Structural-based design, synthesis, and antitumor activity of novel alloxazine analogues with potential selective kinase inhibition
| Autor: | Doaa Samaha, Ashraf N. Abdalla, Ahmed M. Gouda, Juan J. Bustamante, Waleed H. Malki, Hamdy E. A. Ali, Rabaa Al-Rousan, Hamed I. Ali, Zakaria Y. Abd Elmageed |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Allosteric regulation Antineoplastic Agents Apoptosis Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Flavins Drug Discovery Tumor Cells Cultured Humans Structure–activity relationship Cytotoxicity Protein Kinase Inhibitors Cell Proliferation Pharmacology Cyclin-dependent kinase 1 Dose-Response Relationship Drug Molecular Structure Chemistry Kinase Cell growth Organic Chemistry General Medicine Molecular Docking Simulation 030104 developmental biology Drug Design 030220 oncology & carcinogenesis MCF-7 Cells Cancer research Drug Screening Assays Antitumor Protein Kinases Cyclin A1 Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | European Journal of Medicinal Chemistry. 152:31-52 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2018.04.029 |
| Popis: | Protein kinases are promising therapeutic targets for cancer therapy. Here, we applied multiple approaches to optimize the potency and selectivity of our reported alloxazine scaffold. Flexible moieties at position 2 of the hetero-tricyclic system were incorporated to fit into the ATP binding site and extend to the adjacent allosteric site and selectively inhibit protein kinases. This design led to potential selective inhibition of ABL1, CDK1/Cyclin A1, FAK, and SRC kinase by 30-59%. Cytotoxicity was improved by ∼50 times for the optimized lead (10b; IC50 = 40 nM) against breast cancer (MCF-7) cells. Many compounds revealed potential cytotoxicity against ovarian (A2780) and colon carcinoma (HCT116) cells of ∼10-30 time improvement (IC50 5-17 nM). The results of the Annexin-V/PI apoptotic assay demonstrated that many compounds induced significantly early (89-146%) and a dramatically late (556-1180%) cell death in comparison to the vehicle control of MCF-7 cells. SAR indicated that 5-deazaalloxazines have a higher selectivity for Abl-1 and FAK kinases than alloxazines. The correlations between GoldScore fitness into FAK and SRC kinases and IC50 against MCF-7 and A2780 cells were considerable (R2: 0.86-0.98). |
| Databáze: | OpenAIRE |
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