Synthesis and molecular modeling of six novel monastrol analogues: evaluation of cytotoxicity and kinesin inhibitory activity against HeLa cell line

Abstract

Background and the purpose of the study: A common approach in cancer chemotherapy is development of drugs that interrupt the mitosis phase of cell division. Dimethylenastron is a known kinesin inhibitor. In this study, six novel dimethylenastron analogues (4a-f), in which 3-hydroxyphenyl substituent has been replaced with substituted benzylimidazolyl, were synthesized through Biginelli reaction.

Methods: Six novel Biginelli compounds (4a-f) were synthesized through one step Biginelli reaction of imidazole aldehydes (3a-c), dimedone and urea or thioura. In vitro cytotoxicities of prepared compounds were investigated using MTT assay. Furthermore the ELIPA kit was implemented to study inhibitory effects of synthesized compounds on ATPase activity of kinesin by measuring of organic phosphate.

Results: Our results indicated that analogue 4c is the most toxic and analogues 4f, 4b and dimethylenasteron were less cytotoxic in compare with other analogues. On the other hand, analogue 4a, 4b, 4c and 4e showed stronger Kinesin inhibition as compared with analogue 4f and dimethylenasteron. None of synthesized compounds were as potent kinesin inhibitor as Taxol. Docking analysis revealed that hydrogen bond formation and hydrophobic interactions were the key factors affecting inhibitory effects of these compounds.

Conclusion: Newly synthesized compounds were found to have moderate to good cytotoxicity against HeLa cancer cell. Our results may be helpful in further design of dihydropyrimidine as potential anticancer agents.

Figure 1

Monastrol (1) and dimethylenastron (2) structures.

Figure 2

Synthesis of 4-imidazolyl tetrahydroquinazolines (4a-f) under Biginelli condition.

Figure 3

Docked and co-crystalized enasteron in Eg5 enzyme.

Figure 4

Map surface of docked analogs in active site of enzyme (Green: hydrophobic; Violet: H bonding; Blue: mild polar). Crystallized enasteron is indicated by red and stick lines.

Figure 5

2D graph of interactions between synthesized compound 4b and protein made by LigX module of MOE software. In the 2D graphs hydrophobic/aromatic residues are colored in green, whereas polar amino acids are shown in magenta. H-bonds and all π-stacking interactions are represented as green dotted lines. The active site contour is also shown.