Synthesis, Characterization And In Vitro Cytotoxicity Study Of Palladium(Ⅱ) Complex Of Curcumin And Curcumin Derivatives

Research and application of platinum-based anticancer drugs have been rapidly developed since the foundation of the anticancer activity of cisplatin in 1967. Cisplatin and carboplatin in cancer chemotherapy have become indispensable drugs, but its serious side effects, such as nephrotoxicity, ototoxicity, neurotoxicity and resistance, greatly limit the clinical use of these drugs. Palladium and platinum complexes have similar structural characteristics(both dsp2 hybrid mode and square planar structure) and chemical properties.This make palladium complexes become a new class of potential anticancer drugs.Curcumin is the major yellow pigment extracted from turmeric, a commonly used spice, derived from the rhizome of the plant Curcuma longa. It has a wide range of pharmaceutically activities such as antioxidant, anti-inflammatory, anti-viral, anti-cancer and autoimmune diseases, and so on. Pyrazole and its derivatives are an important class of five-membered heterocyclic compounds, which were widely applied in the field of biological medicine and pesticide. Their anti-tumor properties have become a hot research towards chemists in recent years. However, there are also many drawbacks on curcumin,such as poor water solubility, poor stability, low bioavailability and large doses of medication, which greatly limit its application. As we know, the diketone structure of curcumin is a major reason of the degradation in vivo. A highly promising and innovative approach to deal with the bioavailability and degradation issues is the use of metal curcumin complexes.The main works are shown as follows:1. Based on the synthesis of curcumin and its derivatives from aromatic aldehydes, a novel series of palladium(II) complexes with curcumin(or its derivatives) and2,2’-bipyridine(or phenathroline) have been synthesized through a directed self-assembly approach that involves spontaneous deprotonation of the β-diketone ligands in H2O/acetone solution. These complexes have been characterized by 1H(13C) NMR, HRMS and elemental analysis. Crystal structure of 4b has been determined by X-ray diffraction analysis. Thecytotoxicity was tested by MTT. The preliminary results showed that complexes 4b, 4c, 4d have significant inhibition on proliferation of three carcinoma cells. Further mechanistic studies indicated that complexes 4b, 4c and 4d could increase the concentration of reactive oxygen species(ROS) in He La cells. Complexes 4b may disrupted mitochondrial membrane potential and induced apoptosis of tumor cells.2. Based on the synthesis of six pyrazole analogues of curcuminoids from Curcumin and its derivatives, a series of bimetallic palladium(II) complexes(B1-B6) with these ligands and 2,2’-bipyridine have been synthesized through a directed self-assembly approach that involves spontaneous deprotonation of the pyrazole analogues of curcuminoids in H2O/acetone solution. The structure of the obtained supramolecular complexes was verified by 1H(13C) NMR, HRMS and elemental analysis. The crystal stuctures of B2 was determined by X-ray diffraction. The stability of these complexes was also examined by UV-vis spectroscopy, these complexes displayed excellent stability in PBS(containing 10% DMSO).The cytotoxicity of complexes was tested by MTT, the preliminary results showed that most of the obtained complexs are almost equal to that of cisplatin. Furthermore, the DNA-binding properties of B1 and B5 were preliminary investigated by fluorescence spectroscopy, the results indicated that compound B1 and B5 as the DNA-intercalating agent exhibited middle binding affinity with CT-DNA.