Molecular modeling and synthesis of certain substituted aryl compounds which have a potential anticancer activity

Aim: The enzyme methionine synthase (MetS) is linked to the cancer pathogenesis disorders such as myeloid leukemia, prostate and breast tumors. Inhibition of the biosynthesis of methionine amino acid which provides the tumor nucleic acid with one carbon atom building units occurred through the blocking of the natural substrate 5-methyltetrahydrofolate (MTHF) to bind to its binding domain in MetS with the synthesized compounds in this article. Design and methods: The target compounds were designed to interact with the binding site of MTHF in much the same way as the substrate. The crystal structure of MTHF binding region from human source has been deduced. A series of aromatic compounds was synthesized and docked separately into the MTHF binding site of the enzyme. Thermodynamic algorithms were done and compared to the results obtained from the biological cell line assay. Results: The cytotoxicity assay (in vitro) of the most potent compounds 2-hydroxymethyl-5-nitro- 1H-benzimidazole and 1,3,5-trinitrobenzene showed IC50 of 50 ± 5 and 49 ± 5 μM, respectively, with score of the lowest free energy of binding -1610.42 and -1737.10 kJ/mol, respectively. Conclusion: The results of this study had led to the identification of two lead compounds with good inhibitory activities that could overlay for the next generation of the inhibitors for methionine synthase. Preparation of novel potential inhibitors for the methionine synthase that have the ability to avoid the side effects of the other marketed anticancer drugs could be a good step forward towards cancer treatment.