Cyclohexan-1,3-dione (1) reacted with either 2-aminoprop-1-ene-1,1,3-tricarbonitrile (2a) or diethyl 3-amino-2-cyanopent-2-enedioate (2b) to give the 5,6,7,8-tetrahydronaphthalene derivatives 3a and 3b, respectively. The latter compounds underwent further heterocyclization reactions to give the thieno[2',3':5,6]benzo[1,2-e][1,3]oxazine derivatives. On the other hand, the reaction of compound 1 with trichloroacetonitrile afforded the (2,2,2-trichloroethylidene)cyclohexane derivative 14. The latter underwent a series of reactions to produce 2,3,6,7-tetrahydroquinazoline, dihydrothieno[2,3-h]isoquinoline, octahydrobenzo[h]quinazoline and dihydrothieno[2,3-h]isoquinoline derivatives. The synthesized compounds were tested toward six cancer cell lines where most of them gave high inhibitions with c-Met enzymatic activity, with tyrosine kinases and Pim-1 inhibitions. The results obtained will encourage further work through such compounds to produce optimized anticancer agents.
Keywords: Cyclohexan-1,3-dione; cytotoxicity; isoquinoline; quinoline; trichloroacetonitrile.