Study On Synthesis Of 3, 6-Dialkyl-s-Tetrazine Derivatives And Their Structure-Activity Relationships Of Anti-tumor

Cancer is one of the most dangerous diseases that endanger human beings. And it is one of the main fields of new drug research to seek for a new antitumor drug, which has higher activity and lower toxicily. This dissertation includes the following aspects such as:(1). The synthesis of 3.6-dialkyl-hexahydro-s-tetrazinc and its derivatives was studied. Four hexahydro-s-tetrazines and its four 1,4-diacyl derivatives were synthesized and the reaction mechanism was proposed. By the aid of X-ray, the structure of the 1,4-diacyl derivatives was confirmed. The compound of 3,6-diaryl-hexahydro-s-tetrazine, however, could not be obtained from the reaction of azine with hydrazine..(2), Using Pd/C as dehydrogenation catalyst in stead of expensive PtO2. it provides a convenient method to prepare 1.6-dihydro-s-lclrazine with medium yield. Many derivatives of 1,6-dihydro-s-tetrazine, more than 40, were synthesized via the reaction of 1,6-dihydro-s-tetrazine with chloride formate, substituted phenyl isocyanate and anhydride respectively in the presence of pyridine as catalyst. The 1HNMR spectra of 3,6-dialkyl-1.6-dihydro-s-tetrazine-l-carbonate derivatives were discussed, and the molecular structures of two compounds were determined by X-ray. All these compounds have homoaromativity.(3). In the presence of DMAP, N,N' -disubstituted - 3,6 - dialkyl - 1,4 - dihydro - s - tetrazine - 1,4 - dicarboamides were synthesized by two routes. All structures of these compounds were confirmed by IR, NMR, MS, Elemental Analysis and four of them were determined by X-ray. It was found that those four compounds showed a boat conformation and no bomoaromativity.(4), By the aid of the HPLC,UV and NMR, it was found that under the effect of DMAP, the 1,6-dihydro-s-tetrazine could rearrange. The mechanism of the reaction forming the disubstituted derivatives was briefly discussed.(5). The antitumor activity in vitro of most prepared compounds was screened.The relationships between the structure and the activity of anti-cancer of s-tetrazine derivatives were briefly discussed. The IC50 and LD50 of compound A. which has good activity in vitro, were measured. And it was found that compound A has higher antitumor activity and lower toxicity than 5-Fu.(6). By the way, the pest activity of some compounds was screened, and it was found that some of them had good herbicide activity.