Joining Drug Discovery and MCRs: New Spiro[indoline-3,2'-thiazolidin]-2-one Derivatives as Potentially Bioactive Anticancer Compounds

2-Oxindoles, especially 3,3-disubstituted and spiro-fused derivatives, are widely recognized as highly relevant compounds for drug discovery. In particular, spirooxindole-fused thiazolidines have recently aroused great interest as promising anticancer agents, acting by inhibition of the p53-MDM2 protein-protein interaction. 1. As part of our interest in multicomponent reactions (MCRs) applied to the synthesis of oxindole-based compounds,2 we report a novel synthetic approach towards the title compounds based on two sequential MCRs. Starting from isatin derivatives 1, ammonia (2) and mercaptoacetaldehyde (3), spirooxindole-fused 3-thiazolines 4 were easily obtained by means of the underutilized Asinger reaction.3 Intermediates 4 were then subjected to a diastereoselective Joullié-Ugi reaction, which afforded products 7 in high yields, the diastereoisomers being readily separable by flash chromatography. Both MCRs display a broad substrate scope, allowing us to quickly generate a diverse library of compounds 7, for which R1-R4 substituents could be varied extensively. Evaluation of the antiproliferative activity and p53-MDM2 protein-protein interaction inhibition of the entire library is currently underway, as well as docking studies to understand the binding mode of the most promising representatives of this novel class of lead compounds. 1. Bertamino A.; Soprano M.; Musella S.; Rusciano M.R.; Sala M.; Vernieri E.; Di Sarno V.; Limatola A.; Carotenuto A.; Cosconati S.; Grieco P.; Novellino E.; Illario M.; Campiglia P.; Gomez-Monterrey I. J. Med. Chem., 2013, 56, 5407-5421. 2. Stucchi M.; Lesma G.; Meneghetti F.; Rainoldi G.; Sacchetti A.; Silvani A. J. Org. Chem., 2016, 81, 1877-1884; de Graaff C., Ruijter E., Orru R., Chem. Soc. Rev., 2012, 41, 3969-4009. 3. Asinger F. Angew. Chem., 1956, 68, 377.