Regio- and Stereoselective Synthesis of a New Series of Spirooxindole Pyrrolidine Grafted Thiochromene Scaffolds as Potential Anticancer Agents

Abstract

A series of new spiro-heterocycles engrafted spirooxindole/pyrrolidine/thiochromene scaffolds was synthesized by the three-component 1,3-dipolar cycloaddition reactions in a fully controlled regio- and stereo-selective fashion. Condensation of several substituted isatin derivatives with L-proline generated the azomethine ylides which subsequently reacted with chalcones based thiochromene scaffold, and finally afforded the target spiro-compounds. This simple protocol furnished a structurally complex, biologically relevant spiro-heterocycles in good yields through a one-pot process. All synthesized chalcone-based thiochromene, along with the spirooxindole/pyrrolidine/thiochromene scaffolds, were tested for their anticancer activity against four cancer cell lines (PC3, HeLa, MCF-7, and MDA-MB231). Toxicity of these compounds was also evaluated against human fibroblast BJ cell line, and they appeared to be not cytotoxic. For the prostate cancer (PC3) cell line, the most active hybrid, among synthesized series, was compound (7f, IC50 = 8.7 ± 0.7 µM). The most potent spirooxindole/pyrrolidine/thiochromene hybrid against cervical (HeLa) cancer cells was compound (7k, IC50 = 8.4 ± 0.5 µM) having chlorine and p-trifluoromethyl substituents attached to phenyl rings. Finally, against the MCF-7 and MDA-MB231 breast cancer cell lines, compound (7d) was the most active member of this series (IC50 = 7.36 ± 0.37, and 9.44 ± 0.32 µM, respectively).

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

“…Pyrrolidines 8 are five-membered heterocyclic units with only one nitrogen and great pharmaceutical importance [11][12][13], and are easily obtained by 32CA reaction of an azomethine ylide (AY) 6 with a variety of olefins 7 (see Scheme 2). The use of AY 9, generated from isatin, permits the synthesis of spirooxindoles 10 with significant biological activities [14][15][16][17][18]. Scheme 1.…”

“…Pyrrolidines 8 are five-membered heterocyclic units with only one nitrogen and great pharmaceutical importance [11][12][13], and are easily obtained by 32CA reaction of an azomethine ylide (AY) 6 with a variety of olefins 7 (see Scheme 2). The use of AY 9, generated from isatin, permits the synthesis of spirooxindoles 10 with significant biological activities [14][15][16][17][18]. MEDT studies of the 32CA reactions of the simplest AY 1 [5] and the simplest carbonyl ylide CH2-O-CH2 [19] have shown that the presence of a pseudoradical center at each one of the two methylenes of these TACs causes the pdr-type 32CA reactions with nonactivated ethylenes to have an unappreciable electronic activation energy (see Scheme 1) [5,19].…”

Synthesis, Characterization, and Cytotoxicity of New Spirooxindoles Engrafted Furan Structural Motif as a Potential Anticancer Agent

“…Spirooxindole core has been continuously attracting the attention of researchers and has become a dynamic area of research due to its outstanding pharmacological properties. Barakat et al extensively studied this spirooxindole scaffold recently and have reported so many examples so far focusing on the drug discovery research. − In this library, Barakat has reported the synthesis of a new class of new spiro-heterocycles coadministrated with different pharmacophores such thiochromene, benzofuran, benzothiophene, cyclohexanone, pyrrole, and rhodanine scaffolds by the three-component [3 + 2] cycloaddition reaction in a regio- and stereo-selective fashion. All synthesized compounds were subjected to anticancer activity against a variety of cancer cell lines such as PC3, HeLa, MCF-7, MDA-MB231, and so forth, and many of them showed high efficacy against the tested cell lines.…”

Synthesis and Characterization of Spiro Compounds Containing Phenothiazine Moiety and their Anticancer Potential Towards Breast Cancer Cell Lines

“…In the present work we aimed at identifying potential anticancer agents, and efforts were made in search of novel potent molecules using dipolar cycloaddition strategy. In the present work a series of spirooxindole/pyrrolidine scaffolds were synthesized in a fully controlled regio-and stereoselective cycloaddition fashion [8][9][10][11] . Condensation of isatin derivatives, acenapthoquinone and ninhydrins with L-proline, sarcosine, phenyl alanine and phenyl glycine to generate a series of azomethine ylides which subsequently reacted with phenothiazine chalcones afforded the target spiro-compounds in a single-pot process in good yields and are also structurally complex, biologically relevant spiro-heterocycles [12][13][14][15] .…”