| 摘要: | 中文摘要
4-(1-芐基-1H-吲唑-3-基)苯甲酸乙酯(YD-3)是本研究室近期所合成出來，作為一個新型的凝血酶-受體拮抗劑。在此研究中，著者將YD-3當作為一個先導化合物，並製備出一系列的YD-3衍生物(5 - 27)。以間苯二甲酸甲酯(1)為起始原料並加入亞硫醯氯進行氯化反應，接著與1-N-嗎福啉基環己烯反應，得3-[(2-oxocyclohexyl)- carbonyl]benzoate (5)，再將化合物5和聯胺反應成為3-(4-methyl phenyl)-4,5,6,7-tetrahydro-1H-indazole (6)，再與Pd/C進行脫氫反應，得到methyl 3-(1H-indazol-3-yl)benzoate (7)，化合物7在乙醇鈉存在下加入苯甲氯，進行芐基化後，形成兩個主要的衍生物ethyl 3-(1-benzyl-1H-indazol-3-yl)benzoate (8a)與ethyl 3-(2-benzyl-2H- indazol-3-yl)benzoate (9a)。在本研究中，著者以化合物8a和9a為先導化合物，進行系統性的結構改變，製備出一系列化合物8a和9a新型之類緣化合物(13–25)。
所合成之化合物進行對人類前骨髓性血癌細胞HL-60加入(或不加入) 全反式維甲酸(ATRA)之誘導分化活性、抗細胞增殖活性測試，我們也進行培養中人類肝癌細胞(Hep3B)、人類非小細胞肺癌腺癌細胞(A549)、肺癌細胞(NCI-H226)、人類結腸直腸腺癌細胞(colo205)、乳癌(MCF7)、人類子宮頸腺癌細胞(HeLa)生長速率影響之測試，結果顯示化合物3-(1-benzyl-1H-indazol-3-yl)-N-hydroxybenzamide (15a), 3-(1- benzyl-1H-indazol-3-yl)benzamide (15b), 3-(1-benzyl-1H-indazol- 3- yl)-N-(2-(dimethylamino)ethyl)benzamide (15c), (3-(1-benzyl-1H- indazol-3-yl)phenyl)methanol (18)和3-(3-(1-benzyl-1H-indazol-3- yl)- phenyl)acrylic acid (21)均具有分化活性，也有加強ATRA的分化效果。化合物15c對MCF-7 和 HL-60癌細胞具有抗細胞增殖活性，其IC50值分別為7.5 μM和6.7 μM。經生物活性試驗篩選，結果發現化合物15a, 15b, 15c, 18和21可以做為新先導化合物，提供後續研究的參考。
Abstract
Ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) was synthesized in our laboratory as a novel thrombin-receptor antagonist. In this study, YD-3 was used as a lead compound and a series of its derivatives were synthesised. Subsequent the starting material mono-methyl isophthalate was treated with thionyl chloride on chlorination, and then reacts with 1-(N-morpholino)cyclohexene to afford 3-[(2-oxocyclohexyl)- carbonyl]- benzoate (5). Next, the compound 5 reacts with hydrazine hydrate to afford 3-(4-methylphenyl)-4,5,6,7-tetrahydro-1H-indazole (6). Subsequent dehydrogenation of compound 6 reacts with excess Pd/C to afford methyl 3-(1H-indazol-3-yl)benzoate (7). Afterwards in the presence of sodium ethoxide in alcohol, benzylation of compound 7 with benzyl chloride produced the two main derivatives, N1-benzyl- 3-(3- phenyl)indazoles (8a) and N2-benzyl-3-(3-phenyl)indazoles (9a).
In this study, compounds 8a and 9a were selected as lead compounds to systemic structural variation to prepare a series of novel analogues of 8a and 9a compounds .
In this study, the synthesized compounds were screened for their differentiation and proliferation of HL-60 cells with (or without) all-trans retinoic acid (ATRA). And we also examined the antiproliferatory activities of A549 (non-small cell lung cancer), MCF-7 (breast cancer), HeLa (ovarian cancer), Hep3B (liver cancer), NCI-H226 (non-small cell lung cancer) and Colo 205 (colon cancer).
3-(1-Benzyl-1H-indazol-3-yl)-N-hydroxybenzamide (15a), 3-(1-benzyl-1H-indazol-3-yl)benzamide (15b), 3-(1-benzyl-1H- indazol-3-yl)-N-(2-(dimethylamino)ethyl)benzamide (15c), (3-(1-benzyl- 1H-indazol-3-yl)phenyl)methanol (18) and 3-(3-(1- benzyl-1H-indazol- 3-yl)phenyl)acrylic acid (21) were found to be the most effective to differentiat and to be the most effective to potentiate the induction of differentiation by ATRA. Compound 15c exhibited selective antiproliferatory activities for MCF-7 and HL-60 cancer cells with IC50 values of 7.5 μM and 6.7 μM, respectively. This finding suggest that compounds 15a, 15b, 15c, 18 and 21 may be new lead compounds for further research. |
