Discovery of Novel N-alkyl 4-anilinofuro[2,3-b]quinoline Derivatives (CIL-102 Derivatives) Against Castration-resistant Human Prostate Cancers.

A number of N-alkylated 4-anilinofuro[2,3- b ]quinoline derivatives were synthesized and evaluated in vitro against PC-3, A549, and MCF-7 cancer cells and M-10 normal human mammary epithelial cells. The known antimitotic CIL-102 was moderately active against the growth of PC-3 prostate cancer cells with an IC 50 value of 2.69 μM while it was more potent against the growth of A549, MCF-7 and M-10 cells with IC 50 values of 0.61, 0.31 and 0.95 μM, respectively. However, the cytotoxic profiles of its N-alkylated derivatives, 6a - 6c, were reversed and strongly inhibited PC-3 cell growth with IC 50 values of less than 1.0 μM but only weakly against the growth of A549, MCF-7 and M-10 cells. These results indicated that N -alkylation of CIL-102 increased not only selectivity but also the antiproliferative potency against PC-3 cell growth. Among these derivatives synthesized, N -(4-acetylphenyl)- N -(furo[2,3- b ]quinolin- 4-yl)methylamine (6a) and its N -ethyl counterpart 6b are the two most active CIL-102 derivatives against PC-3 cell growth with IC50 value of 0.22 and 0.20 μM, respectively. Compound 6a is less cytotoxic to normal human M-10 cells than 6b and therefore was selected for further mechanism studies. The flow cytometry studies clearly indicated that compound 6a induced cell accumulation in G2/M phase in a dose-dependent manner after 24 h-treatment. While the proliferation of LNCaP C-81 prostate cancer cells was also strongly suppressed by compound 6a; compound 11a exhibited better selective activity toward LNCaP C-81 prostate cancer cells over RWPE-1 non-cancerous prostate epithelia. Thus, this group of compounds has a potential of serving as therapeutic agents toward advanced castration-resistant prostate cancers.