Design,Synthesis And Antiproliferative Activity Studies On 2,4-disubstituted Pyrimidine Fused Heterocyclic Derivatives

Cancer is one of the most common fatal diseases, which death rate ranks only second to cardiovascular disease. Throughout, the development of anticancer drugs has been a concern. Up to date, there are many anti-cancer agents with fused heterocycle structures (such as purine and quinazoline) have been used in the market or in clinical trials. Fused heterocyclic skeleton plays an important role in the design and development of anti-cancer drugs. Wherein pyrimidine fused heterocyclic derivatives (such as quinoline derivatives, pyrido[2,3-d]pyrimidine derivatives) as an important part of fused heterocyclic also play an important role in the design and development of anti-cancer drugs.Quinoline and pyrido[2,3-d]pyrimidine derivatives play an important role in the design of biologically active molecules. Wherein the quinoline derivative has been used as dihydrofolate reductase inhibitors, epidermal growth factor receptor inhibitors, Src kinase inhibitors, vascular endothelial growth factor receptor inhibitors, platelet-derived growth factor receptor inhibitors and Aurora kinase inhibitors etc. The pyrido [2,3-d] pyrimidine derivatives have also been the inhibitor of rapamycin kinase, cyclin-dependent kinase.In this paper, we designed and synthesized a series of quinoline and pyrido[2,3-d]pyrimidine derivatives and tested their anti-tumor activity. Forty four new compounds were synthesized including 39 new targets and 5 new intermediate compounds. The structures of all new compounds have been identified by 1H-NMR, 13C-NMR and (or) HRMS.The target compounds were performed biological evaluation for their anti-proliferative activities against Hela or HT29 cell. The results indicated that some of the compounds showed potent inhibitory activity to human cancer cells. For quinazoline derivative, introducing 3-nitrophenyl, thiophen-3-yl and thiophen-2-yl on C4 position decreased antiproliferative activitivies. Attaching nitro or morpholino on aniline on C2 position didn’t show better inhibition on tumor cell growth. On the other hand, compounds with aniline and 4-methyl aniline on C2 position, furan-2-yl on C4 position exhibit better the antiproliferative activity. Among of them, compound 4u and 4v showed best inhibition on Hela cell. Other turmor cells, such as A549 and MCF-7 cells, also have been used to evaluated the antiproliferative activities for compounds 4u and 4v, but the result showed not good as Hela cell.For pyrido[2,3-d]pyrimidine derivatives, introducing aromatic ring, thiophen-3-yl, thiophen-2-yl and furan-2-yl group on C4 position decreased the inhibitory activities against HT29 cells. When introducing an aromatic benzylamine on C4 position, inhibitory activity against HT29 cells was significantly increased. Representative compounds showed better inhibitory activity against HT29, A549 and PC-3 cell lines than Roscovitine. Wherein the compound 11e showed the best antiproliferative activity, which was 6-7 times than Roscovitine.