Preferred Quinazoline 2,4 - Diketone And 4h-1, 4 - Benzodiazepine (?) -2 - Ketone Derivatives Synthesis And Antitumor Activity

Previliged structures are molecule skeletons that can be derived to react with a variety of receptors with high affinity. Advantages of the ideal previliged structures should meet the following criteria:1) they are rigid molecular scaffolds that can introduce different functional groups; 2) they have different biological activity by reacting with different targets; 3) they have low molecular weight; 4) they can be further optimized to improve selectivity and activity. The introduction of the concept of previliged structure is greatly solved the problem which is usually concerned by medicinal chemists in the design of compound libraries:what kind of skeleton should be chose for synthesis?In this thesis, we had exployed the synthetic routes of two kinds of previliged structures:quinazoline-2,4-diones and 4H-1,4-benzodiapin-2-ones. We also studied the anti-tumor biological activity of quinazoline-2,4-diones.Quinazoline-2,4-diones were synthesized by using 5-chloro-2,4-dinitrobenzoic acid as the starting material. The chlorine atom of 5-chloro-2,4-dinitrobenzoic acid was first replaced by nucleophilic reagents; and then the carboxyl acid group was converted into chloride, followed by condensation with primary amines. The remaining two nitro groups of 5- and N-disubstituted-2,4-dinitrobenzamieds were reduced to offer 5- and N-disubstituted-2,4-diaminobenzoic acid that were cyclized with triphosgene to construct quinazoline-2,4-diones. The amino group was reacted to gain the final product. The method developed in the thesis is over the advantages of mild reaction conditions, short reaction time and high yield that enable us to synthesize 106 quinazoline-2,4-diones.Fifty-one compounds were screened by NCI 60 human tumor cell lines program. Nineteen compounds were positively indicated for their antitumor activities. Five of them including 113 (lgGI50=-6.1),122(lgGI50=-6.13),136 (lgGI50=-6.44),144 (lgGI50=-639),173 (lgGI50=-6.45) significantly inhibited tumor cell growth in vitro.The preliminary structure-activity relationship was analyzed. Firstly, the chloro-substituted phenethyl urea is the necessary substituent at 7-position of quinazolin-2,4-dione, and 2-chlorophenyl ethyl urea achieved the optimal activity. Secondly, the SAR of the 3-position shows that:chloride substituded phenylethyl achieved the best pontentcy; and when 6-position was substituted by 1-methylpiperazine, the 3-position substituted groups,2-(benzo[d][1,3]dioxol-5-yl)ethyl,1-methyl benzyl and 4-fluorobenzyl were better than the phenyl, methyl and hydrogen. Thirdly, methoxy and 1-methylpiperazine for the substitution of the 6-position may had better activity than other groups. Finally, the quinazolin-2,4-dione scaffold could be replaced by 2H-benzo[b][1,4]thiazin- 3(4H)-ones.This paper presents a new route to construct the 4H -1,4- benzodiazepines-2-ones by using 2-nitro-benzaldehyde, amino acid methyl ester hydrochloride salt, acid and isocyanide as the starting materials. To synthesis the target structure, the Ugi reaction product should be prepared as a intermediant, followed by palladium carbon/H2 reduction; after the ester of reduction product was hydrolysis by LiOH, the amide bond was formed by condensation. This method creatively introduced the Ugi reaction to prepare the 4H-1, 4- benzodiazepines-2-ones skeleton. Ugi reaction introduced four diversities in one-time to achieve large diversity of derivatives. Eleven new 4H-1,4-benzodiazepines-2-one derivatives were synthesized by using this methodWe also synthesized a novel derivative structure of 2,3-dihydrobenzo[f]pyrazino [1,2-d][1,4]diazepine-1,4,7 (6H,8H,12bH)-trione by using 2-nitro-benzaldehyde, amino acid methyl ester hydrochloride,2-chloroacetic acid and isocyanide as the starting materials. This kind of compounds had not been reported yet. This route possesses the features of good versatility and mild react condition. By using this method, derivatives of these compounds could be fast and efficiently synthesized in one-pot. Four new compounds were prepared by using this method.