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Bio-Inspired Dual-Selective BCL-2 / c-MYC G-Quadruplex Binders: Design, Synthesis, and Anticancer Activity of Drug-like Imidazo[2,1- i ]purine Derivatives.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Mar 12; Vol. 63 (5), pp. 2035-2050. Date of Electronic Publication: 2019 Jul 10. - Publication Year :
- 2020
-
Abstract
- In the search for new drug-like selective G-quadruplex binders, a bioinspired design focused on the use of nucleobases as synthons in a multicomponent reaction was herein proved to be viable and successful. Hence, a new class of multifunctionalized imidazo[2,1- i ]purine derivatives, easily synthesized with a convergent approach, allowed for the identification of the first dual BCL2 / c-MYC gene promoter G-quadruplex ligand. Biophysical studies involving circular dichroism melting experiments, microscale thermophoresis measurements, NMR titrations, and computational docking calculations, as well as biological investigations including cytotoxicity and apoptotic assays, and quantitative polymerase chain reaction and Western blot analyses, were performed to assess the potency and to characterize the binding mode of the newly identified lead compound. The absence of toxicity toward normal cells, together with the small molecular weight (≅500 Da), the water solubility, the ease of functionalization, and the selectivity profile, are promising and desirable features to develop G-quadruplex binders as safe and effective anticancer agents.
- Subjects :
- Antineoplastic Agents chemistry
Biological Products metabolism
DNA-Binding Proteins antagonists & inhibitors
HCT116 Cells
Humans
Imidazoles chemistry
Imidazoles metabolism
Jurkat Cells
MCF-7 Cells
Molecular Docking Simulation methods
Protein Binding physiology
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Purines chemistry
Purines metabolism
Transcription Factors antagonists & inhibitors
Antineoplastic Agents metabolism
Biological Products chemistry
DNA-Binding Proteins metabolism
Drug Design
G-Quadruplexes
Proto-Oncogene Proteins c-bcl-2 metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31241946
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.9b00262