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

Author(s):

We-Fen Lo, Yu-Wei Chou, Chih-Hua Tseng, Yia-Huei Shiu, Yu-Wen Chen, Shyh-Chyun Yang, Yeh-Long Chen, Ming-Fong Lin and Cherng-Chyi Tzeng   Pages 493 - 500 ( 8 )

Abstract:

A number of N-alkylated 4-anilinofuro[2,3-<i>b</i>]quinoline derivatives were synthesized and evaluated <i>in vitro</i> 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 IC₅₀ value of 2.69 &#956;M while it was more potent against the growth of A549, MCF-7 and M-10 cells with IC₅₀ values of 0.61, 0.31 and 0.95 &#956;M, respectively. However, the cytotoxic profiles of its N-alkylated derivatives, 6a - 6c, were reversed and strongly inhibited PC-3 cell growth with IC₅₀ values of less than 1.0 &#956;M but only weakly against the growth of A549, MCF-7 and M-10 cells. These results indicated that <i>N</i>-alkylation of CIL-102 increased not only selectivity but also the antiproliferative potency against PC-3 cell growth. Among these derivatives synthesized, <i>N</i>-(4-acetylphenyl)-<i>N</i>-(furo[2,3-<i>b</i>]quinolin- 4-yl)methylamine (6a) and its <i>N</i>-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 &#956;M, 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.

Keywords:

Anticancer activity, CIL-102, LNCaP C-81, <i>N</i>-alkylated 4-anilinofuro[2,3-<i>b</i>]quinoline derivatives, PC-3.

Affiliation:

, , , , , , , , Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.

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