Design, Synthesis, Chemical and Biochemical Insights Into Novel Hybrid Spirooxindole-Based p53-MDM2 Inhibitors With Potential Bcl2 Signaling Attenuation

Abstract

The tumor resistance to p53 activators posed a clinical challenge. Combination studies disclosed that concomitant administration of Bcl2 inhibitors can sensitize the tumor cells and induce apoptosis. In this study, we utilized a rapid synthetic route to synthesize two novel hybrid spirooxindole-based p53-MDM2 inhibitors endowed with Bcl2 signaling attenuation. The adducts mimic the thematic features of the chemically stable potent spiro [3H-indole-3,2′-pyrrolidin]-2(1H)-ones p53-MDM2 inhibitors, while installing a pyrrole ring via a carbonyl spacer inspired by the natural marine or synthetic products that efficiently inhibit Bcl2 family functions. A chemical insight into the two synthesized spirooxindoles including single crystal x-ray diffraction analysis unambiguously confirmed their structures. The synthesized spirooxindoles 2a and 2b were preliminarily tested for cytotoxic activities against normal cells, MDA-MB 231, HepG-2, and Caco-2 via MTT assay. 2b was superior to 5-fluorouracil. Mechanistically, 2b induced apoptosis-dependent anticancer effect (43%) higher than that of 5-fluorouracil (34.95%) in three studied cancer cell lines, activated p53 (47%), downregulated the Bcl2 gene (1.25-fold), and upregulated p21 (2-fold) in the treated cancer cells. Docking simulations declared the possible binding modes of the synthesized compounds within MDM2.

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Pseudo(mono)radical Azomethine Ylides with Phenyl Vinyl Sulphone

“…The intrinsic reaction coordinate (IRC) paths [30] were obtained to establish Thus, the 32CA reaction of AY 21, generated in situ from the reaction of 6-chloroisatin 18 and L-proline 19, with phenyl vinyl sulphone 20 yielded the spirooxindole 23 with total meta regio-and endo stereo-selectivities (see Scheme 5) [25]. Very recently, Barakat et al have experimentally studied a series of 32CA reactions of AYs 14, obtained in situ from isatin derivatives and secondary amines, with different ethylene derivatives 15, in the synthesis of spirooxindoles 16 and 17, with high regio-and stereoselectivity (see Scheme 4) [22][23][24]. While these 32CA reactions were endo stereoselective, the regioselective formation of spirooxindoles 16 or 17 was found to be dependent on the substitution on the ethylene derivative 15.…”

Synthesis and Structure Elucidation of Novel Spirooxindole Linked to Ferrocene and Triazole Systems via [3 + 2] Cycloaddition Reaction

“…The chemical architecture was assigned, based on single-crystal X-ray-diffraction analysis and a set of spectroscopic tools, including NMR and IR spectra. The plausible mechanism is depicted in Scheme 2, based on the previously reported literatures [33][34][35][36][37][38][39].…”

Construction of Spirooxindole Analogues Engrafted with Indole and Pyrazole Scaffolds as Acetylcholinesterase Inhibitors

“…Spirooxindoles exhibit a broad range of biological effects and are well-tolerated in biomedical applications . Their applications use AChEs .…”