title: 5-Amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors. Part 2. The impact of bridging groups at position C-2.
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 IC50 values of 42 and 12 nM, respectively. 15 inhibited the tubulin polymerization with an IC50 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 IC50 values of 3.4 nM and microtubule destabilizing potency with an IC50 of 1.5 μM, comparable to that of CA4 (IC50=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 IC50 values of 6.7 and 2.6 nM, respectively.
authors: School of Pharmacy, College of Pharmacy, Taipei Medical University, and Department of Obstetrics and Gynecology, Cheng Hsin General Hospital, 250 Wuxing Street, Taipei 11031, Taiwan, Republic of China.
authors: Hsueh-Yun
authors: HY
authors: Lee
authors: Jang-Yang
authors: JY
authors: Chang
authors: Chih-Ying
authors: CY
authors: Nien
authors: Ching-Chuan
authors: CC
authors: Kuo
authors: Kuang-Hsing
authors: KH
authors: Shih
authors: Chun-Hsein
authors: CH
authors: Wu
authors: Chi-Yen
authors: CY
authors: Chang
authors: Wen-Yang
authors: WY
authors: Lai
authors: Jing-Ping
authors: JP
authors: Liou
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C570538:5-amino-6-methoxy-2-(3',4',5'-trimethoxyphenylsulfonyl)quinoline; C570537:5-hydroxy-6-methoxy-2-(3',4',5'-trimethoxybenzoyl)quinoline; D000634:Aminoquinolines; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006912:Hydroxyquinolines; D011804:Quinolines; D013267:Stilbenes; D013450:Sulfones; D050257:Tubulin Modulators; C058728:fosbretabulin; D003078:Colchicine