Studies On The Design, Synthesis And Antitumor Activities Of Spirocyclic Oxazaindole Derivatives

Spirocyclic oxazaindole is one of the most important spiro-heterocyclic compounds with a broad range of antitumor, antianxiety, antiinflammatory and antihypertensive activities. Recently, it has aroused extensive concern in pharmacy and chemistry field. In order to find new antitumor lead compounds, we designed and synthesized the spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]- 2'(l'H)-one and its library, and studied their anti-tumor activities.The synthetic scheme of the spirocyclic oxazaindole compound named spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one was derived from retrosynthesis method. Using commercial available cheap nicotinic acid as starting material, (2-chloropyridin-3-yl) methanol was obtained after successively oxidized by hydrogen peroxide, chlorinated by phosphorus oxchloride and reduced by sodium borohydride. Then, 2-(2-chloropyridin-3-yl) acetonitrile was synthetized by chlorinating with thionyl chloride and substituting with cyanide anion. After dialkylation with dichloroethylamine, hydrolysation of the cyano group to carboxylic amide and cyclization under Buchwald-Hartwig condition and finally deprotection of the protective group, the spiro[piperidine-4,3'-pyrroIo[2,3-b]pyridin] -2'(l'H)-one was obtained in 15% total yield after nine steps. With minor alternation of the synthetic route, we also synthesized another spirocyclic azazindole analogue, 7-aza-spiro [indoline-3, 4'-piperidine]. According to the literature information of similar analogues, we designed a spirocyclic oxazaindole compound library based on the synthesized compounds. The library compounds were synthesized using twelve representative substituents including aliphatic, aromatic and heterocyclic functional groups by reductive amination reaction.The antitumor activities of all the derivatives were studied against human lung cancer cell A549, human liver cancer cell BEL7402 and human colon cancer cells HCT-8. The results showed that some spirocyclic oxazaindole compounds have little inhibitory activity on human liver cancer cell BEL7402 and on human colon cancer cells HCT-8. To some extent, the derivative containing trifluoromethoxy-substituted aromatic ring may inhibit tumor cell proliferation on cancer cell. Some compounds with furyl group, thienyl group, cyclohexane group and 3 - fluoro-based - 4 -methyl-substituted benzene ring on the tumor cells also have anti-tumor activity. The antitumor activity study is still ongoing in our laboratory. A preliminary study of this compounds' structure-activity relationship was discussed. This work is significant for designing, synthesizing novel and effective anti-tumor spirocyclic oxazaindole compounds and searching leading compounds in drug discovery.