Síntese, caracterização e avaliação antineoplásica de novos derivados 3-hidroxiindolin-2-onas-3-substituídos

Abstract

The growing number of cancer cases, statistics that indicate millions of new cases in the next years and treatment limitations as well make the search for new antineoplastic drug a current necessity. The 3-Substituted-3-hydroxyindolin-2-ones nucleus, present in some natural products, has been considered a privileged structure with several biological activities, including antineoplastic. In this work, it is presented the synthesis and characterization of 21 3-Substituted-3-hydroxyindolin-2-ones derivatives obtained by Morita-Baylis-Hillman reaction; 12 of them are unpublished, and it was used isatin and your derivatives such as electrophilic and acrylonitrile, Acrylate and pnitrophenylacrylamide as Michael acceptors. Most of the adducts were obtained in good to excellent yields (92-99%). The reaction times varied according to the acceptor used, in those adducts containing nitrate group, the reactions were faster (1h - 24h). The preliminary evaluation of cytotoxic activity was executed in 5 tumoral lines and data analysis showed that the compounds with the greatest activities (IC 50 <3µM) 3a, 3c, 3d, 3e, 3f, 3g, 3h, 3i are those containing nitrile group, among these compounds, 3f (IC50= 42 nM) and 3i (IC50= 48 nM) showed very promising results, against the HL60 line (promyelocytic leukemia). The Compound 3f presented an excellent selectivity index (IS = 967.14), much higher than the reference drug doxorubinin (IS = 12.73). The structural characterization of the compounds was performed by spectroscopy of 1H and 13C NMR and high resolution mass.