Stereo/regio-selective access to substituted 3-hydroxy-oxindoles with anti-proliferative assessment and in silico validation

Abstract

The manuscript focuses on a highly stereo-/regioselective approach for synthesizing a diverse array of substituted-3-hydroxy-2-oxindoles. The synthesized compounds were subsequently subjected to anti-proliferative assessment against various cell lines, including colorectal carcinoma, ovarian cancer, and human metastatic melanoma cancer. The structural characterization of the synthesized scaffolds was unambiguously confirmed using X-ray diffraction analysis. Among the synthesized compounds, one compound demonstrated exceptional potency within the series. It exhibited 1.2, 2.12, and 1.55 times greater potency than cisplatin against the HCT116, OVCAR10, and 1205Lu cell lines, respectively. These results were further supported by in vitro caspase-mediated apoptosis studies. Molecular docking studies of these compounds on the target VEGFR2 protein revealed their binding capability.

Fig. 1. Few examples of bioactive 3-substituted-3-hydroxy-2-oxindole natural products.

Scheme 1. Synthetic route to spiro-epoxyoxindoles 3a–e.

Scheme 2. Effect of different solvents and catalytic p-TsOH on % yield of 4a and 5.

Fig. 2. Possible mechanism in the presence of non-polar/polar aprotic solvent in the presence of p-TsOH.

Fig. 3. Possible mechanism in presence of polar protic solvent in absence of p-TsOH.

Fig. 4. The structure of 4a, showing 50% probability displacement ellipsoids and atomic numbering (left) and 3D structure of crystal lattice (right).

Scheme 3. Synthetic route to synthesis of 3-substituted 3-hydroxy-oxindole 4a–o.

Fig. 5. Generalised SAR for the synthesized 3-substituted-3-hydroxy-2-oxindoles.

Fig. 6. To assess the mode of cell death caused by compound 4j, apoptosis assays were performed. (A) The HCT-116 cells were treated with 10 μM of compound 4j for 24 and 48 h and subjected to Annexin V/7-AAD assay and Caspase 3/7 assays. The quantitative assessment of the apoptosis assays is presented as a bar graph in (B) and (C).

Fig. 7. 2D (top) and 3D (bottom) representation of VEGFR2 protein–ligand interaction for compound 4k and 4j.