Synthesis And Biological Activities Of Acyl-hydrazones, And Its Application

Acylhydrazones are a class of compounds with the C=N-N-C=O. They are usually prepared via the condensation of aldehydes or ketones with hydrazines or substituted hydrazine in the presence of an acid as catalyst. Hydrazones have been received much attention because of their particular physical, chemical and biological activities based on their unique structure.This thesis is focused on developing a simple synthesis approach of hydrazones, comprehensively study the biological activities of acylhydrazones on different levels and the potential application of hydrazones in sensing metal ions. We study the suppressing towards cancer cell and normal cell and propose the possible mechanism of anti-proliferative activity of acylhydrazones. The anti-microbial activities has been studied using Escherichia coli and Monilia albican as the model organism. We also study the interactions of hydrazones with serum albumin and ct-DNA focusing on binding mode and binding properties, and explain the molecular mechanism of hydrazones'bioactivities. We also apply some hydrazones in sensing the Al3+, Fe3+Zn2+.This thesis consists of seven chapters.Chapter1:This chapter covered the hottest research field of acylhydrazonse and mainly introduced the structural characteristic, synthesis routine, bioactivities and application of acylhydrazones. We gave a detailed introduction of anti-epilepsy, anti-depressant, anti-inflammatory, anti-platelet, anti-microbial, antimycobacterial and antitumor activities of acylhydrazones. The application of acylhydrazones in pesticide, asymmetric synthesis, photoelectric material and catalysis were illustrated briefly and continuously. This chapter also covered the brief introduction of biomacromolecules and the methodology investigating the interactions between organic molecules and biomacromolecules.Chapter2:We synthesized a serial of acylhydrazones containing substituted aromatic group and improved the synthesis routine. We developed an one-pot synthesis methodology to obtain targeted acylhydrazones with a much higher yield and reduced amount of solvent and catalyst, also reduced energy consumption according to green chemistry principle.Chapter3:We studied the anti-pro liferative activities of acylhydrazones towards HeLa, B16-F10and HEK.293cell lines employing MTT method. Acylhydrazones could generally suppress growth of cancer cell and normal cell, while the cancer cell lines were more sensitive to acylhydrazone than that of normal cell line. The mechanism of anti-proliferative activity might be based on the influence and regulation of iron metabolism in cell.Chapter4:By using microcalorimetry, we studied the biological activity of E. coli and M. albican affected by acylhydrazones. All of the acylhydrazones could generally affect the survival and reproduction of E. coli and M. albican. We screened and found two component with the highest anti-microbial activity. The detailed research showed that IC50of Cpl and Cp23towards E. coli and S. aurcus were56.7?M,44.1?M and38.7?M,31.9?M, respectively. Cp23possessed the higher anti-microbial activity than that of Cpl.Chapter5:We systematically investigated the interaction between acylhydrazone Cp7and ct-DNA employing fluorescent spectroscopy, UV-Visible spectroscopy, circular dichroism and molecular modeling methods. The results showed Cp7could bind to DNA in the minor groove with binding coastant of104mol-1·L. Cp7twisted its molecular structure to adopt minor groove shape, and H-bonding and Van der Waals' force contributed more than others to stabilize the complex.Chapter6:We systematically investigated the interaction between acylhydrazones and serum albumin employing fluorescent spectroscopy, UV-Visible spectroscopy, electrochemistry, circular dichroism,microcalorimetry and molecular modeling methods. The acylhydrazones could bind to both HSA and BSA in an equivalent and independent binding site in Sudlow's site I, forming a1:1complex. The unusual static quenching was caused by large requirement in the binding process, which was a direct consequence of overcoming of the blocking residues outside the bindingpocket. The dominant driving force of these interactions was hydrophobic interaction, whereas hydrogen bonding helped to adopt the shape of the binding pocket. The binding slightly destroyed the natural structure of protein and decreased the content of ?-helix. The presence of acylhydrazones could change the binding mode and binding properties of Fe2+/Fe3+towards serum albumin and thus regulated the metabolism.Chapter7:We investigated fluorescence response of Cpl to Al3+and Cp5to Al3+Fe3+, Zn2+. We found that Cpl can selectively responding towards Al3+forming a2:1fluorescent complex and solvent participated in the coordination complex. The complex reduced intramolecular chaege transfer and gave a strong chelation enhenced fluorescence. Cpl was a fluorescent probe with great potential. Cp5can selectively responded to Al3+, Fe3+, Zn2+, forming different constructed complex with different fluorescence emissio.