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  • Title: Design, synthesis, and molecular docking study of new monastrol analogues as kinesin spindle protein inhibitors.
    Author: El-Hamamsy MH, Sharafeldin NA, El-Moselhy TF, Tawfik HO.
    Journal: Arch Pharm (Weinheim); 2020 Aug; 353(8):e2000060. PubMed ID: 32452567.
    Abstract:
    Lung, colorectal, and breast cancers are the top three types of cancer by incidence and are responsible for one-third of the cancer incidence and mortality. A series of 18 3,4-dihydropyrimidine analogues bearing a 1,2-methylenedioxybenzene component at position 4 with diverse side chains at positions 5 and 6 was designed and synthesized as inhibitors of the Eg5 kinesin enzyme. Target compounds were screened for their anticancer activity according to the NCI-USA protocol toward a panel of 60 cancer cell lines. Compounds 12a and 12b displayed the best antiproliferation activity against many cell lines. Interestingly, compound 12a displayed lethal effects against non-small-cell lung cancer NCI-H522 cells (-42.26%) and MDA-MB-468 breast cancer cells (-1.10%) at a single-dose assay concentration of 10-5  M. Compounds 11c, 11d, 11g, 12a-d, 13, 15, and 18a were assayed against the kinesin enzyme, with IC50 values ranging from 1.2 to 18.71 μM, which were more potent compared with monastrol (IC50  = 20 μM). Cell cycle analysis of NCI-H522 cells treated with compound 12a showed cell cycle arrest at the G2/M phase. Furthermore, the expression levels of active caspase-3 and -9 were measured. A molecular docking study was performed for some demonstrative compounds as well as monastrol docked into the allosteric binding site of the kinesin spindle protein.
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