Discovery of Novel 11-Triazole Substituted Benzofuro[3,2-<i>b</i>]quinolone Derivatives as <i>c-myc</i> G-Quadruplex Specific Stabilizers via Click Chemistry

Zeng, Deying; Kuang, Guotao; Wang, Shi-Ke; Wang, Peng; Lin, Shu‐Ling; Zhang, Qi; Su, Xiao-Xuan; Hu, Minghao; Wang, Honggen; Tan, Jia‐Heng; Huang, Zhi‐Shu; Gu, Lian‐Quan; Ou, Tian‐Miao

doi:10.1021/acs.jmedchem.7b00016

Cited by 75 publications

(31 citation statements)

References 37 publications

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“…In these studies candidate ligands are docked into the binding sites formed by the flanking residues of the c-MYC G-quadruplex molecule from the NMR structures of the drug complexes. These modeling work have either led to the discovery of G-quadruplex-selective binders with micromolar activities 31 , or helped rationalize the binding mechanism of new active compounds 33 .…”

Section: Discussionmentioning

confidence: 99%

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Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment

et al. 2017

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We report the absolute binding free energy calculation and surface plasmon resonance (SPR) experiment for ligand binding with the cMYC G-quadruplex DNA. The unimolecular parallel DNA G-quadruplex formed in the nuclease hypersensitivity element III1 of the c-MYC gene promoter regulates the c-MYC transcription and is recognized as an emerging drug target for cancer therapy. Quindoline derivatives have been shown to stabilize the G-quadruplex and inhibit the c-MYC expression in cancer cells. NMR revealed two binding sites located at the 5′ and 3′ termini of the G-quadruplex. Questions about which site is more favored and the basis for the ligand-induced binding site formation remain unresolved. Here, we employ two absolute binding free energy methods, the double decoupling and the potential of mean force methods, to dissect the ligand binding specificity in the c-MYC G-quadruplex. The calculated absolute binding free energies are in general agreement with the SPR result and suggest that the quindoline has a slight preference for the 5′ site. The flanking residues around the two sites undergo significant reorganization as the ligand unbinds, which provides evidence for ligand-induced binding pocket formation. The results help interpret experimental data and inform rational design of small molecules targeting the c-MYC G-quadruplex.

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Section: Discussionmentioning

confidence: 99%

“…The molecular structures of the c-MYC G-quadruplex and its drug complexes have been determined by solution NMR 24,28,29 . New G-quadruplex-interactive ligands with micromolar activities 30–33 have been identified in recent studies using the NMR structures of apo and ligand-bound c-MYC G-quadruplex molecules.…”

Section: Introductionmentioning

confidence: 99%

Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment

et al. 2017

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“…In addition to the capability to downregulate DNMT proteins, 2a-c and 4a-c were tested to evaluate their eventual DNA G4 stabilizing properties, in analogy to some quinoline compounds reported to bind and stabilize DNA G4 regions involved in repression of transcription at the promoter of oncogenes [31][32][33][34]. Compounds 2a-c and 4a-c were tested at 5 and 10 µM by fluorescence resonance energy transfer (FRET) method with two DNA sequences (F21T and KRAS21R).…”

Section: Off-target Effects: Potential Dna G-quadruplex (G4) Stabilizmentioning

confidence: 99%

Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation

Zwergel

Fioravanti

Stazi

et al. 2020

Cancers

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DNA methyltransferases (DNMTs) play a relevant role in epigenetic control of cancer cell survival and proliferation. Since only two DNMT inhibitors (azacitidine and decitabine) have been approved to date for the treatment of hematological malignancies, the development of novel potent and specific inhibitors is urgent. Here we describe the design, synthesis, and biological evaluation of a new series of compounds acting at the same time as DNMTs (mainly DNMT3A) inhibitors and degraders. Tested against leukemic and solid cancer cell lines, 2a–c and 4a–c (the last only for leukemias) displayed up to submicromolar antiproliferative activities. In HCT116 cells, such compounds induced EGFP gene expression in a promoter demethylation assay, confirming their demethylating activity in cells. In the same cell line, 2b and 4c chosen as representative samples induced DNMT1 and -3A protein degradation, suggesting for these compounds a double mechanism of DNMT3A inhibition and DNMT protein degradation.

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“…Parham cyclialkylation of 3 q occurred smoothly to form dihydrofuroquinoline 11 in 92% yield . The bromated quinoline 3 r could be converted to azide 12 in 98% yield when treated with sodium azide, which could be used for further modifications. Notably, the tetracyclic products 13 and 14 were obtained in 85% and 51% yields, respectively, via corresponding coupling reactions.…”

Section: Resultsmentioning

confidence: 99%

Silver‐Catalyzed Carbocyclization of Azide‐Tethered Alkynes: Expeditious Synthesis of Polysubstituted Quinolines

Bao

Huang

et al. 2019

Adv Synth Catal

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A silver-catalyzed carbocyclization of azide-tethered alkynes has been developed for the synthesis of polysubstituted quinolines in good to high yields. Mechanistic studies indicate that this reaction is initiated by a silver-catalyzed 6-endo-dig azide-yne cyclization, followed by a formal RÀX (X=Cl, Br, or I) insertion with external halide through a ylide intermediate. The salient features of this reaction include readily available materials, inexpensive silver-catalyst, mild reaction conditions, good functional group tolerance, and ease in further transformations.

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Discovery of Novel 11-Triazole Substituted Benzofuro[3,2-b]quinolone Derivatives as c-myc G-Quadruplex Specific Stabilizers via Click Chemistry

Cited by 75 publications

References 37 publications

Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment

Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment

Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation

Silver‐Catalyzed Carbocyclization of Azide‐Tethered Alkynes: Expeditious Synthesis of Polysubstituted Quinolines

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