Design And Synthesis Of Novel Thymidylate Synthetase Inhibitor

Thymidylate synthase (TS), as a folate-dependent enzyme, is essential to cell proliferation since it is the key enzyme which catalyzes the synthesis of thymidine (dTMP) of DNA precursor. Inhibition of TS can inhibit the biosynthesis of DNA, then, inhibit tumor cell proliferation and growth. Consequently, TS is a hot target in cancer chemotherapy. Inhibitor of TS is an important direction of anticancer research.The objective of this research is to design and synthesize of novel thymidylate synthase inhibitors, and obtain some compounds that have relatively activity and possess independent intellectual property rights by means of screening, for further activity. Achievement of this research is as follows:1 A theoretical study of the molecular mechanism of the thymidylate synthase catalyzed reaction was carried out by molecular mechanics and quantum chemistry. The intermediates and transition states for the multistep enzymatic process were optimized. The binding way of 2'-deoxyuridine-5'-monophosphate (dUMP) and the iminium ion 5-methelyl tetrahydrofolic acid forming intermediate was found. The feasibility of the whole intermediate serving as design template was analyzed. AQPs, new chemical entities, regarded as TS double substrate inhibitors were designed, formed a virtual compound library.2 The docking of novel TS double substrate inhibitors to human thymidylate synthase was performed by DOCK6.0, as molecular docking software. The result of the docking was analyzed to select 10 high activity compounds. The situation of the inhibitor molecules and receptor binding sites was analyzed.3 2,6-Dimethyl-3,4-dihydro-4-oxo-quinazoline, as the key intermediate for the synthesis of thymidylate synthase inhibitor Raltitrexed and its derivatives, was synthesized from p-toluidine through addition, oxidation, hydrolysis and bromination. The synthesis process was improved. Relevant experience of synthesizing thymidylate synthase inhibitor was accumulated.4 The synthetic route to the designed thymidylate synthase inhibitor molecule aa was explored by analysis of reverse reaction. The total synthesis of 4-butyrate isatin, the key intermediate for the synthesis of thymidylate synthase inhibitor aa, was completed from benzene via 7 steps such as Friedel-Crafts acylation, nitration, esterification, reduction of nitro, carbonyl reduction, reduced synthesis of oxime and closed-loop into isatin. The synthesis process and the yield of every step were improved. All compounds were confirmed by 1HNMR.5 The synthetic route to the designed thymidylate synthase inhibitor molecule ag was explored. The synthesis of ASOC, the key intermediate for the synthesis of thymidylate synthase inhibitor ag, was completed from paracetamol via methylation, Friedel-Crafts acylation and hydrolysis reaction. The synthesis process and the yield of every step were improved. All compounds were confirmed by 1HNMR.