Discovery of novel N-alkyl 4-anilinofuro[2,3-b]quinoline derivatives (CIL-102 derivatives) against castration-resistant human prostate cancers

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 IC50value of 2.69 μM; while it was more potent against the growth of A549, MCF-7 and M-10 cells with IC50values 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 IC50values 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 IC50value 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.

Original languageEnglish (US)
Pages (from-to)493-500
Number of pages8
JournalAnti-Cancer Agents in Medicinal Chemistry
Volume15
Issue number4
DOIs
StatePublished - May 1 2015

Fingerprint

Castration
Prostatic Neoplasms
Growth
1-(4-(furo(2,3-b)quinolin-4-ylamino)phenyl)ethanone
quinoline
Antimitotic Agents
G2 Phase
MCF-7 Cells
Alkylation
Cell Division
Prostate
Flow Cytometry
Breast
Epithelium
Epithelial Cells

Keywords

  • Anticancer activity
  • CIL-102
  • LNCaP C-81
  • N-alkylated 4-anilinofuro[2,3-b]quinoline derivatives
  • PC-3

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Cancer Research

Cite this

Discovery of novel N-alkyl 4-anilinofuro[2,3-b]quinoline derivatives (CIL-102 derivatives) against castration-resistant human prostate cancers. / Lo, We Fen; Chou, Yu Wei; Tseng, Chih Hua; Shiu, Yia Huei; Chen, Yu Wen; Yang, Shyh Chyun; Chen, Yeh Long; Lin, Ming-Fong; Tzeng, Cherng Chyi.

In: Anti-Cancer Agents in Medicinal Chemistry, Vol. 15, No. 4, 01.05.2015, p. 493-500.

Research output: Contribution to journalArticle

Lo, We Fen ; Chou, Yu Wei ; Tseng, Chih Hua ; Shiu, Yia Huei ; Chen, Yu Wen ; Yang, Shyh Chyun ; Chen, Yeh Long ; Lin, Ming-Fong ; Tzeng, Cherng Chyi. / Discovery of novel N-alkyl 4-anilinofuro[2,3-b]quinoline derivatives (CIL-102 derivatives) against castration-resistant human prostate cancers. In: Anti-Cancer Agents in Medicinal Chemistry. 2015 ; Vol. 15, No. 4. pp. 493-500.
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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 IC50value of 2.69 μM; while it was more potent against the growth of A549, MCF-7 and M-10 cells with IC50values 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 IC50values 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 IC50value 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.",
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