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

Assem Barakat,M Ali,Saeed Alshahrani,Sammer Yousuf,Abdullah Mohammed Al-Majid,Mohammad Shahidul Islam,M Iqbal Choudhary,Abdullah Saleh Alamary

doi:10.3390/sym13081426

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).

Highlights

IntroductionSpirooxindole/pyrrolidine heterocycles are ubiquitous in many natural products, such as tryprostatins A and B [2,3], formosanine [4], coerulescine [5], elacomine [6], horsfiline [7], pteropodine, isopteropodine [8], alstonisine [9], rychno-phyilline [10], strychnofoline [11], and other many alkaloids (Figure 1)
Based on literature reports which highlight the biological importance of thiochromene sub-structure and spirooxindole/pyrrolidine scaffolds, our aim was to synthesize a new hybrids comprising three pharmacophores, spirooxindole/pyrrolidine/thiochromene employing three components 1,3-dipolar cycloaddition reaction
Three steps synthesis of the target compounds are presented in Schemes 1 and 2

Summary

Introduction

Spirooxindole/pyrrolidine heterocycles are ubiquitous in many natural products, such as tryprostatins A and B [2,3], formosanine [4], coerulescine [5], elacomine [6], horsfiline [7], pteropodine, isopteropodine [8], alstonisine [9], rychno-phyilline [10], strychnofoline [11], and other many alkaloids (Figure 1). These spiro-heterocycles with oxindole and pyrrolidine scaffolds possesses wide spectrum pharmacological activities, such as.

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Results

Conclusion