Chemo-/Regio-Selective Synthesis of Novel Functionalized Spiro[pyrrolidine-2,3'-oxindoles] under Microwave Irradiation and Their Anticancer Activity.

Abstract

A novel series of nitrostyrene-based spirooxindoles were synthesized via the reaction of substituted isatins <b>1a</b>-<b>b</b>, a number of α-amino acids <b>2a</b>-<b>e</b> and (E)-2-aryl-1-nitroethenes <b>3a</b>-<b>e</b> in a chemo/regio-selective manner using [3+2] cycloaddition (Huisgen) reaction under microwave irradiation conditions. The structure elucidation of all the synthesized spirooxindoles were done using ¹H and ¹³C NMR and HRMS spectral analysis. The single crystal X-ray crystallographic study of compound <b>4l</b> was used to assign the stereochemical arrangements of the groups around the pyrrolidine ring in spiro[pyrrolidine-2,3'-oxindoles] skeleton. The in vitro anticancer activity of spiro[pyrrolidine-2,3'-oxindoles] analogs <b>4a</b>-<b>w</b> against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines shows promising results. Out of the 23 synthesized spiro[pyrrolidine-2,3'-oxindoles], while five compounds (<b>4c</b>, <b>4f</b>, <b>4m</b>, <b>4q</b>, <b>4t</b>) (IC₅₀ = 34.99-47.92 µM; SI = 0.96-2.43) displayed significant in vitro anticancer activity against human lung (A549) cancer cell lines, six compounds (<b>4c</b>, <b>4f</b>, <b>4k</b>, <b>4m</b>, <b>4q</b>, <b>4t</b>) (IC₅₀ = 41.56-86.53 µM; SI = 0.49-0.99) displayed promising in vitro anticancer activity against human liver (HepG2) cancer cell lines. In the case of lung (A549) cancer cell lines, these compounds were recognized to be more efficient and selective than standard reference artemisinin (IC₅₀ = 100 µM) and chloroquine (IC₅₀ = 100 µM; SI: 0.03). However, none of them were found to be active as compared to artesunic acid [IC₅₀ = 9.85 µM; SI = 0.76 against lung (A549) cancer cell line and IC₅₀ = 4.09 µM; SI = 2.01 against liver (HepG2) cancer cell line].