Synthesis and Biological Activity of N1- and N2-benzyl-3-(3-substituted phenyl)indazole Analogues

• Main Authors: Chiung-Wen Kuo, 郭瓊文
• Other Authors: 黃麗嬌
• Format: Others
• Language: zh-TW
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/01241532472425325682

碩士 === 中國醫藥大學 === 藥物化學研究所碩士班 === 94 === 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.