3412-99-5Relevant articles and documents
Discovery of novel 4(1H)-quinolone derivatives as potential antiproliferative and apoptosis inducing agents
Zhou, Ping,Huang, Linsheng,Zhou, Jie,Jiang, Bin,Zhao, Yanmei,Deng, Xuehua,Zhao, Qin,Li, Fei
, p. 4185 - 4189 (2017)
A series of novel 4(1H)-quinolone derivatives was synthesized and evaluated for antiproliferative activity in vitro. The results showed that these compounds exhibited more potent antiproliferative effect against a panel of human tumor cell lines than the lead compound 7-chloro-4(1H)-quinolone 1. Compound 7e was found to be the most potent antiproliferative agent and to exhibit selective cytotoxic activity against HepG2 cell lines with IC50 value lower than 1.0 μM. Annexin V/FITC-PI assay showed that compound 7e induced apoptosis in HepG2 cells with a dose-dependent manner. Western blotting analysis indicated that compound 7e induced cell cycle arrest in G2/M phase by p53-depedent pathway.
Crystal Packing Modulation of the Strength of Resonance-Assisted Hydrogen Bonds and the Role of Resonance-Assisted Pseudoring Stacking in Geminal Amido Esters: Study Based on Crystallography and Theoretical Calculations
Venkatesan, Perumal,Thamotharan, Subbiah,Percino, M. Judith,Ilangovan, Andivelu
, p. 779 - 798 (2021/01/13)
A detailed experimental and theoretical investigation of a series of substituted geminal amido esters (ethyl (2E)-3-(arylamino)-2-(arylcarbamoyl)prop-2-enoate, AME-1-8) leading to the identification of a unique angularly fused pseudotricyclic (S(6),S(6),S(6)) ring system stabilized by an intramolecular resonance-assisted hydrogen bond (RAHB) and a non-RAHB are presented in addition to weak intermolecular interactions. An analysis of X-ray and theoretical models reveals that the strength of the intramolecular RAHB (N1-H1N···O1) varies in a wide range (6.9-11.4 kcal mol-1) due to crystal-packing constraints arising from different aromatic ring substitutions. However, the effect is less significant and the strength differs only in a narrow range (8.2-9.9 kcal mol-1) in the case of non-RAHB. The downfield shift (δ～12.3) observed for the N-Haniline signal in 1H NMR spectra of AME-1-8 is due to the presence of intramolecular RAHB. A PIXEL energy analysis suggests that the molecular dimer formed by stacking of RAHB pseudorings is found to be strong (Etot = -14.4 to -17.9 kcal mol-1), and this dimer forms the basic motif in most of the structures reported herein. A detailed analysis of the isostructurality suggests that the basic motif exists in most of the structural combinations. The weak intermolecular C-H···O, C-H···Cl, and C-H···πinteractions play a vital role in the stabilization of these crystal structures, as evaluated by PIXEL and Bader's quantum theory of atoms in molecules approach (QTAIM). A lattice energy analysis suggests that the Coulombic contribution and total lattice energies are higher in the para-substituted compounds (AME-2, AME-5, and AME-8) in comparison to the other isomeric compounds. Further, the crystal packing of these compounds is analyzed on the basis of the energy frameworks. It shows that most of the crystals show similar 3D topologies, suggesting that these compounds may have similar mechanical behavior.
3-(Benzo[: D] thiazol-2-yl)-4-aminoquinoline derivatives as novel scaffold topoisomerase i inhibitor via DNA intercalation: Design, synthesis, and antitumor activities
Chen, Nan-Ying,Gu, Zi-Yu,Li, Xiao-Juan,Liao, Hao-Ran,Mo, Dong-Liang,Pan, Cheng-Xue,Su, Gui-Fa,Yuan, Jing-Mei,Zhang, Guo-Hai
, p. 11203 - 11214 (2020/07/15)
Twenty-seven 3-(benzo[d]thiazol-2-yl)-4-aminoquinoline derivatives have been designed and synthesized as topoisomerase I inhibitors. The in vitro anti-proliferation evaluation against four human cancer cell lines (MGC-803, HepG-2, T24, and NCI-H460) and one normal cell line (HL-7702) indicated that most of them exhibited potent cytotoxicity. Among them, 5a was identified as the most promising candidate with a low IC50 value of about 2.20 ± 0.14 and was selected for further exploration. Spectroscopic analyses and agarose-gel electrophoresis assays indicated that 5a could interact with DNA and strongly inhibit topoisomerase I (Topo I). Further screening of the Topo I activity of compounds 5b, 5c, 5e, 5f, 5h, 5i, 5j, 5l, and 5n suggested that some of the compounds might exert quite a different cytotoxicity profile to that of 5a. Molecular modeling studies confirmed that 5a adopts a unique mode to interact with DNA and Topo I. Other molecular mechanistic studies suggested that the treatment of MGC-803 cells with 5a induces S phase arrest, up-regulates the pro-apoptotic protein, down-regulates the anti-apoptotic protein, activates caspase-3, and subsequently induces mitochondrial dysfunction so as to induce cell apoptosis. The in vivo efficiency of 5a was also evaluated on MGC-803 xenograft nude mice and the relative tumor growth inhibition was 42.4percent at 12 mg kg-1 without an obvious loss in the body weight. This journal is
Defined concatenated α6α1β3γ2 GABAA receptor constructs reveal dual action of pyrazoloquinolinone allosteric modulators
Simeone,Iorio,Siebert,Rehman,Schnürch,Mihovilovic,Ernst
supporting information, p. 3167 - 3178 (2019/06/17)
Pyrazoloquinolinones (PQs) have been extensively studied as modulators of GABAA receptors with different subunit composition, exerting modulatory effects by binding at α+/β- interfaces of GABAA receptors. PQs with a substituent in position R7 have been reported to preferentially modulate α6- subunit containing GABAA receptors which are mostly expressed in the cerebellum but were also found in the olfactory bulb, in the cochlear nucleus, in the hippocampus and in the trigeminal sensory pathway. They are considered potentially interesting in the context of sensori-motor gating deficits, depressive-like behavior, migraine and orofacial pain. Here we explored the option to modify the lead ligands’ R7 position. In the compound series we observed two different patterns of allosteric modulation in recombinantly expressed α6β3γ2 receptors, namely monophasic and biphasic positive modulation. In the latter case the additional phase occurred in the nanomolar range, while all compounds displayed robust modulation in the micromolar range. Nanomolar, near silent binding has been reported to occur at benzodiazepine binding sites, but was not investigated at the diazepam insensitive α6+/γ2- interface. To clarify the mechanism underlying the biphasic effect we tested one of the compounds in concatenated receptors. In these constructs the subunits are covalently linked, allowing to form either the α6+/γ2- interface, or the α6+/β3- interface, to study the resulting modulation. With this approach we were able to ascribe the nanomolar modulation to the α6+/γ2- interface. While not all compounds display the nanomolar phase, the strong modulation at the α6+/β3 interface proved to be tolerant for all tested R7 groups. This provides the future option to introduce e.g. isotope labelled or fluorescent moieties or substituents that enhance solubility and bioavailability.
