2-苯乙烯喹啉及2-呋喃乙烯喹啉類衍生物之合成及抗增生活性的評估

Synthesis and Antiproliferative Evaluations of 2-Phenylvinylquinoline (2-Styrylquinoline) and 2-Furanylvinylquinoline Derivatives

張峯碩(Feng-Shuo Chang)

指導教授 ： 曾誠齊

共同指導教授 ： 陳義龍(Yeh-Long Chen)

高雄醫學大學/生命科學院/醫藥暨應用化學研究所/博士(2010年)

摘要

我們合成出一系列的2-phenylvinylquinoline (styrylquinoline) 和 2-furanylvinylquinoline 衍生物，發現(E)-2-styrylquinolin-8-ol (4)對MCF-7 (Breast), NCI-H460 (Lung), and SF-268 (CNS)沒有任何活性。但當我們將苯環取代為5-nitrofuran-2-yl的雜環時，明顯地提升抗細胞增生的活性。特別是(E)-2-(2-(5-nitrofuran-2-yl)vinyl)quinolin-8-ol (23i)及其4位上的苯胺取代的(E)-1-{4-{2-[2-(5-Nitrofuran-2-yl)-
vinyl]quinolin-4-ylamino}phenyl}ethanone hydrochloride (40a), (E)-1-{3-{2-[2-(5-Nitrofuran-2-yl)vinyl]quinolin-4-ylamino}phenyl}ethanone hydrochloride (40b), (E)-1-{4-{2-[(E)-2-(5-nitrofuran-2-yl)vinyl]
quinolin-4-ylamino}phenyl}ethanone oxime hydrochloride (41a), (E)-1-{3-{2-[(E)-2-(5-nitrofuran-2-yl)vinyl]quinolin-4-ylamino}phenyl}ethanone oxime hydrochloride (41b), (E)-1-{4-{2-[(E)-2-(5-nitro-
furan-2-yl)vinyl]quinolin-4-ylamino}phenyl}ethanone O-methyl oxime hydrochloride(42a), (E)-1-{3-{2-[(E)-2-(5-nitrofuran-
2-yl)vinyl]quinolin-4-ylamino}phenyl}ethanone O-methyl oxime hydrochloride (42b)，對於MCF-7, LNCaP, 和PC-3都有不錯的生物活性而且oxime的衍生物中，氫鍵的提供者(E)-1-{4-{2-[(E)-2-(5-nitro-
furan-2-yl)vinyl]quinolin-4-ylamino}phenyl}
ethanone oxime hydrochloride (41a)活性優於氫鍵的接受者(E)-1-{3-{2-[(E)-2-(5-nitrofuran-2-yl)vinyl]quinolin-4-ylamino}phenyl}ethanone oxime hydrochloride (41b)。這些化合物中，尤其是23i其對於LNCaP 和 PC-3 擁有IC50 = 0.35 ?嵱及 IC50 = 0.14 ?嵱，因此針對23i進行細胞週期分析發現，23i會使LNCap及PC-3的細胞週期停滯於S phase。証明23i對於DNA有嵌入作用，進而抑制topoI或topoII的作用。所以我們試著繼續往4位苯胺類衍生物發展，希望藉由拉長4位苯胺類上的長碳鏈，期許主架構嵌入DNA後，利用側鏈的官能基使得化合物與DNA形成的錯合物更加的穩定。很幸運地，我們合成出(E)-N-(2-(diethylamino)ethyl)-4-(2-(2-(5-nitrofuran-2-yl)vinyl)-
quinolin-4-ylamino)benzamide(56a)對於PC-3 (0.19 ± 0.02 ?嵱)、MCF-7 (0.09 ± 0.01 ?嵱)及LNCaP (0.61 ± 0.05 ?嵱)都有很強的抗增生活性。

關鍵字

抗增生 ； 苯乙烯喹啉呋喃乙烯喹啉

並列摘要

The present study describes the synthesis of 2-phenylvinylquinoline (styrylquinoline) and 2-furanylvinylquinoline derivatives and evaluations of their antiproliferative activities. (E)-2-Styrylquinolin-8-ol (4) was inactive against a 3-cell line panel consisting of MCF-7 (Breast), NCI-H460 (Lung), and SF-268 (CNS). Replacement of the phenyl ring with 5-nitrofuran-2-yl group significantly enhanced antiproliferative activity in which (E)-2-(2-(5-nitrofuran-2-yl)vinyl)quinolin-8-ol (23i) and its 4-substituted derivatives (E)-1-{4-{2-[2-(5-Nitrofuran-2-yl)-
vinyl]quinolin-4-ylamino}phenyl}ethanone hydrochloride (40a), (E)-1-{3-{2-[2-(5-Nitrofuran-2-yl)vinyl]quinolin-4-ylamino}phenyl}ethanone hydrochloride (40b), (E)-1-{4-{2-[(E)-2-(5-nitrofuran-2-yl)vinyl]
quinolin-4-ylamino}phenyl}ethanone oxime hydrochloride (41a), (E)-1-{3-{2-[(E)-2-(5-nitrofuran-2-yl)vinyl]quinolin-4-ylamino}phenyl}ethanone oxime hydrochloride (41b), (E)-1-{4-{2-[(E)-2-(5-nitro-
furan-2-yl)vinyl]quinolin-4-ylamino}phenyl}ethanone O-methyl oxime hydrochloride(42a), (E)-1-{3-{2-[(E)-2-(5-nitrofuran-
2-yl)vinyl]quinolin-4-ylamino}phenyl}ethanone O-methyl oxime hydrochloride (42b) exhibited strong inhibitory effects against the growth of all three cancer cells. These compounds were further evaluated for their IC50 against the growth of MCF-7, LNCaP, and PC-3. Our results indicated that a hydrogen bond donating oxime derivative 41a was more active than its hydrogen bond accepting methyloxime derivative 41b. Compound 23i is the most active with an IC50 value of 0.35 and 0.14 ?嵱 respectively against the growth of LNCaP and PC-3 cancer cells. Therefore, compound 23i was evaluated by flow cytometric analysis for its effects on cell cycle distributions. Results indicated that 23i effectively induced cell cycle arrest at S phase for both cell lines, which consequently trigger late apoptosis for both LNCaP and PC3 cells. It not only could proof 23i is a DNA intechelator, but also could be the inhibitor of topo I or topo II. Therefore, we try to develop 4-aniline derivatives and try to stabilize the complex of compound and DNA. Luckily, we have synthsesized (E)-N-(2-(diethylamino)ethyl)-4-(2-(2-(5-nitrofuran-2-yl)-
vinyl)-quinolin-4-ylamino)benzamide (56a) which exhibited potent antiproliferative activity against PC-3 (0.19 ± 0.02 ?嵱), MCF-7 (0.09 ± 0.01 ?嵱), and LNCaP (0.61 ± 0.05 ?嵱).

並列關鍵字

antiproliferative ； quinoline ； styrylquinoline

參考文獻

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