In an attempt to improve anti-breast cancer activity, a new series of 4-piperazinylquinoline derivatives based on the urea/thiourea scaffold were designed and synthesised by a pharmacophore hybrid approach. We then examined for their antiproliferative effects on three human breast tumor cell lines, MDA-MB231, MDA-MB468 and MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Among those 26 novel compounds examined, 5, 9, 17, 18, 21, 23 and 29 showed significantly improved antiproliferative activity on breast cancer cells. Compound 23 (4-(7-chloro-quinolin-4-yl)-piperazine-1-carbothioic acid (2-morpholin-4-yl-ethyl)-amide) (RL-15) is especially desirable, since its antigrowth/cell-killing activity is 7-11 fold higher on cancer than non-cancer cells. Data from cell biological studies demonstrated that cancer cells compromised plasma membrane integrity in the presence of compound 23. The cancer cell-specific property of compound 23 shown in cell culture stands in vivo test, this compound can be an excellent lead for effective and safe anticancer drug.
Keywords: 4-Aminoquinoline; anticancer agents; pharmacophore approach; repurposing; thiourea; urea.