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 1a–b, a number of α-amino acids 2a–e and (E)-2-aryl-1-nitroethenes 3a–e 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 4l 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 4a–w 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 (4c, 4f, 4m, 4q, 4t) (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 (4c, 4f, 4k, 4m, 4q, 4t) (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].

Recent advances in microwave-assisted multicomponent synthesis of spiro heterocycles

“…By this Huisgen reaction, treatment of readily available substituted isatins (1), several α-amino acids (3), and ( E )-2-aryl-1-nitroethenes (38) under microwave irradiation using 300 W of power in methanol as solvent afforded the corresponding desired spiro adducts in good-to-high yield. 190 …”

“…By this Huisgen reaction, treatment of readily available substituted isatins (1), several a-amino acids (3), and (E)-2-aryl-1nitroethenes (38) under microwave irradiation using 300 W of power in methanol as solvent afforded the corresponding desired spiro adducts in good-to-high yield. 190 The stereochemical arrangements around the pyrrolidine ring of the spiro pyrrolidine-2,3 0 -oxindoles (56) were determined using single-crystal X-ray analysis. The compounds were also shown to have promising anticancer activity when tested against human lung cancer A549, human liver cancer HepG2, and immortalized normal human lung and liver cell lines.…”