Tzeng C C, Lee K H, Wang T C, Han C H, Chen Y L
School of Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
Pharm Res. 2000 Jun;17(6):715-9. doi: 10.1023/a:1007534416561.
The main objective of this investigation was to explore the cytotoxic structure-activity relationships of gamma-substituted gamma-aryloxymethyl-alpha-methylene-gamma-butyrolactones against cancer cells.
The target compounds were synthesized in two steps commencing with aryl-OH which was treated with a bromomethyl ketone followed by the Reformatsky-type condensation.
Seven types of alpha-methylene-gamma-butyrolactones were evaluated in vitro against 60 human cancer cell lines derived from nine cancer cell types. The average values of log GI50 indicated that for the aryl portion, potencies of these alpha-methylene-gamma-butyrolactones are in a decreasing order of quinolin-2(1H)-one (or 2-hydroxyquinoline, 21, -5.89) > quinoline (19, -5.79) > 2-methylquinoline (20, -5.69) >8-hydroxyquinoline (17,-5.64) > 2-naphthalene (16, -5.59) > benzene (15, -4.90). The same order was obtained for both log TGI and log LC50. However, for the gamma-substituent, the potencies are in a decreasing order of biphenyl (16f-21f) > phenyl and 4-substituted phenyl (16b-e-21b-e) > methyl (16a-21a).
Unlike cardiovascular activities of alpha-methylene-gamma-butyrolactones in which a gamma-methyl substituent is necessary for vasorelaxing effect while a phenyl or a halogen-substituted phenyl is prefer for the antiplatelet activities, a gamma-biphenyl substituent proved to be the best for their cytotoxicities against various cancer cell lines tested.
本研究的主要目的是探索γ-取代的γ-芳氧基甲基-α-亚甲基-γ-丁内酯对癌细胞的细胞毒性构效关系。
目标化合物通过两步合成，起始于芳基-OH，先用溴甲基酮处理，然后进行Reformatsky型缩合反应。
七种α-亚甲基-γ-丁内酯在体外对源自九种癌细胞类型的60种人类癌细胞系进行了评估。log GI50的平均值表明，对于芳基部分，这些α-亚甲基-γ-丁内酯的活性顺序为喹啉-2(1H)-酮（或2-羟基喹啉，21，-5.89）>喹啉（19，-5.79）>2-甲基喹啉（20，-5.69）>8-羟基喹啉（17，-5.64）>2-萘（16，-5.59）>苯（15，-4.90）。log TGI和log LC50也得到相同顺序。然而，对于γ-取代基，活性顺序为联苯（16f - 21f）>苯基和4-取代苯基（16b - e - 21b - e）>甲基（16a - 21a）。
与α-亚甲基-γ-丁内酯的心血管活性不同，其中γ-甲基取代基对血管舒张作用是必需的，而苯基或卤素取代苯基更有利于抗血小板活性，γ-联苯取代基被证明对测试的各种癌细胞系具有最佳的细胞毒性。
