Green Synthesis of Spiro Compounds with Potential Anticancer Activity through Knoevenagel/Michael/Cyclization Multicomponent Domino Reactions Organocatalyzed by Ionic Liquid and Microwave-Assisted
Regina Westphal,
Eclair Venturini Filho,
Laiza Bruzadelle Loureiro,
Cláudio Francisco Tormena,
Claudia Pessoa,
Celina de Jesus Guimarães,
Mariana Palmeira Manso,
Rodolfo Goetze Fiorot,
Vinicius Rangel Campos,
Jackson Antônio Lamounier Camargos Resende,
Fabrizio Medici,
Sandro José Greco
Affiliations
Regina Westphal
Chemistry Department, Federal University of Espírito Santo, Fernando Ferrari Avenue 514, Vitória 29075-910, ES, Brazil
Eclair Venturini Filho
Chemistry Department, Federal University of Espírito Santo, Fernando Ferrari Avenue 514, Vitória 29075-910, ES, Brazil
Laiza Bruzadelle Loureiro
Institute of Chemistry, University of Campinas, Josué de Castro Street, Campinas 13083-970, SP, Brazil
Cláudio Francisco Tormena
Institute of Chemistry, University of Campinas, Josué de Castro Street, Campinas 13083-970, SP, Brazil
Claudia Pessoa
Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza 60430-275, CE, Brazil
Celina de Jesus Guimarães
Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza 60430-275, CE, Brazil
Mariana Palmeira Manso
Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza 60430-275, CE, Brazil
Rodolfo Goetze Fiorot
Campus do Valonguinho, Institute of Chemistry, Fluminense Federal University, Niterói 24020-141, RJ, Brazil
Vinicius Rangel Campos
Campus do Valonguinho, Institute of Chemistry, Fluminense Federal University, Niterói 24020-141, RJ, Brazil
Jackson Antônio Lamounier Camargos Resende
Exact and Earth Sciences Institute, Federal University of Mato Grosso, Campus Universitário do Araguaia, Pontal do Araguaia 78698-000, MT, Brazil
Fabrizio Medici
Chemistry Department, University of Milan, Via Golgi 19, 20133 Milan, Italy
Sandro José Greco
Chemistry Department, Federal University of Espírito Santo, Fernando Ferrari Avenue 514, Vitória 29075-910, ES, Brazil
In this work a microwave-assisted Knoevenagel/Michael/cyclization multicomponent domino methodology, using ethanol as solvent and the ionic liquid 1-methylimidazolium chloride as catalyst was developed for the synthesis of spiro compounds. The reaction conditions considered ideal were determined from a methodological study varying solvent, catalyst, amount of catalyst, temperature, and heating mode. Finally, the generality of the methodology was evaluated by exploring the scope of the reaction, varying the starting materials (isatin, malononitrile, and barbituric acid). Overall, the twelve spiro compounds were synthesized in good yields (43–98%) and the X-ray structure of compound 1b was obtained. In addition, the in vitro antiproliferative activities of the spirocycles against four types of human cancer cell lines including HCT116 (human colon carcinoma), PC3 (prostate carcinoma), HL60 (promyelocytic leukemia), and SNB19 (astrocytoma) were screened by MTT-based assay. It is noteworthy that spiro compound 1c inhibited the four cell lines tested with the lowest IC50 values: 52.81 µM for HCT116, 74.40 µM for PC3, 101 µM for SNB19, and 49.72 µM for HL60.
