3-Hydroxyisoindolin-1-one derivates: Synthesis by palladium-catalyzed CH activation as BRD4 inhibitors against human acute myeloid leukemia (AML) cells
| Autor: | Jiping Tian, Fangqing Zhang, Lingyun Yang, Yifei Yang, Jinpei Zhou, Huibin Zhang, Pan Chen |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
BRD4
Protein family Antineoplastic Agents Apoptosis Cell Cycle Proteins Phthalimides 01 natural sciences Biochemistry Catalysis Structure-Activity Relationship Drug Discovery Transcriptional regulation medicine Tumor Cells Cultured Humans Molecular Biology IC50 Cell Proliferation Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Cancer Myeloid leukemia medicine.disease 0104 chemical sciences Bromodomain Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Leukemia Leukemia Myeloid Acute Cancer research Drug Screening Assays Antitumor Palladium Transcription Factors |
| Zdroj: | Bioorganic chemistry. 86 |
| ISSN: | 1090-2120 |
| Popis: | Bromodomain protein 4 (BRD4) is a member of the bromodomain and extra-terminal domain (BET) protein family, which plays a key role in transcriptional regulation. Recent biological and pharmacological studies have enabled linking of the BET bromodomains with diseases, including inflammation and cancer, suggesting that bromodomains are druggable targets. In this study, we made further structural modifications of our previously reported BRD4 inhibitors, to develop new chemical scaffold 3-Hydroxyisoindolin-1-One. Then a series of compounds (10a-q) were synthesized via palladium-catalyzed C H activation and BRD4-inhibitory activities and anti-proliferative effects of these compounds were evaluated. Compound 10e exhibited excellent BRD4-inhibitory activity with IC50 value of 80 nM and anti-proliferation potency with IC50 value of 365 nM in HL-60 (human promyelocytic leukemia) cancer cell lines. We have demonstrated compound 10e modulated the intrinsic apoptotic pathway. In conclusion, these results suggested that compound 10e could be utilized as a BRD4 inhibitor for further leukemia treatment. |
| Databáze: | OpenAIRE |
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