Structural-based design, synthesis, and antitumor activity of novel alloxazine analogues with potential selective kinase inhibition.
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).
['Malki|Waleed H|WH|', 'Gouda|Ahmed M|AM|', 'Ali|Hamdy E A|HEA|', 'Al-Rousan|Rabaa|R|', 'Samaha|Doaa|D|', 'Abdalla|Ashraf N|AN|', 'Bustamante|Juan|J|', 'Abd Elmageed|Zakaria Y|ZY|', 'Ali|Hamed I|HI|']
D000970:Antineoplastic Agents D017209:Apoptosis D049109:Cell Proliferation D004305:Dose-Response Relationship, Drug D015195:Drug Design D004354:Drug Screening Assays, Antitumor D005415:Flavins D006801:Humans D061986:MCF-7 Cells D062105:Molecular Docking Simulation D015394:Molecular Structure D047428:Protein Kinase Inhibitors D011494:Protein Kinases D013329:Structure-Activity Relationship D014407:Tumor Cells, Cultured
Antitumor Alloxazine Apoptosis Docking Kinase inhibitor