Synthesis and in vitro evaluation of novel 5-nitroindole derivatives as c-Myc G-quadruplex binders with anticancer activity

  • Lead-optimization strategies for compounds targeting c-Myc G-quadruplex (G4) DNA are being pursued to develop anticancer drugs. Here, we investigate the structure-activity- relationship (SAR) of a newly synthesized series of molecules based on the pyrrolidine-substituted 5-nitro indole scaffold to target G4 DNA. Our synthesized series allows modulation of flexible elements with a structurally preserved scaffold. Biological and biophysical analyses illustrate that substituted 5-nitroindole scaffolds bind to the c-Myc promoter G-quadruplex. These compounds downregulate c-Myc expression and induce cell-cycle arrest in the sub-G1/G1 phase in cancer cells. They further increase the concentration of intracellular reactive oxygen species. NMR spectra show that three of the newly synthesized compounds interact with the terminal G-quartets (5′- and 3′-ends) in a 2 : 1 stoichiometry.

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Author:Vijaykumar D. Nimbarte, Julia Wirmer-BartoschekORCiD, Santosh Lakshmi Gande, Islam Alshamleh, Marcel Seibert, Hamid Reza Nasiri, Frank SchnütgenORCiDGND, Hubert ServeORCiDGND, Harald SchwalbeORCiDGND
Parent Title (English):ChemMedChem : chemistry enabling drug discovery
Place of publication:Oxford
Document Type:Article
Date of Publication (online):2021/01/28
Date of first Publication:2021/01/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/08/23
Tag:G-quadruplex binders; c-Myc; nitroindoles; oncogene promoters; reactive oxygen species; structure-activity relationships
Page Number:13
First Page:1667
Last Page:1679
This work was additionally supported by the Deutsche Forschungsgemeinschaft (SFB1177; SCHN1166/4-1 (to F.S.). Open access funding enabled and organized by Projekt DEAL.
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0