ChemInform Abstract: Synthesis, G‐Quadruplex Stabilization, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains.

Lavrado, João; Borralho, Pedro M.; Ohnmacht, Stephan A.; Castro, Rui E.; Rodrigues, Cecília M.P.; Moreira, Rui; Santos, Daniel Terrón; Neidle, Stephen; Paulo, Alexandra

doi:10.1002/chin.201408184

Cited by 3 publications

(1 citation statement)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results were consistent with previously reported conclusions. 45 Specifically, the introduction of a side chain onto the quindoline skeleton was beneficial for its interaction with the loops or grooves of the G-quadruplex, which increased the binding activity of the G-quadruplex. The overall binding activity to the G-quadruplex by the series III ligand group, which was characterized by a single positive charge at N5 of the quindoline ring, was enhanced.…”

Section: ■ Resultsmentioning

confidence: 99%

New Disubstituted Quindoline Derivatives Inhibiting Burkitt’s Lymphoma Cell Proliferation by Impeding c-MYC Transcription

et al. 2017

View full text Add to dashboard Cite

The c-MYC oncogene is overactivated during Burkitt's lymphoma pathogenesis. Targeting c-MYC to inhibit its transcriptional activity has emerged as an effective anticancer strategy. We synthesized four series of disubstituted quindoline derivatives by introducing the second cationic amino side chain and 5-N-methyl group based on a previous study of SYUIQ-5 (1) as c-MYC promoter G-quadruplex ligands. The in vitro evaluations showed that all new compounds exhibited higher stabilities and binding affinities, and most of them had better selectivity (over duplex DNA) for the c-MYC G-quadruplex compared to 1. Moreover, the new ligands prevented NM23-H2, a transcription factor, from effectively binding to the c-MYC G-quadruplex. Further studies showed that the selected ligand, 7a4, down-regulated c-MYC transcription by targeting promoter G-quadruplex and disrupting the NM23-H2/c-MYC interaction in RAJI cells. 7a4 could inhibit Burkitt's lymphoma cell proliferation through cell cycle arrest and apoptosis and suppress tumor growth in a human Burkitt's lymphoma xenograft.

show abstract

Section: ■ Resultsmentioning

confidence: 99%

New Disubstituted Quindoline Derivatives Inhibiting Burkitt’s Lymphoma Cell Proliferation by Impeding c-MYC Transcription

et al. 2017

View full text Add to dashboard Cite

show abstract

G-quadruplexes in cancer-related gene promoters: from identification to therapeutic targeting

Romano,

Di Porzio,

Iaccarino

et al. 2023

Expert Opinion on Therapeutic Patents

View full text Add to dashboard Cite

G-Quadruplex Structures in the Human Genome as Novel Therapeutic Targets

et al. 2013

View full text Add to dashboard Cite

G-quadruplexes are secondary structures that may form within guanine-rich nucleic acid sequences. Telomeres have received much attention in this regard since they can fold into several distinct intramolecular G-quadruplexes, leading to the rational design and development of G-quadruplex-stabilizing molecules. These ligands were shown to selectively exert an antiproliferative and chemosensitizing activity in in vitro and in vivo tumor models, without appreciably affecting normal cells. Such findings point to them as possible drug candidates for clinical applications. Other than in telomeres, G-quadruplexes may form at additional locations in the human genome, including gene promoters and untranslated regions. For instance, stabilization of G-quadruplex structures within the promoter of MYC, KIT, or KRAS resulted in the down-regulation of the corresponding oncogene either in gene reporter assays or in selected experimental models. In addition, the alternative splicing of a number of genes may be affected for a therapeutic benefit through the stabilization of G-quadruplexes located within pre-mRNAs. It is now emerging that G-quadruplex structures may act as key regulators of several biological processes. Consequently, they are considered as attractive targets for broad-spectrum anticancer therapies, and much effort is being made to develop a variety of ligands with improved G-quadruplex recognition properties. Quarfloxin, a fluoroquinolone derivative designed to target a G-quadruplex within ribosomal DNA and disrupt protein-DNA interactions, has entered clinical trials for different malignancies. This OPEN ACCESSMolecules 2013, 18 12369 review will provide some hints on the role of G-quadruplex structures in biological processes and will evaluate their implications as novel therapeutic targets.

show abstract

ChemInform Abstract: Synthesis, G‐Quadruplex Stabilization, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains.

Abstract: The synthesized compounds, especially compounds (IIIb) and (IVb) show high G‐Quadruplex (G4) thermal stabilization over duplex DNA and selectivity for the HCT116 cancer cell line over primary rat hepatocytes.

Cited by 3 publications

References 1 publication

New Disubstituted Quindoline Derivatives Inhibiting Burkitt’s Lymphoma Cell Proliferation by Impeding c-MYC Transcription

New Disubstituted Quindoline Derivatives Inhibiting Burkitt’s Lymphoma Cell Proliferation by Impeding c-MYC Transcription

G-quadruplexes in cancer-related gene promoters: from identification to therapeutic targeting

G-Quadruplex Structures in the Human Genome as Novel Therapeutic Targets

Contact Info

Product

Resources

About