Studies On Synthesis And Anti-tumor Activity Of The Novel Derivatives Of 1, 3, 4-Thiadiazoles Thioether

Despite significant progress achieved in anticancer therapy, the management of malignancies in humans still constitutes a major challenge for contemporary medicine. Chemotherapy very often causes severe side effects, which are in part a consequence of destruction of normal cells. It is of crucial importance that anticancer drugs display antiproliferative activity in tumor cells without affecting normal tissues. Therefore, the development of safe and effective novel anticancer drug is eagerly being pursued.1,3,4-Thiadiazoles are five-membered aromatic heterocycles with two nitrogen atoms and one sulfur atom, and their derivatives for a long-standing anti-cancer research. In this paper a series of novel derivatives of 1,3,4-Thiadiazoles thioether was designed and synthesized with the 1,3,4-Thiadiazoles as lead compound and the basic theories of drug design, such as bioisosterism and combination of activity. We expect to found safe, efficient and novel antitumor compounds.Part One : Target Compounds DesignIn this paper 40 new compounds and 27 target compounds of 5 types have been designed and synthesized with the 1,3,4-Thiadiazoles as lead compound and the basic theories of drug design, such as bioisosterism and combination of activity.Most of the 1,3,4-thiadiazole derivatives antitumor research has been focused on different substituents at NH2 of C-2 position of 2-amin-1,3,4-thiadiazole (ATDA). Some structural-activity relationships studies have shown that it is not necessary to link the substituent at C-2 by means of amine atom of nitrogen, and it can be substituted by bioisosteres, such as S, O atom. However, it is regrettable that little research in this area. Therefore, Using S atom as bioisosteres of the NH group of ATDA and joining functional moiety, the 1,3,4-Thiadiazoles thioether derivatives containing oxime ether (Ⅰ), dihydrazone (Ⅱ), acylhydrazone (Ⅲ), thioamide hydrazone (Ⅳ) and fluoroquinolone (Ⅴ) were designed. Part Two : Target Compounds SynthesisIn this paper a series of novel 1,3,4-thiadiazole thioether derivatives containing oxime ether, dihydrazone, acylhydrazone, thioamide hydrazone and fluoroquinolone was synthesized by chemical methods, their structure were determinated by elemental analysis, 1H NMR, IR and MS.2.1 Synthesis of the target compoundsⅠ2-mercapto-5-substituted-1,3,4-thiadiazole dissolved in methol and water was treated with sodium hydroxide, then was substituted with 3-chlorophenyl-propano- ne to give the corresponding intermediates. The intermediates followed by oximation with hydroxyl-amine in alcohol media and etherification with 2-phenyl-5-chloromethyl-1,3,4-oxadiazole and Potassium carbonate as acid-bind- ing agent in DMF media to give the target compoundsⅠ.2.2 Synthesis of the target compoundsⅡ2-mercapto-5-phenyl-1,3,4- thiadiazole dissolved in methol and water was treated with sodium hydroxide, then was substituted with 3-chlorophenyl-propan- one to give the corresponding intermediates. Catalyzed by glacial acetic acid in alcohol media, the intermediates sequentially followed by condensation with hydrazine hydrate and aromatic aldehydes to produce the corresponding mono- hydrazone and the target compoundsⅡ, respectively.2.3 Synthesis of the target compoundsⅢandⅣ2-substituted-5-mercapto-1,3,4-thiadiazole dissolved in methol and water was treated with sodium hydroxide, then was substituted with 3-chlorophenyl- propanone to give the corresponding intermediates. Catalyzed by glacial acetic acid in alcohol media, the intermediates followed by condensation with benzoyl hydrazine (thiosemicarbazide) to give the target compounds (ⅢandⅣ).2.4 Synthesis of the target compoundsⅤOfloxacin and hydrazine hydrate refluxed in alcohol media to give hydrazide, then was condensed with Carbon disulfide in alcohol solution of potassium hydroxide under heating. Under ice-salt bath, it was cyclized in concentrated Sulfuric acid to give the intermediate thio-1,3,4-thiadiazole. The intermediate dissolved in methol and water media was treated with sodium hydroxide, then with RX to give the corresponding target compoundsⅤ.Part Three: Studies on Bioactivity of Target CompoundsThe in vitro cytotoxicity of 10 ofⅠ,ⅡandⅢcompounds against CHO and all theⅣandⅤcompounds against SMMC-7721 cell lines was evaluated by MTT assay respectively, the results showed that some of these new compounds have good antitumor activity, especially it is of greastest interest to further study antitumor properties of derivatives(Ⅴ) of 1,3,4-thiadiazole thioether with fluoroq- uinolone group. The IC50 values of compoundⅠ4,Ⅱ2 andⅢ5 on B16 cells were 15.14μM, 21.45μM and 12.06μM respectively, and coumpoundⅣ4,Ⅴ1,Ⅴ2,Ⅴ3 on SMMC-7721 cells were 18.97μM, 32.85μM, 24.65μM and 30.51μM, and all these compounds were worth futher developing candidatate drugs.