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

Abstract

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 IC50 value of 2.69 μM 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 μM, 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 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.

• Authors: We-Fen Lo, Yu-Wei Chou, Chih-Hua Tseng, Yia-Huei Shiu, Yu-Wen Chen, Shyh-Chyun Yang, Yeh-Long Chen, Ming-Fong Lin, Cherng-Chyi Tzeng
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 15 Issue 4 Pg. 493-500 ( 2015) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 25612680 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(4-(furo(2,3-b)quinolin-4-ylamino)phenyl)ethanone
• Acetophenones
• Aminoquinolines
• Aniline Compounds
• Antineoplastic Agents
• N-(4-acetylphenyl)-N-(furo(2,3-b)quinolin-4-yl)ethylamine
• N-(4-acetylphenyl)-N-(furo(2,3-b)quinolin-4-yl)methylamine
• Quinolines

Topics

• Acetophenones (chemical synthesis, chemistry, pharmacology)
• Aminoquinolines (chemical synthesis, chemistry, pharmacology)
• Aniline Compounds (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Humans
• Male
• Prostatic Neoplasms, Castration-Resistant (pathology)
• Quinolines (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship