Synthesis, Crystal Structure, DNA-binding Of Demethylcantharate Thiazole Derivatives And Transition-metal Complexes

Cantharidin is the dried body of the Chinese Mylabris phalerala Pall. and M. cichorii Linn. Cantharidin which is used as a traditional medicine in China can be traced back more than 2000 years. In recent studies, it has been found that cantharidin possess anticancer properties, increases the number of leucocytes, and has irritant effects on the urinary organs. But the renal toxicity of this drug has prevented it from using in mainstream oncology. Therefore, design and synthesis of a number of cantharidin derivatives of selective inhibition to tumor cells, but small toxicity and less effect on the immune response is of great significance. Demethylcantharidin (NCTD), the demethylated analogue of cantharidin, also possesses anticancer activity and stimulates the bone marrow, but its nephrotoxicity weakens significantly. Many derivatives of norcantharidin have been synthesized and some of them have good anti-tumor activity in vitro.We have designed and synthesized N-thiazole or N-thiadiazole norcantharidin acylamide acid and novel demethylcantharate transition-metal complexes. We also have studied the interaction between calf thymus DNA (ct-DNA) and the antiproliferative activity of the compounds. The main work are as following:1. N-thiazole norcantharidin acylamide acid (L1) and N-thiadiazole norcantharidin acylamide acid (L2) have been synthesized. They were characterized by elemental analysis, IR and 1H NMR spectra. The interaction between the compounds and DNA was studied by means of fluorescence quenching studies and viscosity measurements. The compounds bond to DNA in the same mode of partial interaction because of their similarity in structure.2. Two new mixed-ligand complexes, [M(atdz)(DCA)(H2O)2]·2H2O, (M=Co(Ⅱ)(1), Zn(Ⅱ)(2); atdz=2-amino-1,3,4-thiadiazole, C2H3N3S; DCA2-=demethylcantharate, C8H8O5) were prepared and characterized by elemental analysis, molar conductance, IR and TG-DTG. The structures of the complexes were determined by X-ray diffraction. The DNA binding properties of the complexes were investigated by electronic absorption spectra, thermal denaturation studies, fluorescence quenching studies and viscosity measurements. All the results showed the interaction modes between the complexes and DNA were partial intercalation and the binding activity with DNA of complex 2 was stronger than complex 1. The antiproliferative activities of the complexes against human hepatoma cells (SMMC7721) in vitro were evaluated with MTT assay. The result was consistent with the DNA binding experiments. The inhibition rates of complex 1 (IC50=87.04±12.26μmol·L-1) and complex 2 (IC50=79.43±4.74μmol·L-1) were much higher than that of NCTD (IC50=115.5±9.5μmol·L-1).3. Three new mixed-ligand complexes, [Zn(atz)3(DCA)]-2H2O(3) [Co(atz)(DCA)(H2O)2]·2H2O(4) and [Ni(atz)(DCA)(H2O)2]·2H2O(5), (atz =2-amino-thiadiazole, C3H4N2S) were prepared and characterized by elemental analysis, molar conductance, IR and TG-DTG. The structures of the complexes were determined by X-ray diffraction. The DNA binding properties of the complexes 4 and 5 were investigated by fluorescence quenching studies and viscosity measurements. The antiproliferative activities of the complexes against human hepatoma cells (SMMC7721) in vitro were evaluated with MTT assay. The inhibition rates of complex 4 (IC50=83.86±6.97μmol·L-1) was much higher than that of complex 5 (IC50=114.70±4.52μmol·L-1) and NCTD (IC50=115.5±9.5μmol·L-1).4. Two new mixed-ligand complexes, [Zn3(Im)2(HIm)2(DCA)2]n(6) and [Cd(Him)2(DCA)]n (7) (HIm=imidazole, C3H4N2; Im=imidazolate, C3H3N2) were prepared and characterized by elemental analysis, IR and TG-DTG. The structures of the complexes were determined by X-ray diffraction.