Regio- and stereoselective synthesis of new spirooxindoles via 1,3-dipolar cycloaddition reaction: Anticancer and molecular docking studies

Abstract

Owing to their structural novelty and inherent three-dimensionality, spiro scaffolds have been shown indisputable promise as chemopreventive agents. A new series of heterocycles containing spirooxindole and pyrrolidine rings were synthesized by the 1,3-dipolar cycloaddition of an azomethine ylide, which was generated in situ by the condensation of a secondary amino acid (l‑proline) and dicarbonyl compounds (isatin), with dipolarophiles. This method is simple and provides diverse and biologically interesting products. The new series of compounds with a high degree of stereo- and regioselectivity were evaluated against breast cancer cell lines (MCF-7) and leukemia (K562). Among them, compound 4g was identified as the most potent with IC₅₀ values of 15.49 ± 0.04 μM, against breast cancer cell lines (MCF-7) compared to standard drug 5-Fu (IC₅₀ = 78.28 ± 0.2 μM) and compound 4i IC₅₀ values of 13.38 ± 0.14 μM against leukemia (K562) compared to standard drug 5-fluorouracil (5-FU) (IC₅₀ = 38.58 ± 0.02). The selective apoptotic effects of 4g were investigated against MCF-12 normal mammary cell and the cytotoxicity of 4g was not associated with any induction of necrosis compared to untreated cells. Molecular docking studies were investigated. From the docking data, these compounds could be act as small molecules that inhibit the MDM2-p53 interaction.

Keywords: 1,3-Dipolar cycloaddition; Azomethine ylide; Breast cancer; Leukemia.; MCF-12 normal mammary cell; MDM2-p53; Pyrrolidine; Spirooxindole.