Study On Synthesis And Antitumor Activities Of Substituted Phenyl Methyl Pyrazolone Acylhydrazones Complexes

Coordination chemistry is one of the frontier subject in the modern chemistry, includes the design and synthesis of functional coordination complexes, and studies on their physicochemical and biological property. The designing of coordination complexes which have pharmacological and biological activities is the fundamental way of chemotherapy towards cancer, a killer disease which threaten to the human being health. In this article, we use d vitamin B3, namely nicotinamide, derivatives isoniaziode to have nucleophilic addition reaction with substituted benzoyl pyrazolone and condensation forming novel substituted benzoyl-pyrazolone acylhydrazone schiff bases and their transition metal complexes. We also compared the antitumor activities of schiff base ligands and their coordination complexes with others in vitro, an d screened the most effective one. Then, we studied the possible antitumor mechanism and structure-activity relationship of this complexes through antioxidation experiment and pathological method by a S180 tumor model in vivo. Those studies had practical value on broaden the biological applications of bioactive amines and schiff base metal complexes, moreover, the article provides theoretical and experimental basis on the development of novel chemotherapy drugs. The main contents of this paper are as follows:Synthesised eleven kinds of novel substituted benzoyl-pyrazolone hydrazone ligands and their transition metal complexes had not been reported yet by solvothermal methods. Those eleven novel complexes include four new substituted benzoyl-pyrazolone Schiff base ligand, 1-phenyl-3-methyl-4-(4-toluoyl)-pyrazolone-5(A1) and furfuryl amine(L11), aminobenzothiazole(L12) schiff bases; 1-phenyl-3-methyl-4-(4-chlorobenzene formyl)-pyrazolone-5(A2) and isonicotinyl hydrazide(L21), furfuryl amine(L22)schiff bases. Seven N-(1-phenyl-3-methyl-4-(4-toluoyl)-pyrazolone-5)-isonicotinic acyl hydrazone base(L21) Cu(Cu L21), Zn(Zn L21), Fe(Fe L21), Co(Co L21), Cr(Cr L21), Ni(Ni L21), Mn(Mn L21) complexes.All those eleven kinds of schiff bases and their transitional metal complexes we mentioned before were characterized by elemental analysis, molar conductance, IR spectra, UV spectra, TG-DTA, XRD and X-ray photoelectron spectroscopy to determine their composition, chemical structure and the coordination mode.We compared the proliferative inhibition activity of two pyrazolone isonicotinic acyl hydrazoneone ligand(HL11, HL12) and the transition metal coordination complexes of HL21(Cu L21, Zn L21) on human Lo Vo cells by MTT. Results showed that both pyrazolone isonicotinic acyl hydrazoneone schiff bases and the coordination complexes have a significantly dose-dependent proliferative inhibition effect on those Lo Vo cells, of which Cu L21 have the most significant antitumor activity.To assess the activity of schiff bases and their metal complexes in vivo, we established a S180 mice tumor model and ascites tumor model. Results showed that Cu L21 have significantly inhibition effect on the growth of S 180. The S180 tumor inhibition rate of low, medium and high dose group was 35.82%, 41.19%, 37.46%, respectively, survival curves of ascitic tumor was 11.7%, 50%, 55%, respectively. Meanwhile, Cu L21 have no significant effect on the thymus index and spleen index of mice. Moreover, amounts of apoptosis cell other than necrosis cells in the mice that treated with coordination complexes was observed by HE staining, transmission electron microscope and TUNEL staining.We determined the level of MDA, SOD and GSH-Px in mice serum, and results showed that Cu L21 could decrease the level of MDA in serum and increase the level of SOD and GSH-Px. We also found that the level of cytochrome c and caspase-3 was up regulation in the Cu L21 group mice by immunohistochemistry. The mechanism of Cu L21 maybe alleviate the level of oxidation stress and up-regulate the level of cytochrome c and caspase 3, and eventually induced apoptosis. In conclusion, Cu L21 could induce the apoptosis of tumor through the mitochondrial pathway, and the antitumor activity was in a manner of dose dependent.