A Nucleus-Imaging Probe That Selectively Stabilizes a Minor Conformation of c-MYC G-quadruplex and Down-regulates c-MYC Transcription in Human Cancer Cells.
The c-MYC proto-oncogene is a regulator of fundamental cellular processes such as cell cycle progression and apoptosis. The development of novel c-MYC inhibitors that can act by targeting the c-MYC DNA G-quadruplex at the level of transcription would provide potential insight into structure-based design of small molecules and lead to a promising arena for cancer therapy. Herein we report our finding that two simple bis-triazolylcarbazole derivatives can inhibit c-MYC transcription, possibly by stabilizing the c-MYC G-quadruplex. These compounds are prepared using a facile and modular approach based on Cu(I) catalysed azide and alkyne cycloaddition. A carbazole ligand with carboxamide side chains is found to be microenvironment-sensitive and highly selective for "turn-on" detection of c-MYC quadruplex over duplex DNA. This fluorescent probe is applicable to visualize the cellular nucleus in living cells. Interestingly, the ligand binds to c-MYC in an asymmetric fashion and selects the minor-populated conformer via conformational selection.
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India.
Deepanjan
D
Panda
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India.
Manish
M
Debnath
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India.
Samir
S
Mandal
Institute of Organic Chemistry and Chemical Biology, Goethe University Frankfurt and Centre for Biomolecular, Magnetic Resonance, Max-von-Laue Strasse 7, 60438, Frankfurt am Main, Germany.
Irene
I
Bessi
Institute of Organic Chemistry and Chemical Biology, Goethe University Frankfurt and Centre for Biomolecular, Magnetic Resonance, Max-von-Laue Strasse 7, 60438, Frankfurt am Main, Germany.
Harald
H
Schwalbe
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India.
Jyotirmayee
J
Dash
D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D015536:Down-Regulation; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D005456:Fluorescent Dyes / Q000378:metabolism; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D015335:Molecular Probes / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D002227:Carbazoles; D005456:Fluorescent Dyes; D008024:Ligands; C000715470:MAS1 protein, human; D015335:Molecular Probes; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc