Two series of amino‐1,4‐benzoquinones (AQ1–18) based on the structural analogs of plastoquinones were synthesized and the structure–activity relationship against chronic myelogenous leukemia activity was examined. All of the synthesized compounds were tested for their cytotoxic effects on different leukemic cell lines. Of interest, AQ15 exhibited a better selectivity than the reference drug imatinib on cancer cells. Owing to this, AQ15 was selected for a further apoptosis/necrosis evaluation where AQ15‐treated K562 cells demonstrated similar apoptotic effects like imatinib‐treated cells at their IC50 values. The inhibitory effects of AQ15 and the other three compounds with various activities against eight tyrosine kinases, including ABL1, were investigated. AQ15 showed weak activity against ABL1, and a correlation was observed between the anti‐K562 and anti‐ABL1 activities. The binding mode of AQ15 into the ATP binding pocket of ABL1 kinase was predicted in silico, showing the formation of some key interactions. In addition, AQ15 was shown to suppress the downstream signaling of BCR‐ABL in K562 cells. Finally, AQ15 obviously cleaved DNA in the presence of an iron(II) complex system, indicating that this can be the major mechanism of its antiproliferative action, whereas the mild inhibition of ABL kinase is just in‐part mechanism of its overall outstanding cellular activity.
A series of 2-arylamino-3-chloro-1,4-naphthoquinone derivatives (3a–h) by the reaction of 2,3-dichloro-1,4-naphthoquinone with aryl amines (2a–h) and benzo[b]phenazine-6,11-dione derivatives (4a–c) by the treatment of 2-arylamino-3-chloro-1,4-naphthoquinone derivatives (3a–h) with sodium azide were synthesized and tested for theirin vitroantibacterial and antifungal activities. The results suggest that compounds3dand3ghad potent antifungal activity againstCandida albicans(MIC = 78.12 μg/mL). All synthesized compounds (3a–h,4a–c) possessed activity againstE. faecaliswith MIC values of between 312.5 and 1250 μg/mL. Benzo[b]phenazine-6,11-dione derivatives (4a–c) were mostly active against Gram-positive bacteria. The structures of the new members of the series were established on the basis of their spectral properties (IR,1H NMR,13C NMR, and mass spectrometry).
Herein, we report the synthesis and cytotoxic effects of novel chlorinated plastoquinone analogs (ABQ1–17) against different leukemic cells. Compounds ABQ3, ABQ11, and ABQ12 demonstrated a pronounced antiproliferative effect against chronic myelogenous leukemia (CML) K562 cell line with IC50 values of 0.82 ± 0.07, 0.28 ± 0.03, and 0.98 ± 0.22 μM, respectively. Among them, ABQ11 showed approximately three times higher selectivity than imatinib on CML. ABQ11‐treated CML cells induced significant apoptosis at low concentration. Inhibitory effect of ABQ11 against eight different tyrosine kinases, including ABL1, was investigated. ABQ11 inhibited ABL1 with IC50 value of 13.12 ± 1.71 μM, indicating that the moderate inhibition of ABL1 kinase is just an in‐part mechanism of its outstanding cellular activity. Molecular docking of ABQ11 into ABL1 kinase ATP‐binding pocket revealed the formation of some key interactions. Furthermore, DNA cleavage assay showed that ABQ11 strongly disintegrated DNA at 1 μM concentration in the presence of iron (II) complex system, assuming that the major mechanism for the anticancer effects of ABQ11 is DNA cleavage. In silico ADMET prediction revealed that ABQ11 is a drug‐like small molecule with a favorable safety profile. Taken together, ABQ11 is a potential antiproliferative hit compound that exhibits unique cytotoxic activity distinct from imatinib.
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