Search

Cancer cells need to carefully regulate their metabolism to keep them growing and dividing under the influence of different nutrients and oxygen levels. Muscle isoform 2 of pyruvate kinase (PKM2) is a key glycolytic enzyme involved in the generation of ATP and is critical for cancer metabolism. PKM2 is expressed in many human tumors and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various modulators regulate PKM2, shifting it between highly active and less active states. In the presented work, a series of 8-quinolinesulfonamide derivatives of PKM2 modulators were designed using molecular docking and molecular dynamics techniques. New compounds were synthesized using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Compound 9a was identified in in silico studies as a potent modulator of muscle isoform 2 of pyruvate kinase. The results obtained from in vitro experiments confirmed the ability of compound 9a to reduce the intracellular pyruvate level in A549 lung cancer cells with simultaneous impact on cancer cell viability and cell-cycle phase distribution. Moreover, compound 9a exhibited more cytotoxicity on cancer cells than normal cells, pointing to high selectivity in the mode of action. These findings indicate that the introduction of another quinolinyl fragment to the modulator molecule may have a significant impact on pyruvate levels in cancer cells and provides further directions for future research to find novel analogs suitable for clinical applications in cancer treatment.

Depending on temperature, the 2-amino-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-dione forms two polymorphic structures, which differ in the spatial arrangement of the amine group. Both polymorphs were investigated using different experimental methods as well as various quantum chemical calculations in order to characterise their molecular structures. We used X-ray diffraction, FT-IR and NMR (solid-state and liquid) methods supplemented by the density functional theory (DFT) calculations, molecular electrostatic potential (MEP) and molecular orbital (HOMO, LUMO) analyses. It was found that the arrangement of the amine group affected the crystal structure, formation of H-bonds, the amine and carbonyl vibration bands in the FT-IR spectra, chemical shift of amine group in 15 N CP/MAS NMR and chemical shift of amine protons in 1 H NMR spectra. Both polymorphs were tested on anticancer activity against a panel of human cancer cell lines. Comparing the activity of both compounds showed that activity against MCF-7, MDA-MB-231 and Caco-2 lines depend on the arrangement of the amine group. Moreover, both polymorphs exhibited the highest activity against cell line with high NQO1 protein level, such as: A549, MCF-7 and Caco-2. The molecular docking was used to examine the probable interaction between the ligand of the tested polymorphs and the NQO1 enzyme. The analysis showed that ligands formed a hydrophobic interaction with tryptophan (Trp105), phenylalanine (Phe126 and Phe178) and tyrosine (Tyr 126)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Natural 5,8-quinolinedione antibiotics exhibit a broad spectrum of activities including anticancer, antibacterial, antifungal, and antimalarial activities. The structure-activity research showed that the 5,8-quinolinedione scaffold is responsible for its biological effect. The subject of this review report is a presentation of the pharmacological activity of synthetic 5,8-quinolinedione compounds containing different groups at C-6 and/or C-7 positions. The relationship between the activity and the mechanism of action is included if these data have been included in the original literature. The review mostly covers the period between 2000 and 2019. Previously published literature data were used to present historical points.

The lipophilicity of a series of anticancer propargylquinoline derivatives is investigated using both chromatographic and computational methods. The parameters of the tested compounds' relative lipophilicity (logkw) are determined experimentally by the high-performance liquid chromatographic method (RP-HPLC, Accucore C18 column), using mixtures of acetonitrile and water as mobile phases. Mobile phase acetonitrile concentrations range between 50 and 80%. The logk values of the investigated compounds are linearly dependent upon the acetonitrile concentration. The analysis led to the calculation of the logkw parameter values for each of the tested compounds. The parameter logkw is discussed in terms of the relationship between structure and lipophilicity and consequently, transformed into the parameter logPHPLC using the calibration curve. The partition coefficients of the tested compounds (logPcalc) are also calculated by selected computer programs. A regression analysis and the sum of ranking differences are used to compare the lipophilic parameters of 15 acetylenequinoline derivatives, which were experimentally obtained (logPHPLC) and calculated using different mathematical methods (logPcalc). The 13C NMR spectra are used to examine the electronic relationships between properties and lipophilicity for the studied compounds. A regression study conducted on 15 compounds exhibits a linear correlation between lipophilicity and electronic properties, expressed as the 13C NMR chemical shift (R2 = 0.98)., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The compounds produced by a living organism are most commonly as medicinal agents and starting materials for the preparation of new semi-synthetic derivatives. One of the largest groups of natural compounds consists of products containing a 1,4-benzoquinone subunit. This fragment occurs in three enediyne antibiotics, dynemicin A, deoxydynemicin A, and uncilamicin, which exhibit high biological activity. A series of alkoxy derivatives containing 1,4-naphthoquinone, 5,8-quinolinedione, and 2-methyl-5,8-quinolinedione moieties was synthesized. Moreover, the 1,4-benzoquinone subunit was contacted with an enediyne fragment. All obtained compounds were characterized by spectroscopy and spectrometry methods. The resulting alkane, alkene, alkyne and enediyne derivatives were tested as antitumor agents. They showed high cytotoxic activity depending on the type of 1,4-benzoquinone subunit and the employed tumor cell lines. The synthesized derivatives fulfill the Lipinski Rule of Five and have low permeability through the blood-brain barrier.

