Synthesis and evaluation of 7-substituted-5,6-dihydrobenzo[ c ]acridine derivatives as new c- KIT promoter G-quadruplex binding ligands
| Autor: | Qian-Liang Guo, Ding Li, Jia-Heng Tan, Yu-Ting Lu, Zhi-Shu Huang, Hua-Fei Su, Ning Wang, Tian-Miao Ou, Sheng-Rong Liao |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Molecular model Stereochemistry Antineoplastic Agents Apoptosis Ligands 010402 general chemistry G-quadruplex 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Transcription (biology) Drug Discovery Humans heterocyclic compounds Promoter Regions Genetic Cell Proliferation Pharmacology Cell growth Organic Chemistry General Medicine Ligand (biochemistry) 0104 chemical sciences G-Quadruplexes Proto-Oncogene Proteins c-kit 030104 developmental biology chemistry Biochemistry Acridine Acridines K562 Cells DNA |
| Zdroj: | European Journal of Medicinal Chemistry. 130:458-471 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2017.02.051 |
| Popis: | It has been shown that treatment of cancer cells with c-KIT G-quadruplex binding ligands can reduce their c-KIT expression levels thus inhibiting cell proliferation and inducing cell apoptosis. Herein, a series of new 7-substituted-5,6-dihydrobenzo[c]acridine derivatives were designed and synthesized. Subsequent biophysical evaluation demonstrated that the derivatives could effectively bind to and stabilize c-KIT G-quadruplex with good selectivity against duplex DNA. It was found that 12-N-methylated derivatives with a positive charge introduced at 12-position of 5,6-dihydrobenzo[c]acridine ring had similar binding affinity but lower stabilizing ability to c-KIT G-quadruplex DNA, compared with those of nonmethylated derivatives. Further molecular modeling studies showed possible binding modes of G-quadruplex with the ligands. RT-PCR assay and Western blot showed that compound 2b suppressed transcription and translation of c-KIT gene in K562 cells, which was consistent with the property of an effective G-quadruplex binding ligand targeting c-KIT oncogene promoter. Further biological evaluation showed that compound 2b could induce apoptosis through activation of the caspase-3 cascade pathway. |
| Databáze: | OpenAIRE |
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