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Design, Synthesis, and Evaluation of Isaindigotone Derivatives To Downregulate c-myc Transcription via Disrupting the Interaction of NM23-H2 with G-Quadruplex
- Source :
- Journal of medicinal chemistry. 60(4)
- Publication Year :
- 2017
-
Abstract
- Transcriptional control of c-myc oncogene is an important strategy for antitumor drug design. G-quadruplexes in the promoter region have been proven to be the transcriptional down-regulator of this gene. The transcriptional factor NM23-H2 can reactivate c-myc transcription by unwinding the G-quadruplex structure. Thus, down-regulation of c-myc transcription via disrupting G-quadruplex-NM23-H2 interaction might be a potential approach for cancer therapy. Here, a series of new isaindigotone derivatives were designed and synthesized based on our previous study. The abilities of these derivatives on interacting with G-quadruplexes or NM23-H2, and disrupting G-quadruplex-NM23-H2 interaction were evaluated. Among these derivatives, 19d and 22d showed remarkable abilities on disrupting G-quadruplex-NM23-H2 interaction. They exhibited significant effects on c-myc-relating processes in SiHa cells, including inhibiting the transcription and translation, inhibiting cellular proliferation, inducing apoptosis, and regulating cell cycle. Our findings provided the basis for the anticancer strategy based on c-myc transcriptional regulation via small molecules disrupting G-quadruplex-protein interaction.
- Subjects :
- 0301 basic medicine
Transcriptional Activation
Transcription, Genetic
Down-Regulation
Uterine Cervical Neoplasms
Antineoplastic Agents
Apoptosis
G-quadruplex
Proto-Oncogene Proteins c-myc
03 medical and health sciences
0302 clinical medicine
Alkaloids
Transcription (biology)
Cell Line, Tumor
Drug Discovery
Transcriptional regulation
Humans
heterocyclic compounds
Regulation of gene expression
Oncogene
Chemistry
Cell Cycle
Promoter
Cell cycle
NM23 Nucleoside Diphosphate Kinases
Molecular biology
Cell biology
G-Quadruplexes
Gene Expression Regulation, Neoplastic
030104 developmental biology
030220 oncology & carcinogenesis
Drug Design
Quinazolines
Molecular Medicine
Female
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 60
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....88ca0f2ab785731bfc4367ea3f42e0ad