Structure based design, synthesis, and evaluation of anti-CML activity of the quinolinequinones as LY83583 analogs

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

doi:10.1016/j.cbi.2021.109555

Cited by 21 publications

(45 citation statements)

References 69 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%

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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%

“…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%

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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“…As a part of our research program in the development of new biologically active compounds, the syntheses, experimental details, some results, and discussion of quinolinequinones have been reported in our previous report and references cited therein. [19]…”

Section: Chemistrymentioning

confidence: 99%

“…[25][26][27] Quinolinequinones and their related compounds have a wide range of pharmaceutical applications due to their antibacterial, antifungal, and anticancer properties. [19,28,29] Based on the standard Staphylococcus spp. 's MIC results, we also aimed to determine the potential antibacterial activities of selected active molecules QQ3 and QQ5 against 32 clinically obtained resistant strains of Staphylococcus spp.…”

Section: In Vitro Antimicrobial Activitymentioning

confidence: 99%

“…The quinolinequinones (QQ1-QQ10) shown in Figure 1 have been reported previously and references cited therein. [19] In Vitro Antimicrobial Activity and Candida tropicalis ATCC 750 were tested for susceptibility to QQ1 -QQ10 molecules by using CLSI reference broth microdilution methods with Mueller-Hinton broth for bacteria and RPMI 1640 medium for the yeasts strains and results were interpreted by using the CLSI clinical breakpoints for the tested standard antibiotics. [20,38] The MIC was defined as the lowest concentration of antibiotic giving complete inhibition of visible growth.…”

Section: Chemistrymentioning

confidence: 99%

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Active Quinolinequinones against Methicillin‐Resistant Staphylococcus spp

Mataracı-Kara

Bayrak

Yıldız

et al. 2021

Chemistry & Biodiversity

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Serious bacterial infections could be caused by Gram-positive microorganisms, in particular methicillinresistant Staphylococcus aureus and Staphylococcus epidermidis. Aiming to address this challenging issue by developing the potent and selective antimicrobial lead structures against methicillin-resistant Staphylococcus spp., herein, we report in vitro evaluation of quinolinequinones (QQ1-QQ10) against the Gram-negative and Gram-positive strains using the broth microdilution technique. The design principle of the quinolinequinones was based on the variation of the structures attached to the 1,4-quinone moiety and substituent(s) within amino phenyl moiety. A series of ten quinolinequinones displayed activity mainly against the Gram-positive strains with a minimal inhibitory concentration (MIC = 1.22-1250 mg/L) within the Clinical and Laboratory Standards Institute (CLSI) levels. Interestingly, QQ3, QQ5, and QQ6 displayed equal antibacterial inhibitory activity against S. aureus (MIC = 1.22 mg/L), respectively, to the standard positive control Cefuroxime-Na. QQ2, QQ3, and QQ5 had the best inhibitory activity with the MIC value of 1.22 mg/L (4-fold more potent compared reference standard Cefuroxime) against S. epidermidis. On the other hand, QQ3 was the most effective quinolinequinone against fungi, in particular C. albicans. The identified lead quinolinequinones (QQ3 and QQ5) with a comprehensive analysis of structure-activity relationships and further studies showed high activity against methicillin-resistant Staphylococcus spp. It is worth noting that the isopropyl group has importance for excellent bioactivity. Remarkably, the in vitro antibiofilm and bactericidal activities (each of 32 clinically obtained strains of Grampositive bacteria) of the selected two quinolinequinones (QQ3 and QQ5) have been evaluated for the mode of action in addition to the time-kill curve study.

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Analysis of Quinolinequinone Analogs with Promising Cytotoxic Activity against Breast Cancer

Yilmaz Goler,

Tarbin Jannuzzi,

Biswas

et al. 2023

Chemistry & Biodiversity

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In an effort to develop potent and secure antiproliferative lead compounds, five quinolinequinones (AQQ1‐5) described previously have been selected and submitted to the National Cancer Institute (NCI) of Bethesda. Four of five quinolinequinones (AQQ2‐5) were selected for five‐dose screening and they displayed promising antiproliferative effects against several cancer types. All AQQs showed a super anticancer profile with low micromolar GI50 and TGI values against most cell lines. AQQ2‐5 reduced the proliferation of all some cell lines at a single dose and five additional doses. We investigated the in vitro cytotoxic activities of the most promising compounds, AQQ2 and AQQ3. Concomitantly, IC50 values of AQQ2 against MCF7 and T‐47D cell lines of breast cancer, DU‐145 cell line of prostate cancer, HCT‐116 cell line of colon cancer, and HaCaT human keratinocytes were determined. AQQ2 exhibited anticancer activity through the induction of apoptosis and caused alterations in the cell cycle. In silico pharmacokinetic studies of all analogs have been carried out against ATR, CHK1, WEE1, CDK1, and CDK2. In addition to this, in vitro ADME and in vivo pharmacokinetic profiling for the most effective AAQ (AAQ2).

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Structure based design, synthesis, and evaluation of anti-CML activity of the quinolinequinones as LY83583 analogs

Cited by 21 publications

References 69 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

Active Quinolinequinones against Methicillin‐Resistant Staphylococcus spp

Analysis of Quinolinequinone Analogs with Promising Cytotoxic Activity against Breast Cancer

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