title: 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.forename: We-Fen
authors.initials: WF
authors.lastname: Lo
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Chou
authors.forename: Chih-Hua
authors.initials: CH
authors.lastname: Tseng
authors.forename: Yia-Huei
authors.initials: YH
authors.lastname: Shiu
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Shyh-Chyun
authors.initials: SC
authors.lastname: Yang
authors.forename: Yeh-Long
authors.initials: YL
authors.lastname: Chen
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Lin
authors.affiliation: Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. tzengch@kmu.edu.tw.
authors.forename: Cherng-Chyi
authors.initials: CC
authors.lastname: Tzeng
mesh_terms: D000098:Acetophenones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C510259:1-(4-(furo(2,3-b)quinolin-4-ylamino)phenyl)ethanone; D000098:Acetophenones; D000634:Aminoquinolines; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000603608:N-(4-acetylphenyl)-N-(furo(2,3-b)quinolin-4-yl)ethylamine; C000603607:N-(4-acetylphenyl)-N-(furo(2,3-b)quinolin-4-yl)methylamine; D011804:Quinolines