Design, synthesis, and molecular docking study of new monastrol analogues as kinesin spindle protein inhibitors.

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  M. Compounds 11c, 11d, 11g, 12a-d, 13, 15, and 18a were assayed against the kinesin enzyme, with IC values ranging from 1.2 to 18.71 μM, which were more potent compared with monastrol (IC  = 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.