Study On The Design, Synthesis And Antitumor Activity Of 4,5 - Diaryl - 3H - 1,2 - Dithiol - 3 - Thione Compounds And Their Derivatives

Natural stilbenoids,including Combretastatin A-4,were found to be tubulin polymerization inhibitors and display strong anfimitotic activity to a broad spectrum of human cancer lines.For the purpose of searching for novel antitumor agents,through 3D-QSAR study,three series of heterocyclic compounds(4,5-Diaryl-3H-1,2-dithiole-3-thione,-one,-oxime derivatives),known as the analogues of Combretastafin A-4,were designed and synthesized.Retro-synthetic analyses of the target compounds led to two kinds of important intermediates ethyl 2-aryl-acetate(ethyl 2-(3,4,5-trimethoxyphenyl)acetate and ethyl 2-(naph thalen-1-yl)acetate)and substituted benzoyl chlorides.Using 3,4,5- trimethoxy benzaldehyde as the starting material,via reduction and chlorination et al.,an important intermediate ethyl 2-(3,4,5-trimethoxyphenyl)acetate was obtained with an overall yield 49.6%.The substituted benzoyl chlorides could be synthesized from substituted benzoic acids or substituted benzaldehyde.Treatment of these two kinds of intermediates with LDA led to the formation of ethyl 3-oxo-2,3-diarylpropanoate.By cyclization with phosphorus pentasulfide and followed by oxidation or reacted with hydroxylamines,4,5-Diaryt-3H-1,2-dithiole-3-thione,-one,-oxime derivatives were obtained.In summary,the first synthesis of ninteen novel 4,5-Diaryl-3H-1,2-dithiole-3-thione,-one, -oxime derivatives,Combretastatin A-4 analogues had been achieved.The target compounds were characterized by ~1H-NMR,MS.The in vitro antitumor activities of these compounds were tested and some of the compounds were found to show potent antitumor activities.