Design, Synthesis And Antitumor Activity Research Of Novel Tricyclic Higher Carbon Sugar Nucleoside Analogues

Nucleoside drugs paly an important role in antimumor therapy field, there are some problems to overcome, such as drug resistance and toxicity. It is still a significant research in medicinal chemistry and related field to find high-efficiency antitumor nucleoside drugs.A structurally unique C10 higher carbon sugar was synthesized by using cheap and available natural product D-xylose as the starting material, a series of novel bis-nucleobases CIO higher carbon sugar deoxynucleosides were designed and synthesized. Another series of 1,2,3-triazole nucleosides were synthesized, and their biological activity have been evaluated in human cancer cell lines (SMCC-7721, MGC-803 and A549). The detailed works was described as follows:1. The key intermediate 5 was prepared from D-xylose under five steps and the synthesis and purification method of each reaction step were optimized. This route has the advantages of easy purification and relatively high yield. So this new method is more suitable for scale-up production.2. C10 higher carbon sugar 7 was dehydroxylated from compound 5, and then developed bis-pyrimidine tricyclic nucleosides via vorbruggen reaction with SnCl4 as the catalyst.3. A series of novel triazole nucleosides 14 have been synthesized through Click reaction, and the antitumor activity were tested. Compound 14e showed good activity at a level of IC50=1.822μM against MGC-803 cell lines.In summary, C10 higher carbon sugar with special tricyclic structure was synthesized with optimized method; and two series of novel higher carbon sugar nucleoside analogues were designed, synthesized and evaluated. The antitumor activity of 1,2,3-triazole nucleoside analogues were tested, compound 14b-14h showed good antitumor activity against MGC-803 cell lines.