In this study, a series of regioisomeric acetylenic sulfamoylquinolines are designed, synthesized, and tested in vitro for their antiproliferative activity against three human breast cacer cell lines (T47D, MCF-7, and MDA-MB-231) and a human normal fibroblast (HFF-1) by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2 H -5-tetrazolio]-1,3-benzene disulfonate (WST-1) assay. The antiproliferative activity of the tested acetylenic quinolinesulfonamides is comparable to that of cisplatin. The bioassay results demonstrate that most of the tested compounds show potent antitumor activities, and that some compounds exhibit better effects than the positive control cisplatin against various cancer cell lines. Among these compounds, 4-(3-propynylthio)-7-[ N -methyl- N -(3-propynyl)sulfamoyl]quinoline shows significant antiprolierative activity against T47D cells with IC 50 values of 0.07 µM. In addition, 2-(3-Propynylthio)-6-[ N -methyl- N -(3-propynyl)sulfa-moyl]quinoline and 2-(3-propynylseleno)-6-[ N -methyl- N -(3-propynyl)sulfamoyl]quinoline display highly effective atitumor activity against MDA-MB-231 cells, with IC 50 values of 0.09 and 0.50 µM, respectively. Furthermore, most of the tested compounds show a weak cytotoxic effect against the normal HFF-1 cell line. Additionally, in order to suggest a mechanism of action for their activity, all compounds are docked into the binding site of two human cytochrome P450 (CYP) isoenzymes. These data indicate that some of the title compounds display significant cytotoxic activity, possibly targeting the CYPs pathways.

The natural 7-amino-5,8-quinolinodione antibiotics were the substrate for the NQO1 protein. The structure-activity relationship showed that the 5,8-quinolinedione moiety was responsible for the interaction with the enzyme. In our research, we presented the synthesis, cytotoxic activity and theoretical study of a 5,8-quinolinedione compound as a potential inhibitor of the NQO1 enzyme. Mono and disubstituted alkynyloxy derivatives of the 5,8-quinolinedione were synthesized and characterized by 1 H, 13 C NMR, IR and HR-MS spectra. Newly synthesized derivatives were also tested for their biological activity in vitro against the human cancer cell lines. They showed high cytotoxic activity depending on the type of substituent and the employed tumor cell lines. Moreover, two breast cancer cell lines, MDA-MB-231 and MCF-7, were chosen for analysis as they are characterized by different NQO1 protein levels. It was found that cytotoxic activities of all studied compounds increased against the cell line with a higher NQO1 protein level. The molecular docking was used to examine the probable interaction between the molecules of alkynyloxy derivatives and human NAD[P]H-quinone oxidoreductase (NQO1) protein. The computational studies showed that the 5,8-quinolinedione moiety of all docked compounds was located deeply in the hydrophobic matrix of the active site near the side chains of aromatic residues in positions Trp 105, Phe 178, Tyr 126 and Tyr 128. In every case, introduction of aromatic moieties into the 5,8-quinolinedione molecule led to an increase in the binding affinity in relation to the 6,7-dichloro-5,8-quinolinedione., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A series of 5,8-quinolinedione derivatives containing one or two alkoxy groups was synthesized and characterized by ¹H- and (13)C-NMR, IR and MS spectra. X-ray diffraction was used to investigate the crystal structures of 6-chloro-7-(2-cyjanoethoxy)-5,8-quinolinedione and 6,7-di(2,2,2-trifloroethoxy)-5,8-quinolinedione. All studied compounds were tested in vitro for their antiproliferative activity against three human cancer cell lines and human normal fibroblasts. Most of the compounds showed higher cytotoxicity than the starting compound, 6,7-dichloro-5,8-quinolinedione, and cisplatin, which was used as a reference agent.

The series of new acetylenic thioquinolines containing propargyl, 2-butynyl, 4-bromo-2-butynyl, and 4-hydroxy-2-butynyl groups has been prepared and tested for antiproliferative activity in vitro against human [SW707 (colorectal adenocarcinoma), CCRF/CEM (leukemia)] and murine [P388 (leukemia), B16 (melanoma)] cancer lines. All the compounds obtained exhibited antiproliferative activity. The most active compounds 7, 16, 17, and 19 have the ID(50) values ranging from 0.2 to 4.6 microg/ml comparable to that of cisplatin used as reference compounds.

