Synthesize Of Novel Thymidylate Synthase Inhibitorsquinazolinone-pyrimidin Ones

The folate-dependent enzyme--thymidylate synthase(TS) plays a key role in the synthesis ofthymidine(dTMP),and dTMP is the necessary material in the synthesis and repairof DNA. Inhibition of TS can lead tothat the synthesis of tumor cells’ DNA is blocked due to lack of dTMP and that the proliferation and propagation of tumor cellsare preventted. Therefore, TS has become an important target for anticancer drugs.Since most TS inhibitors have been produce chemical resistant and strong side effects, looking for new TS inhibitors which are high selectivity, low toxicity, easy to produce drug resistance is an important way for tumor’s therapy.The purpose of this project is to synthesize quinazoline-pyrimidine ketones for the subsequent activity measurement in order to obtain a compound having good thymidylate synthase inhibitors.The paper mainly do the following work:1 Synthesis of 2-substituted-4-oxo-3(4H)–quinazoline-5-carboxylic acid: a series of 2-substituted-4-oxo-3(4H)-quinazolin-5-carboxylic acid compounds are obtained by 2-amino-6-methylbenzoic acid, which are went through the rings, oxidation reaction.This paper also optimizes the reaction conditions to yield up to 66%.2 Synthesis of 3-benzyl-5-substituted uracil compounds: 5-amino uracil is synthesized by uracil which iswent through nitration reaction, reduction reaction. Then benzyl bromide can be reacted with three kinds of 5-substituted uracils to obtain the corresponding 3-benzyl-5-substituted uracil compounds. At the same time, this paper also optimizes synthesis route, improves the reaction yield and gains valuable experience on such synthetic compounds.3 Synthesis of target compounds: using the synthesized important intermediate, this paper obtains target compound M 2-substituted-3(4H)-quinazolin-4-one-5’-methyl-5-pyrimidine-3’-benzyl-2’,4’-dione which is linked by methylene and explores the synthesis of target compound N 2-substituted-3(4H)-quinazolin-4-one-5-carboxamido-5’- pyrimidine-2’,4’-dione which is linked by amide bond. The synthesized target compound M is confirmed by means of NMR spectra. And the target compound M is in TS inhibitory activity assay now.