Synthesis and Cytotoxic Evaluation of Benzo[g]quinoline-4(1H)-one and 6-Oxorotenoid Derivatives

• Main Authors: Shu-Lin Hsu, 徐淑玲
• Other Authors: Cherng-Chyi Tzeng
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/72549999811079196964

博士 === 高雄醫學大學 === 藥學研究所博士班 === 92 === (I) The present report describes the synthesis and evaluation of tricyclic benzo[g]quinolin-4(1H)-one derivatives (CAB type) in which an additional aromatic ring is linearly fused on the antibacterial quinolone-3-carboxylic acid to maintain a free carboxylic acid (increase water-solubility) and a coplanar tricyclic DNA-intercalating chromophore (improve antitumor activity). 1H-Benzo[g]Quinoline -4,5,10-trione (2), 1-methyl-1H-benzo[g]quinoline-4,5,10-trione (3), and ethyl 1-methylbenzo[g]quinoline-4,5,10-trione- 3-carboxylate (5) exhibited significant cytotoxicity against all 60 cancer cells with mean GI50 values of 5.92, 7.75, and 2.52µM respectively while 1-methylbenzo[g]quinoline-4,5,10-trione-3-carboxylic acid (8) and 5-hydroxy-10-methoxy-1-methylbenzo[g]quinoline-4(1H)-one-3-carbox ylic acid (12) were inactive, indicated free carboxylic acid at C-3 position is unfavorable. The results have also implied the importance of carbonyl moieties at C-5 and C-10 due to the inactiveness of reduced products ethyl 5-hydroxy-10-methoxy-1- methylbenzo[g]quinoline- 4(1H)-one-3-carboxylate (9), and ethyl 10-benzyloxy- 5-hydroxybenzo [g]quinoline-4(1H)-one-3-carboxylate (10). (II) Isoflavonoids are a ubiquitous family of phytochemicals that possess a wide variety of biological activities including anticancer, antioxidant, anti-inflammatory, gastroprotective, antiviral, antimutagenic activities, etc. However, diversed biological activities sometimes are disadvantageous because other biological effects will become side effects when these compounds are used as, for example, anticancer drugs. In general, the substituents on isoflavoniods and their conformations will affect the biological activities. The present report describes the preparation and anticancer evaluation of conformationally locked isoflavone derivatives in which the phenyl and the chromone rings are linked by a six-membered ester ring. To optimize the anticancer activities and improve water solubility of these conformationally locked isoflavone derivatives, Mannich bases and the isosteric isomers have also been prepared for evaluation. Among them, 9-[2-(4-chlorophenyl)- 2-hydroxyiminoethoxy] chromeno[3,4-b]chromen-6,12-dione(8c) exhibits selective cytotoxicity against K526(GI50 = 1.99 µM), F-295(GI50 = 1.99 µM), RXF393(GI50 = 2.13 µM), and DA-MB-435(GI50 = 2.45 µM).