Synthesis and structure-activity relationship studies of novel 3,9-substituted α-carboline derivatives with high cytotoxic activity against colorectal cancer cells
| Autor: | Li-Jiau Huang, Li Shin Tseng, Sheng-Chu Kuo, Kuo Hsiung Lee, Ning-Sun Yang, Yi Chien Lin, Yueh Hsuan Lee, Susan L. Morris-Natschke, Yi Fong Chen |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Colon Antineoplastic Agents Apoptosis HL-60 Cells Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Cell Line Tumor Drug Discovery Structure–activity relationship Humans Cytotoxicity Cell Proliferation Pharmacology Indazole Cell growth Organic Chemistry Rectum General Medicine Cell cycle 030104 developmental biology chemistry Biochemistry 030220 oncology & carcinogenesis Benzyl group Signal transduction Drug Screening Assays Antitumor Colorectal Neoplasms Carbolines |
| Zdroj: | European journal of medicinal chemistry. 110 |
| ISSN: | 1768-3254 |
| Popis: | In our continued focus on 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) analogs, we synthesized a novel series of 3,9-substituted α-carboline derivatives and evaluated the new compounds for antiproliferactive effects. Structure activity relationships revealed that a COOCH3 or CH2OH group at position-3 and substituted benzyl group at position-9 of the α-carboline nucleus were crucial for maximal activity. The most active compound, 11, showed high levels of cytotoxicity against HL-60, COLO 205, Hep 3B, and H460 cells with IC50 values of 0.3, 0.49, 0.7, and 0.8 μM, respectively. The effect of compound 11 on the cell cycle distribution demonstrated G2/M arrest in COLO 205 cells. Furthermore, mechanistic studies indicated that compound 11 induced apoptosis by activating death receptor and mitochondria dependent apoptotic signaling pathways in COLO 205 cells. The new 3,9-substituted α-carboline derivatives exhibited excellent anti-proliferative activities, and compound 11 can be used as a promising pro-apoptotic agent for future development of new antitumor agents. |
| Databáze: | OpenAIRE |
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