Design, Synthesis And Anti-Tumor Activities Of 3-Aryl-8H-Thieno[2, 3-b]Pyrrolizines

Cancer is the most common disease of badly threatening health in the world. Microtubules,which are essential for cellular integrity and cell division,represent an attractive target for cancer therapy.In this paper we focused on the biological characteristics of microtubule and advance of their inhibitors.3-Aryl-8H-thieno[2,3-b]pyrrolizin-8-one derivatives,which possessed a new tripentacyclic skeleton,were a new series of antitubulin inhibitors.They were found to display good cell growth inhibitory activity over a large panel of human tumoral cell lines.A flow cytometric study showed that treated L1210 cells were arrested in the G₂/M phases of the cell cycle.With the aim of searching for new anti-tumor agents and understanding their SARs,we designed and synthesized a novel series of 2-alkylthio/sulfinyl/sulfonyl-3-aryl-8H-thieno[2,3-b]pyrrolizin-8-oximino derivatives,focusing our attention on modifying position 2,3 and 8 on thieno[2,3-b]pyrrolizine scaffold.Total 59 novel 3-aryl-8H-thieno[2,3-b]pyrrolizines were synthesized,and their chemical structures were confirmed by IR,MS and ¹H-NMR.All the compounds have not been reported in the literature.The anti-tumor activities of these target compounds were tested by the MTT method in vitro against Bel-7402（Human Liver Cancer）,HT-1080（Human Fibro Sarcoma）,SGC-7901 （Human Gastric Cancer）and A549（Lung Cancer）cell Lines,with Cisplatin as positive control.Among them,compounds GC-18,GC-19,GC-20,GC-43,GC-44 and GC-45 were more active than or as active as Cisplatin against the four cancer cell lines,and compounds GC-12,GC-13,GC-14,GC-15,GC-16,GC-22,GC-24,GC-26 and GC-40 displayed superior or comparable activities to Cisplatin against Bel-7402,HT-1080 and A549 cell lines.The structure-activity relationships of these compounds were discussed,which would provide useful information for further study in this field.