Substituted spirooxindole derivatives as potent anticancer agents through inhibition of phosphodiesterase 1

Abstract

Spirooxindole is a promising chemo therapeutic agent. Possible targets include cancers of the liver, prostate, lung, stomach, colon, and breast. Here, we demonstrate a one-pot three-component reaction via a [3 + 2] cycloaddition/ring contraction sequence of a dipolarophile (activated alkene) with in situ-generated azomethine ylide (1,3-dipoles) without the use of any catalyst. The reaction provides efficient access to synthetically useful and biologically important spirooxindoles in high yield (69-94%) with high diastereoselectivity. The synthesized compounds were subjected to cytotoxicity evaluation using colorectal cancer (HCT-116), hepatocellular carcinoma (HepG2), and prostate cancer (PC-3) cells. Compounds 4i, 4j, and 4k showed potent cytotoxic activity and high selectivity against HCT-116 cells when compared to cisplatin. Meanwhile compound 4d retained high cytotoxic activity and selectivity against HepG2 and PC-3 cells in comparison to cisplatin. The mechanism of compound 4d was further studied using phosphodiesterase 1 enzyme and showed 74.2% inhibitory activity. A possible binding mode for compound 4d to PDE-1 was investigated by molecular modeling using OpenEye software. Pose predictions for the active compounds were demonstrated by ROCS alignments. Compound 4d has a special geometry and differs from other active compounds.

Fig. 1. Chemical structures of reported anticancer spirooxindoles and the modified spirooxindole (4a–n).

Scheme 1. The synthesis of the target spirooxindole derivatives 4a–n.

Scheme 2. Plausible approach for the target compounds 4a–n.

Fig. 2. Microscopic examination of the effect of compound 4i on the growth of hepatocellular carcinoma (HepG2).

Fig. 3. Visual representation of 4d docked with 1NOP showing two HB interactions and hydrophobic–hydrophobic interactions as shown by VIDA.

Fig. 4. ROCS run for compound 4d with compounds 4k, 4j and 4i with dissimilarity and not completely matched.

Fig. 5. ROCS for 4d with specific geometry of the 2,4-dichlorophenyl and indole moiety perpendicular to each other.

Fig. 6. Superposition for compounds 4j and 4k by ROCS exhibited structural similarity.

Fig. 7. ROCS for compound 4i exhibited a buckled shape with a different pose inside the 1NOP.