Synthesis and biological evaluation of bisspirooxindole-hexahydroindolizines as potential anticancer agent

In this study, we report an efficient three-component domino reaction of isatin, pipecolic acid, and alkyl 2-(1-methyl-2-oxoindolin-3-ylidene) acetate that provided a simple and convenient route to synthesis of novel methyl-2,2″-dioxo-1',5',6',7',8',8a'-hexahydrodispiro[indoline-3,2'-indolizine-3',3″-indoline]-1'-carboxylate derivatives. This regio- and diastereoselective transformation presumably proceeds through a domino sequence involving azomethine ylide formation followed by a [3 + 2] cycloaddition reaction, leading to the construction of the bisspirooxindole scaffold in a one-pot operation. Preliminary biological evaluation revealed that the synthesized compounds exhibited significant cytotoxic activity against MCF-7 breast cancer cells. The docking study suggested that compound 3d can act as an estrogen receptor alpha (ER-α) modulator, and can be considered a promising lead compound.