Synthesis Of Thymidylate Synthase Inhibitors-nolatrexed And Its Analogues

Nolatrexed (Fig. 1) is a potent, water soluble, non-classical TS inhibitor, whose design was based on crystal structures of quinazoline derivatives liganded to E. coli TS at the folate cofactor site. Its structural formula was showed in Figure 1. This pharmacal molecule has strong antiproliferation both in vivo and in vitro, especially good for liver cancer. In addition, this medicine can be taken orally and be absorbed efficiently, but has little side effect. At present, It has entered phase III clinical trials. If Nolatrexed was warranted by FDA, it would be the first clinical medicament for liver cancer. It reveals extremely fantastic research prospect.The work was composed of two parts: For one thing, a new synthetic method for Nolatrexed was deeply studied aimed at lower cost, more conventient operation and suitable industrialization. Then we got the pure Nolatrexed. The yield of our route is 9.5%, higher than hose described in the literatures. For another, the activity-structure relationships of classical or nonclassical TS inhibitors indicate: there are some groups responsible for TS inhibition in those present TS inhibitors including the plane strcture of bicyclic-ring systems, the lone pair of Nland H-bonding between H₂O·430, as well as the aromatic moiety at C-5. At the same time, the results of computer-assisted pharmaceutical design showed that the thiopyridine moiety at C-5 and C-6-methyl group is necessary for the inhibition activity of Nolatrexed. Thus, we retained the essential parts described upon for TS inhibition and designed two kinds of mother-structures. Then ten compounds were synthesized of which two were de-novo. Their structures were determined by IR,¹HNMR and MS spectra. Assays in vitro were conducted in CEM cells to mensurate the inhibition of these derivatives.