European Journal of Biomedical and Pharmaceutical Sciences

SYNTHESIS OF NEW SPIRO[AZETIDINE-2,3'-INDOLINE]-2',4-DIONES AS POSSIBLE ANTICANCER AGENTS: IN VITRO AND IN SILICO STUDIES

Mustapha N. Abubakar, José Rubén García-Sánchez, Rocio Requena-Castro, Francisco Reyes-Espinosa, Alfredo Juárez-Saldivar, Virgilio Bocanegra-García, Gildardo Rivera and Girija S. Singh*

ABSTRACT

The paper describes the synthesis, and in vitro and in silico biological evaluation of twelve new spiro[azetidine- 2,3ʹ-indoline]-2ʹ,4-diones as possible anti-cancer agents. A series of six compounds have been synthesized by a 1:2 molar reaction of 3-(N-substituted)imino-5-chloroisatin with 2-diazo-1,2-diphenylethanone. Treatment of the products with ethanolic sodium hydroxide leads to the formation of a new series of six spiro[azetidine-2,3ʹ- indoline]-2ʹ,4-diones bearing free-NH on 2-oxindole ring. The compounds have been characterized based on analytical and spectral data. The biological evaluation in vitro on breast cancer cells (MDA-MB-231 and MCF-7) was performed. Additionally, an in silico analysis on active site of MDM2 protein was done to understand potential mechanism of action as anti-cancer agents. The compounds 6a, 6c and 6f exhibited cytotoxic activity (IC50 from 2.24 to 22.8 μM) against MDA-MB-231 and MCF-7 cells. Regarding breast cancer cell versus breast normal cells (MCF10A) or normal cells (3T3-L1) 6a, 6c and 6f showed selectivity for growth inhibition of cancerous cells. Molecular docking analysis revealed an equal binding pattern between compound 6a and compound spiro-oxindole 6SS (a potent MDM2 inhibitor) on active site of MDM2 protein.

Keywords: Spiro-oxindoles, 2-azetidinones, cycloaddition, amide-cleavage, anticancer, MDM2.