Synthesis, Molecular Docking Study and Evaluation of Cytotoxic Activity of Two Homoisoflavonoids Containing Morpholinoethoxy Substitution

Chemotherapy is one of the most common methods available for the treatment of cancer. Resistance to anticancer drugs can result in failures in chemotherapy of cancers. Therefore, investigation is necessary for the discovery of new drugs. Homoisoflavonoids are well-known natural products that possess a wide range of pharmacological activities. Hence, synthesis and assessment of cytotoxicity of homoisoflavonoids containing morpholinoethoxy moiety and their molecular docking simulation were taken into consideration.

Two 7-morpholinoethoxyhomoisoflavonoids synthesized via three steps including SN2 reaction of 7-hydroxychromanine with morpholino ethyl chloride hydrochloride in the basic media under reflux condition to produce intermediate 3. The second step included aldol condensation of the intermediate with suitable aldehydes in the presence of gaseous HCl in ethanol, and finally neutralization with NaOH 5%. The structures of the products were confirmed using IR, 13CNMR, and 1HNMR techniques. Cytotoxic effects of final products on HT-29 and 3T3 cell lines were assessed. To evaluate the binding mode of compounds with tubulin protein, docking simulation was performed by using MOE.

Two morpholinoethoxy homoisiflavonoids were prepared with moderate to good production yield. Cytotoxic evaluation of these compounds showed satisfactory results. The results of molecular docking simulation showed an acceptable binding energy of the interaction between the ligands with the tubulin protein binding site: (E)-7-(2-morpholinoethoxy)-3-(3,4,5-trimethoxybenzylidene) chroman-4-one= -7.3727 Kcal/mol and (E)-3-(4-methoxybenzylidene)-7-(2-morpholinoethoxy) chroman-4-one released -7.6838 Kcal/mol per mole of energy.

The results showed that compound (E)-3-(4-methoxybenzylidene)-7-(2-morpholinoethoxy) chroman-4-one has higher cytotoxicity than (E)-7-(2-morpholinoethoxy)-3-(3,4,5-trimethoxybenzylidene) chroman-4-one against HT-29 and 3T3 cell lines. The in-silico results confirmed the results obtained from in vitro experiments and showed three interactions between ligand (E)-3-(4-methoxybenzylidene)-7-(2-morpholinoethoxy)chroman-4-one and αThr179, αThr145, and αTyr224 amino acids in tubulin active site.