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Targeting the BCL2 Gene Promoter G-Quadruplex with a New Class of Furopyridazinone-Based Molecules
- Source :
- ChemMedChem, 13 (2018): 406–410. doi:10.1002/cmdc.201700749, info:cnr-pdr/source/autori:Amato J.; Pagano A.; Capasso D.; Di Gaetano S.; Giustiniano M.; Novellino E.; Randazzo A.; Pagano B./titolo:Targeting the BCL2 Gene Promoter G-Quadruplex with a New Class of Furopyridazinone-Based Molecules/doi:10.1002%2Fcmdc.201700749/rivista:ChemMedChem (Print)/anno:2018/pagina_da:406/pagina_a:410/intervallo_pagine:406–410/volume:13
- Publication Year :
- 2017
-
Abstract
- Targeting of G-quadruplex-forming DNA in the BCL2 gene promoter to inhibit the expression of anti-apoptotic Bcl-2 protein is an attractive approach to cancer treatment. So far, efforts made in the discovery of molecules that are able to target the BCL2 G-quadruplex have succeeded mainly in the identification of ligands with poor drug-like properties. Here, a small series of furo[2,3-d]pyridazin-4(5H)-one derivatives were evaluated as a new class of drug-like G-quadruplex-targeting compounds. Biophysical studies showed that two derivatives could effectively bind to BCL2 G-quadruplex with good selectivity. Moreover, one such ligand was found to appreciably inhibit BCL2 gene transcription, with a substantial decrease in protein expression levels, and also showed significant cytotoxicity toward the Jurkat human T-lymphoblastoid cell line.
- Subjects :
- 0301 basic medicine
Models, Molecular
G-quadruplexes
antitumor agents
Ligand
G-quadruplex
Biochemistry
Jurkat cells
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
hemic and lymphatic diseases
Drug Discovery
Humans
heterocyclic compounds
General Pharmacology, Toxicology and Pharmaceutics
Cytotoxicity
Promoter Regions, Genetic
G-quadruplexe
Pharmacology
Bcl-2 transcriptional down-regulation
Dose-Response Relationship, Drug
Molecular Structure
ligands
gene promoters
Organic Chemistry
Antitumor agent
Promoter
G-Quadruplexes
Pyridazines
030104 developmental biology
chemistry
Proto-Oncogene Proteins c-bcl-2
Cell culture
Gene promoter
Pharmacology, Toxicology and Pharmaceutics (all)
Molecular Medicine
Selectivity
DNA
Subjects
Details
- ISSN :
- 18607187
- Volume :
- 13
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- ChemMedChem
- Accession number :
- edsair.doi.dedup.....fca7376ba363ad201eb83f712c48e461