfection of miRNA mimetics, immunoblotting, reporter analysis and the MTT test. Using MCF7 breast cancer cells and MCF7/T tamoxifen-resistant sub-line, we have found that some miRNAs, suppressors of oestrogen receptor signalling, are overexpressed in the exosomes of the resistant breast cancer cells. The multiple (but not single) transfection of one of the identified miRNA, miR-181a-2, into oestrogen-dependent MCF7 cells induced the irreversible tamoxifen resistance associated with the continuous block of the oestrogen receptor signalling and the activation of PI3K/Akt pathway. We suppose that the miRNAs-ERα suppressors may act as trigger agents inducing the block of oestrogen receptor signalling and breast cancer cell transition to an aggressive oestrogen-independent state.

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Design, synthesis and investigation of the mechanism of action underlying anti-leukemic effects of the quinolinequinones as LY83583 analogs

Cited by 24 publications

References 77 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

EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy

Towards Unravelling the Role of ERα-Targeting miRNAs in the Exosome-Mediated Transferring of the Hormone Resistance

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