Design, synthesis and characterization of novel quinacrine analogs that preferentially kill cancer over non-cancer cells through the down-regulation of Bcl-2 and up-regulation of Bax and Bad

Both quinacrine, which contains a 9-aminoacridine scaffold, and thiazolidin-4-one are promising Anticancer leads. In an attempt to develop effective and potentially safe Anticancer agents, we synthesized 23 novel hybrid compounds by linking the main structural unit of the 9-aminoacridine ring with the thiazolidin-4-one ring system, followed by examination of their Anticancer effects against three human breast tumor cell lines and matching non-cancer cells. Most of the hybrid compounds showed good activities, and many of them possessed the preferential killing property against Cancer over non-cancer cells. In particular, 3-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-2-(2,6-difluoro-phenyl)-thiazolidin-4-one (11; VR118) effectively killed/inhibited proliferation of Cancer cells at IC₅₀ values in the range of 1.2-2.4 μM. Furthermore, unlike quinacrine or cisplatin, compound 11 showed strong selectivity for Cancer cell killing, as it could kill Cancer cells 7.6-fold (MDA-MB231 vs MCF10A) to 14.7-fold (MCF7 vs MCF10A) more effectively than matching non-cancer cells. Data from flow cytometry, TUNEL and Western blot assays showed that compound 11 kills Cancer cells by Apoptosis through the down-regulation of Bcl-2 (but not Bcl-X_L) survival protein and up-regulation of Bad and Bax pro-apoptotic proteins. Thus, compound 11 is a highly promising lead for an effective and potentially Anticancer therapy.

9-aminoacridine; Anticancer agents; Apoptosis; Hybrid approach; Quinacrine; Thiazolidin-4-one.