N-取代 4-苯胺呋喃[2,3-b]喹啉類衍生物之合成研究

Studies on the synthesis of N-substituted 4-anilinofuro[2,3-b]quinoline derivatives

陳煜勳(Yu-Hsun Chen)

指導教授 ： 曾誠齊

高雄醫學大學/生命科學院/醫藥暨應用化學研究所/碩士(2014年)

摘要

本研究利用天然生物鹼白鮮鹼(dictamnine)的三環呋喃喹啉 (furoquinoline)衍生物為骨架，在4-苯胺呋喃[2,3-b]喹啉(4-anilinofuro[2,3-b]quinoline) C-4胺基上進行修飾，數據指出，1-[4-(呋喃[2,3-b]喹啉-4-胺基)-苯基]乙酮(1-[4-(furo[2,3-b]quinoline- 4-ylamino)-phenyl]ethanone) (CIL-102, 1) (GI50 = 0.025 μM)及3-氯- 4-[(4-甲氧基苯基)胺基]呋喃[2,3-b]喹啉(3-chloro-4- [(4-methoxyphenyl)-amino]furo[2,3-b]quinoline) (CIL-378, 2)(GI50 = 0.025 μM)在抗腫瘤細胞增生表現出色且優於以上市藥物柔紅黴素(daunomycin)，但水溶解度低與其無選擇性的細胞毒性，是需克服的問題。本研究主要在4-苯胺呋喃[2,3-b]喹啉C-4胺基以較具親水性的羧酸進行取代修飾，期望能提升在水中的溶解度及更好抑制癌細胞選擇性，進一步成為有效抗增生藥物。

關鍵字

N-取代 4-苯胺呋喃[2,3-b]喹啉

並列摘要

The skeleton of natural dictamnine alkaloid belongs to a tricyclic furoquinoline derivative. Previous reports indicated that the introduction of a suitable substituent at the C-4 position of furoquinoline ring afforded certain potential antiproliferative agents. For examples, 1-[4-(furo[2,3-b]quinoline-4-ylamino)phenyl]ethanone (1, GI50 = 0.025 μM) and 3-chloro-4-[(4-methoxyphenyl)amino]furo[2,3-b]quinoline(2, GI50 = 0.025 μM) exhibited more potent antiproliferative activities than the clinically used anticancer drug, daunomycin. However, poor water solubility and general cytotoxicities exhibited by both compounds 1 and 2 prompted extensive structural optimizations to overcome these problems. This thesis describes the synthesis of N-substituted 4-anilinofuro[2,3-b]quinoline derivatives with hydrophilic carboxylic acid with an aim to obtain novel furoquinoline derivatives with higher water solubility as well as better selective anticancer activity. We expect to discover novel antiproliferative agents with high selectivity and water solubility.

並列關鍵字

N-substituted 4-anilinofuro[2,3-b]quinoline derivatives

參考文獻

1. Chen, I. L.; Chen, Y. L.; Tzeng, C. C.; Chen, I. S. Synthesis and cytotoxic evaluation of some 4-anilinofuro[2,3-b]quinoline derivatives. Helv. Chim. Acta.2002, 85, 2214–2221.

2. Chen, Y. L.; Chen, I. L.; Lu, C. M.; Tzeng, C. C.; Tsao, L. T.; Wang, J. P. Synthesis and anti-inflammatory evaluation of 9-phenoxyacridine and 4-phenoxyfuro[2,3-b]quinoline derivatives. part 2.Bioorg. Med. Chem.2003, 11, 3921–3927.

3. Chen, Y. L.;Chen, I.L.; Lu, C. M.;Tzeng, C. C.; Tsao, L. T.; Wang, J. P.Synthesis and anti-inflammatory evaluation of 4-anilinofuro[2,3-b]quinoline and 4-phenoxyfuro[2,3-b]quinoline derivatives. part5. Chem.Biodiver.2008, 4, 267–278.

4. Chen, Y. L.; Lu, C. M.;Chen, I. L.; Tsao, L. T.; Wang, J. P. Synthesis and antiinflammatory evaluation of 9-anilinoacridine and 9-phenoxyacridine derivatives. J. Med. Chem.2002,45,4689–4694.

5. Chen, Y. L.; Lu, C. M.; Chen, I. L.; Tsao, L. T.; Wang , J. P. Synthesis and antiinflammatory evaluation of 9-anilinoacridine and9-phenoxyacridine derivatives. J. Med. Chem.2000, 43, 2332–2349.