A química das indirubinas: síntese e caracterização de novos derivados hidrossolúveis

Abstract

The present dissertation, entitled "The chemistry of indirubins: synthesis and characterization of new water-soluble derivatives", deals with the preparation and characterization of compounds derived from indirubin with improved solubility in water and ethanol, and the experimental determination of LogP values. Eight previously undescribed compounds were prepared. All were characterized by their melting ranges, UV-Vis, IR, 1H, 13C and two-dimensional NMR spectroscopies and mass spectrometry (HRMS-LDI-TOF). Experimental data obtained for the previously described compounds are consistent with the literature data. Four synthetic routes were examined for the proposed target compounds: 5-substituted indirubin-3'-hydrazones (10), 5-substituted indirubin-3'-azino-phenylhydrazones (14), N-1-hydroxymethyl-5-substituted indirubins (16 and 17). A number of unexpected results were encountered during the course of this project, which resulted in the syntheses of eight novel compounds (10c, 17a-f and 19) whose structures are unprecedented in the literature. From the detailed analysis of the spectral data, it was possible to propose its structures. The preparation of indirubin-3'-hydrazones (10), previously reported in the literature, was executed with difficulty, forming several complex mixtures, with evidence of nucleophilic competition between hydrazine and hydroxide ion formed in the reaction medium. The Mannich Bases of indirubins (16) were not obtained and N-1-hydroxymethyl-indirubins (17a-f and 19) were formed, which were promising for the purpose of this work. The solubility and LogP values were determined experimentally for the compounds obtained and compared with calculated values. All compounds showed increased solubility in water and ethanol when compared to their 5-substituted indirubin analogues, while the 3'-hydrazone derivatives proved to be very water soluble, providing LogP values beyond or near the limit (1-5) proposed by Lipinski. Strategies for future work are proposed to biologically test the new compounds, overcome the difficulties encountered and suggest alternative routes for the synthesis of indirubins with possible biological activities.