5-Amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors. Part 2. The impact of bridging groups at position C-2
| Autor: | Chih Ying Nien, Kuang Hsing Shih, Wen Yang Lai, Ching Chuan Kuo, Chi Yen Chang, Hsueh Yun Lee, Jang Yang Chang, Chun Hsein Wu, Jing Ping Liou |
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| Rok vydání: | 2011 |
| Předmět: |
Sulfide
Stereochemistry Ether Angiogenesis Inhibitors Antineoplastic Agents Sulfone chemistry.chemical_compound Structure-Activity Relationship Cell Line Tumor Drug Discovery Stilbenes Human Umbilical Vein Endothelial Cells Structure–activity relationship Humans Sulfones Cell Proliferation chemistry.chemical_classification Combretastatin Chemistry Tubulin Modulators Biological activity Drug Resistance Neoplasm Aminoquinolines Hydroxyquinolines Quinolines Molecular Medicine Amine gas treating Drug Screening Assays Antitumor Colchicine |
| Zdroj: | Journal of medicinal chemistry. 54(24) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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