Synthesis and in Vitro Evaluation of Novel 5-Nitroindole Derivatives as c-Myc G-Quadruplex Binders with Anticancer Activity.

Autor: Nimbarte VD; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany., Wirmer-Bartoschek J; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany., Gande SL; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany.; German Cancer Research Center and German Cancer Consortium, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Alshamleh I; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany., Seibert M; Department of Medicine 2, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany., Nasiri HR; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany., Schnütgen F; German Cancer Research Center and German Cancer Consortium, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Department of Medicine 2, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.; Frankfurt Cancer Institute (FCI), Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany., Serve H; German Cancer Research Center and German Cancer Consortium, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Department of Medicine 2, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.; Frankfurt Cancer Institute (FCI), Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany., Schwalbe H; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany.; German Cancer Research Center and German Cancer Consortium, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Frankfurt Cancer Institute (FCI), Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2021 May 18; Vol. 16 (10), pp. 1667-1679. Date of Electronic Publication: 2021 Mar 22.
DOI: 10.1002/cmdc.202000835
Abstrakt: 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.
(© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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