5-Amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors. Part 2. The impact of bridging groups at position C-2

Hsueh Yun Lee, Jang Yang Chang, Chih Ying Nien, Ching Chuan Kuo, Kuang Hsing Shih, Chun Hsein Wu, Chi Yen Chang, Wen Yang Lai, Jing Ping Liou

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Abstract

A variety of studies on the modification of combretastatin A-4 triggered our interest in the impact of the linkers between the 3,4,5-trimethoxyphenyl ring and 5-amino-6-methoxyquinoline on biological activity. The replacement of the carbonyl group with bond, amine, ether, sulfide, and sulfone groups was evaluated in this study. The results showed that compounds 14 and 15 containing sulfide and sulfone groups between the 3,4,5-trimethoxyphenyl ring (A-ring) and 5-amino-6-methoxyquinoline exhibited substantial antiproliferative activity against KB, HT29, and MKN45 cells with mean IC 50 values of 42 and 12 nM, respectively. 15 inhibited the tubulin polymerization with an IC 50 value of 2.0 μM, similar to that with CA4. The continued work on the C-5 substituents of 3′,4′,5′-trimethoxybenzoyl-6- methoxyquinoline derivatives demonstrated that compound 7 possessing OH at C-5 exhibited excellent antiproliferative activity with mean IC 50 values of 3.4 nM and microtubule destabilizing potency with an IC 50 of 1.5 μM, comparable to that of CA4 (IC 50 = 1.9 μM). It also exhibited substantial vascular disrupting effects. Compounds 7 and 15 exhibited significant efficacy against MDR/MRP-related drug-resistant cell lines (KB-vin10, KB-S15, and KB-7D) with mean IC 50 values of 6.7 and 2.6 nM, respectively. (Figure presented)

Original languageEnglish
Pages (from-to)8517-8525
Number of pages9
JournalJournal of Medicinal Chemistry
Volume54
Issue number24
DOIs
Publication statusPublished - Dec 22 2011

Fingerprint

Tubulin Modulators
Sulfones
Sulfides
HT29 Cells
Tubulin
Microtubules
Polymerization
Ether
Amines
Blood Vessels
Cell Line
Pharmaceutical Preparations
6-methoxyquinoline

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

5-Amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors. Part 2. The impact of bridging groups at position C-2. / Lee, Hsueh Yun; Chang, Jang Yang; Nien, Chih Ying; Kuo, Ching Chuan; Shih, Kuang Hsing; Wu, Chun Hsein; Chang, Chi Yen; Lai, Wen Yang; Liou, Jing Ping.

In: Journal of Medicinal Chemistry, Vol. 54, No. 24, 22.12.2011, p. 8517-8525.

Research output: Contribution to journalArticle

Lee, Hsueh Yun ; Chang, Jang Yang ; Nien, Chih Ying ; Kuo, Ching Chuan ; Shih, Kuang Hsing ; Wu, Chun Hsein ; Chang, Chi Yen ; Lai, Wen Yang ; Liou, Jing Ping. / 5-Amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors. Part 2. The impact of bridging groups at position C-2. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 24. pp. 8517-8525.
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