The structure-activity relationships of new quinoline based compounds were investigated. Quinoline-5,8-dione and styrylquinoline scaffolds were used for the design of potentially active compounds. The novel analogues had comparable antiproliferative activity to cisplatin when evaluated in a bioassay against the P388 leukemia cell line. However, these compounds appeared far less efficient against SK-N-MC neuroepithelioma cells. Analogues without the 5,8-dione structure but containing the 8-carboxylic acid group were also found to induce antiproliferative activity. Hydrophobicity as measured by HPLC did not correlate with antiproliferative activity.

The lipophilicity of a series of anticancer propargylthioquinoline derivatives has been investigated using chromatographic and computational methods. The parameters of relative lipophilicity (R(MO) and logk0) of the tested compounds were determined experimentally both by reversed-phase thin layer (RP-TLC), and high-performance liquid chromatographic methods (RP-HPLC, LiChrospher RP18 column), with mixtures of acetonitrile and water as mobile phases. Their phospholipophilicity (logk(0IAM)) was determined using immobilized artificial membrane HPLC (IAM. PC DD2 Regis column). Mobile phase acetonitrile concentrations were in the ranges 50-90% (RP-TLC), 55-90% (RP-HPLC) and 35-60% (IAM-HPLC). The R(M), logk and logk(IAM) values of the compounds investigated were linearly dependent on acetonitrile concentration. The analysis led to the calculation of R(MO), logk0 and logk(0IAM) parameter values for each of the tested compounds. Their partition coefficients (logP) were also calculated with the Pallas and CAChe programs. The obtained results indicated that, among experimental methods, both RP-TLC and RP-HPLC gave similar results, and these methods enable the determination of lipophilicity of derivatives of thioquinolines. Using the IAM-HPLC technique a simple method of estimation of phospholipoplilicity was described. The CAChe program might better predict calculated lipophilicity logP values, and therefore is a useful tool for the early stage of design of new propargyl thioquinolines., (Copyright 2006 John Wiley & Sons, Ltd.)

A series of new acetylenic thioquinolines containing propargyl, 2-butynyl, or 4-bromo-2-butynyl groups has been prepared and tested for antiproliferative activity in vitro against the cells of human [SW707 (colon cancer), CCRF/CEM (leukemia)] and murine [P388 (leukemia), B16 (melanoma)] cancer lines. All the compounds obtained exhibited antiproliferative activity. The most active compounds 4h and 41-m have ID50 values ranging from 0.2 to 3.6 microg/ml, comparable to that of the reference compound cisplatin.

The series of the propargyl thioquinolines has been prepared on the basis of the reaction of thioquinanthrene (1) (1,4-dithiino[2,3-c:5,6-c']-diquinoline) with sodium alkoxides. Some of these compounds have revealed good antiproliferative activity in vitro against the cells of human and murine cancer lines. 13C NMR spectra were measured for the studied compounds to examine the electronic properties-activity relationships. A regression study on 10 compounds showed a linear correlation of antiproliferative activity with electronic properties, expressed as the 13C NMR chemical shift for C-4 carbon atom (R2 = 0.97). It was found that compounds with chemical shift for C-4 value falling in the range of 135-140 ppm exhibited significant antiproliferative activity, while compounds which possess moderate or low activity are located in the range 140-165 ppm. This finding leads to the expectation that the antiproliferative activity of propargyl thioquinolines can be predicted using the 13C NMR chemical shift value of their C-4 carbon atom.

The series of new 3,4-disubstituted thioquinolines which possess one or two O, S, Se-propargyl groups has been synthesized on the basis of the reaction of thioquinanthrene with alkoxides. All the compounds obtained were tested for their antiproliferative activity in vitro against the cells of three human cancer cell lines: SW707 (colon cancer), T47D (breast cancer), and HCV29T (bladder cancer). Two compounds, 4-(3-hydroxypropoxy)-3'-propargylthio-3,4'-diquinolinyl sulfide (3) and 3-methylthio-4-propargylselenoquinoline (13) exhibited significant cytostatic activity (ID50 < 4 micrograms/ml) against the cells of all the human cancer lines used and are good candidates for further anticancer activity studies in vitro using a broad panel of human and murine cell lines and for in vivo preclinical screening in different mouse transplantable tumor models.

The molecular structure of the title compound, C(25)H(18)N(2)O(2)S(2), in the crystal is characterized by almost parallel quinoline and propargyl groups that point in opposite directions out of the quinoline planes. Intermolecular C[triple-bond]C-H...N hydrogen bonding is observed, but the hydrogen-bond geometry is poor.