- 學位論文
?喃??類衍生物之合成及生物活性研究
Studies on the Synthesis and Biological Activities of Furoquinoline Derivatives
摘要
從天然的生物鹼dictamnine合成4-苯胺?喃[2,3-b]??衍生物，並針對九類癌細胞(包括白血病、非小細胞肺癌、結腸癌、中樞神經癌、黑色素皮膚癌、卵巢癌、腎癌、前列腺癌、及乳癌)共六十株人類癌細胞進行細胞毒性評估。1-[4-(Furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone (5) (GI50 = 0.025 mM)，在?喃[2,3-b]??的C(4)上有4-乙醯苯胺取代，比它的3-乙醯苯胺類似物(7) (GI50 = 5.27 mM)有更好的活性。並比較所有合成的化合物和二種在臨床上使用的抗癌藥m-AMSA (GI50 = 0.44 mM)及daunomycin (GI50 = 0.044 mM)的抗癌活性。 由於天然資源有限，所以以全合成的方式製備這些具生物活性的半合成品及他們的衍生物是必須且重要的。因此一系列4-苯胺-及4-苯氧?喃[2,3-b]??衍生物(22-27)被合成，並評估它們的細胞毒性及抗發炎活性。在這當中，(E)-1-[4-(3-chlorofuro[2,3-b]quinolin-4-ylamino)phenyl]ethanone oxime (23a) (IC50 = 6.5 mM)對於以compound 48/80刺激誘發大鼠腹膜肥胖細胞釋放b-glucuronidase比參考抑制劑mepacrin (IC50 = 20.6 mM)有更強的抑制作用。而且化合物23a也顯示對嗜中性白血球釋放溶解體酵素及b-glucuronidase具有抑制活性，IC50值分別為11.6及7.2 mM。 4-苯胺?喃[3,2-c]??衍生物，為4-苯胺?喃[2,3-b]??的結構異構物，也被合成並進行細胞毒性的評估。但這類化合物並無明顯的細胞毒性，尤其是1-[3-(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone (30) (GI50 = 25.5 mM)。然而，它的oxime (32a) 及 O-methyloxime (32b) 衍生物具有明顯的細胞毒性，對腎癌細胞UO-31 (GI50 ≤ 0.03 mM)和兩種黑色素皮膚癌細胞UACC-257 (GI50 ≤ 0.04 mM)及UACC-62 (GI50 < 0.01 mM)的成長有很強的抑制作用。 另外，化合物32和33的異構物，2-phenyloxazolo[3,2-a]quinoliniums (38) 也被合成。將1-benzoylethylquinolin-2(1H)-ones (37)與濃硫酸反應，除了經由一個Z-型?醇中間物進行環化得到目標產物38外，也會經由E-型?醇中間物得到dibenzo[a,f]quinoliziniums (39)。但這類化合物並無明顯的細胞毒性。從結構上取代基的觀察，我們發現在苯環的對位有一個甲氧基基團的存在，對要環化成四環的化合物39而言是必須的。
關鍵字
?喃??類衍生物並列摘要
Some 4-anilinofuro[2,3-b]quinoline derivatives were synthesized from dictamnine, a natural alkaloid, and evaluated for their cytotoxicity in the NCI’s full panel of 60 human cancer cell lines derived from nine cancer cell types, including leukemia, non-small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer. 1-[4-(Furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone (5) (GI50 = 0.025 mM), bearing an 4-acetylanilino substituent at C(4) of furo[2,3-b]quinoline, was more active than its 3-acetylanilino counterpart (7) (GI50 = 5.27 mM). All newly synthesized compounds were compared with both clinically used anticancer drugs, N-[4-(acridin-9-ylamino)-3-methoxyphenyl]methanesulfonamide (m-AMSA; GI50 = 0.44 mM) and daunomycin (GI50 = 0.044 mM). Due to limited natural resources, total synthesis of these bioactive alkaloids and their derivatives is necessary and important. A series of 4-anilino- and 4-phenoxyfuro[2,3-b]quinoline derivatives (22-27) were synthesized and evaluated for their cytotoxicity and antiinflammatory activity. Among them, (E)-1-[4-(3-chlorofuro[2,3-b]quinolin-4-ylamino)phenyl]ethanone oxime (23a) (IC50 = 6.5 mM) showed to have more potent inhibitory effect than the reference inhibitor mepacrin (IC50 = 20.6 mM) on the release of b-glucuronidase from rat peritoneal mast cells stimulated with compound 48/80. It also exhibited potent activity in hihibiting the secretion of lysosomal enzyme and b-glucuronidase from neutrophils with IC50 values of 11.6 and 7.2 mM, respectively. 4-Anilinofuro[3,2-c]quinoline derivatives, isomers of 4-anilinofuro[2,3-b]quinoline derivatives, were also synthesized and evaluated for their cytotoxicity. These compounds had no significant cytotoxicity especially 1-[3-(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone (30) (GI50 = 25.5 mM). However, the oxime (32a) and O-methyloxime (32b) derivatives of compound 30 exhibit potent cytotoxicity on the inhibition of the renal cancer cells, UO-31, and two of the melanoma cancer cells, UACC-257 and UACC-62 cell growth in culture with GI50 values of ≤ 0.03, 0.04 and 0.01 mM, respectively. The isosteric isomer of compound 32 and 33, namely 2-phenyloxazolo[3,2-a]quinoliniums(38) were synthesized. Reaction of 1-(benzoylethyl)quinolin-2(1H)-ones(37) with conc.H2SO4 afford the desired product 38, together with dibenzo[a,f]quinoliziniums (39) via the cyclization of a Z-form and E-form enol intermediate, respectively. These compounds were evaluated for their cytotoxicity, but they had no significant activity. We examined the structure of substrates and found that the existence of a methoxy group para to the position to be cyclized in the phenyl moiety of the starting N-alkylated quinolin-2(1H)-ones is required to form tetracyclic dibenzo[a,f]quinolizinium perchlorates.