Synthesis, Antimicrobial And Anti-Tumor Activity Of Thiosemicarbazones And Their Transition Metal Complexes

Thiosemicarbazones and their transition metal complexes have received considerable attention in biology,chemistry,medical industry, because of their marked and antimicrobial, antitumor, antiviral biology properties. Heterocyclic thiosemicarbazones and their transition metal complexes has become a hotspot research in recent years due to their more remarkable biology properties and the study has showed that their biological properties are often related to the donor sequence of the ligands and metal ion coordination. So it is significant to study the synthesis and biological activities of heterocyclic thiosemicarbazones and their transition metal to develop high-effective and low-adverse new drugs against bacteria and cancer.In this paper, Three kinds of heterocyclic thiosemicarbazones and their transition metal complexes have been synthesized, that have included 2-acetylpyridine,2-benzoylpyridine and thiophene type,and have studied the anti-tumor activity and the possible mechanism,Their cytotoxic effect on normal cells in vitro and antibacterial activity .The work has been finished as follows:(1) We have synthesized acetylpyridine thiosemicarbazone ligand HL¹,2-acetylpyridine S-methyl thiosemicarbazone ligand HL²,2-benzoylpyridine S-methyl thiosemicarbazone HL³,thiophene-2-carbox -aldehyde N(4)-methylthiosemicarbazone HL⁴ and their metal complexes Mn(L¹)₂(1),Mn(L²)₂ (2),[Zn(L³)₂(ClO⁴)] (3),[Cu2(L³)₂(CH³COO)](ClO⁴) (4),[Ag₆(L⁴)₆·4DMF](5).We have analyzed C,H,N elemental by Perkin-Elmer 240C Element Analytical Instruments.(2) The antitumor of four ligands and their transition metal complexes have been studied. The results have indicated that they have different effects against hepatoma cells SMMC-7721 and esophageal EC109.In the four ligands, the HL³ and HL² is strongest, followed by HL¹,and HL⁴ has no antitumor activity at all. But after introducing metal ion,their metal complexes have exhibited different aititumor activity .The compound 4 is stronger than HL³ after introducing Copper Ion,but The compound 3 exhibits weaker aititumor than HL³. The compound 5 has significant antitumor activity after introducing Ag ion. In the nine compounds, The half inhibitory concentrations (IC50) of The compounds 4 and 5 for esophageal EC109 are 1.14μg/ml and 4.77μg/ml respectively ,IC50 for hepatoma cells SMMC-7721 1.04μg/ml and 2.75μg/ml respectively .They exhibit distinct aititumor activity in a dose-and-time dependent manner.Then testing the toxicity of the compounds 4 and 5 for mouse embryonic fibroblasts, the results have indicated that they display different toxicity toward normal cells. Further we have studied the possible anti-tumor mechanism of them, Giemsa staining and acridine orange (AO) fluorescence staining are used to observe the morphological changes of the esophageal EC109 treated with the compounds 4 and 5; Cell apoptosis and cell cycle distribution are detected by flow cytometry; whether DNA ladder is observed by Agarose Gel Electrophoresis if cells occure in apoptosis. The results have indicated that The compound 5 inhibits the proliferation of EC109 by inducing apoptosis in lower concentration, inhibit G0/G1 phase from entering S phase and inhibit the proliferation in normal;The compound 4 inhibit the proliferation of EC109 both in apoptosis and in necrosis in lower concentration, and in necrosis mainly.(3) The antimicrobial activity of HL³,HL⁴,the compounds 4 and 5 have been tested,the results have indicated that the compound 4 display significant antimicrobial activity.It has dual traits: significant antitumor and antimicrobial activity.