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

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.

Antiproliferative Effect and Autophagy Inhibition of Dihydropyrimidinone‐Cinnamic Acid Hybrids

“…[16,17] Since its discovery, the anti-cancer activity of DHPMs has been much explored, and various reports have described Monastrol and its derivatives as good antiproliferative and cytotoxic agents. [16,[18][19][20][21][22][23][24][25] Molecular hybridization is a powerful tool for designing new drug prototypes; this strategy is based on the combination of two or more drugs or its pharmacophores into a single molecule, aimed at improving the biological properties when compared to the parent molecules. [26,27] The hybrids can be classified as directly linked hybrids, spacer-linked hybrids, fused hybrids and merged hybrids, based on the mode of connecting the two involved molecules and the type of connection have direct impact on the bioactivity, pharmacokinetics and pharmacodynamics.…”

“…Monastrol is a small molecule that selectively inhibits the mitotic kinesin Eg5, a critical motor enzyme that is required for the correct bipolar formation of the mitotic spindle [16,17] . Since its discovery, the anti‐cancer activity of DHPMs has been much explored, and various reports have described Monastrol and its derivatives as good antiproliferative and cytotoxic agents [16,18–25] …”

Pancreas organoid development, behaviour and structural maintenance: a multiscale analysis

“…To validate this assumption, the dynamic transport of cytoskeleton components via kinesin and dynein can be investigated separately. By inhibiting kinesin (e.g., Inspinesib (Blagden et al, 2008) or Monoastrol (El-Hamamsy et al, 2020), the anterograde transport of vesicles can be interrupted and by inhibiting dynein (e.g., Dynarrestin (Höing et al, 2018) or Ciliobrevin (Firestone et al, 2012), the retrograde transport can be interrupted. The organoids' reactions in terms of volume fluctuations can be measured by using the brightfield pipeline.…”