| 摘要: | 在本實驗室過去之研究中，磷酸化兩個極具發展潛力之2-arylquinoline (2AQ)類緣化合物，2-(2-fluorophenyl)-6,7-methylenedioxy-quinolin-4-one (2AQ-1)及2-(3-fluorophenyl)-5-hydroxy-6-methoxy-quinolin-4-one (2AQ-2)，並使之成為抗癌之候選藥物。為了開發更多新的2AQ類緣化合物之先導化合物，並且討論其結構與活性之相互關係。本研究合成了2-selenophenylquinolin-4-one和與之相關化合物做為標的化合物，並且以血癌細胞(HL-60 cells)、 肝癌細胞(Hep 3B cells)及肺癌細胞(H460 cells)等細胞株，進行了體外抗癌活性測試。比較其結果發現， 6,7-methylenedioxy-2-(substituted selenophenyl)quinolin-4-ones (52, 55, 58 and 70)及其2號位置上改變之等價異構物thiophenyl (53, 56, 59 and 71) 與furanyl (54, 57, 60 and 72)，有著結構與活性強弱之相關性順序如下： selenophenyl 衍生物 ?l thiophenyl 衍生物 > furanyl 衍生物。另外5,6-substituted-2-(substituted selenophenyl)quinolin-4-ones (61, 63, 65, 67, 68, 75, 77, 79, 73, 74 and 81) 也有著結構與活性強弱之相關性順序如下：5-hydroxy-6-methoxy 衍生物 > 6-methoxy 衍生物 > 5,6-dimethoxy 衍生物。在所有的受測化合物中，發現6,7-methylenedioxy-2-(5- methylselenophen-2-yl)quinolin-4-one (55)被發現為最具潛力之抗癌藥劑。在NCI 60株人類腫瘤細胞活性篩選中，化合物55在人類血癌HL-60細胞株上表現出了高選擇性細胞致毒活性。此外，由COMPARE分析結果發現，化合物55雖具有抗有絲分裂活性，但其作用模式不僅與傳統之抗有絲分裂試劑如：colchicine、vincristine、vinblastine及paclitaxel等不同，甚至與2AQ-1和 2AQ-2等具有和化合物55相同骨架化合物也不相同。因此，著者確認化合物55可做為先導化合物，並值得做進一步之優化。
In our prior work, the phosphorylation of two promising lead 2-arylquinoline (2AQ) analogues, 2-(2-fluorophenyl)-6,7-methylenedioxy-quinolin-4-one (2AQ-1) and 2-(3-fluorophenyl)-5-hydroxy-6-methoxy-quinolin-4-one (2AQ-2) led to the production of two anticancer drug candidates. In order to develop additional new lead compounds among 2AQ analogues and elucidate structure-activity relationships (SAR), 2- selenophenylquinoline and related compounds were synthesized as target compounds and evaluated for in vitro anticancer activity against HL-60, Hep 3B, and H460 cancer cell lines. Comparison of the 6,7-methylenedioxy-2- (substituted selenophenyl)quinolin-4-ones (52, 55, 58 and 70), with their thiophenyl (53, 56, 59 and 71) and furanyl isosteres (54, 57, 60 and 72) gave the following rank order of potency: selenophenyl derivatives ?l thiophenyl derivatives > furanyl derivatives. The anticancer activity of 5,6-substituted-2-(substituted selenophenyl)quinolin-4-ones (61, 63, 65, 67, 68, 75, 77, 79, 73, 74 and 81) was ranked in the following order: 5-hydroxy-6-methoxy derivatives > 6-methoxy derivatives > 5,6-dimethoxy derivatives. Among all tested compounds, 6,7-methylenedioxy-2-(5- methylselenophen-2-yl)quinolin-4-one (55) was found to be the most promising anticancer agent. In screening against NCI’s 60 human tumor cell line panel, compound 55 exhibited highly selective cytotoxicity activity against HL-60 leukemia. Furthermore, the results of COMPARE analysis suggested that 55 is an antimitotic agent with a different mechanism of action not only from the conventional antimitotic agents, such as colchicine, vincristine、vinblastine and paclitaxel, but also from 2AQ-1 and 2AQ-2, which have the same quinolin-4-one scaffold as 55. Therefore, compound 55 was identified as a new lead compound that merits further optimization. |
