Novel synthesis, cytotoxic evaluation, and structure-activity relationship studies of a series of α-alkylidene-γ-lactones and lactams
Novel synthesis, cytotoxic evaluation, and structure-activity relationship studies of a series of α-alkylidene-γ-lactones and lactams
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DOI：
10.1021/jm048970a
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发表时间：
2005-05-19
影响因子：
7.3
通讯作者：
Rózalski, M
中科院分区：
文献类型：
--
作者：
Janecki, T;Blaszczyk, E;Rózalski, M
利用2-二乙氧基磷酰基-4-硝基链烷酸乙酯9a-e作为常用中间体合成了5-烷基-和5-芳烷基-3-亚甲基二氢呋喃-2-酮13 a-e、3-亚烷基二氢呋喃-2-酮18 a-c和3-亚甲基吡咯烷-2-酮16 a-e。所有获得的化合物针对L-1210、HL-60和NALM-6白血病细胞进行测试。观察到最高的细胞毒活性为3-亚甲基呋喃酮13 d，e轴承苄基或3，4-二甲氧基苯基甲基取代基在5位，与IC 50值分别为5.4和6.0 μ M。与文献报道相反，当比较呋喃酮13 a、B、d和5-（1 ′-羟烷基）-3-亚甲基二氢呋喃-2-酮6a、B、d的细胞毒性时，没有发现由于羟基的存在而导致的活性增强。吡咯烷酮16 a-e和3-亚烷基呋喃酮18 a-c的抗癌活性远低于呋喃酮13 a-e。
5-Alkyl- and 5-arylalkyl-3-methylenedihydrofuran-2-ones 13a-e, 3-alkylidenedihydrofuran-2-ones 18a-c, and 3-methylenepyrrolidin-2-ones 16a-e were synthesized utilizing ethyl 2-diethoxyphosphoryl-4-nitroalkanoates 9a-e as common intermediates. All obtained compounds were tested against L-1210, HL-60, and NALM-6 leukemia cells. The highest cytotoxic activity was observed for 3-methylenefuranones 13d,e bearing benzyl or 3,4-dimethoxyphenylmethyl substituents at position 5, with IC50 values of 5.4 and 6.0 mu M, respectively. Contrary to the literature reports, no enhancement in activity due to the presence of a hydroxy group was found when the cytotoxicity of furanones 13a,b,d and 5-(1'-hydroxyalkyl)-3-methylenedihydrofuran-2-ones 6a,b,d was compared. The anticancer activity of pyrrolidinones 16a-e and 3-alkylidenefuranones 18a-c was much weaker than that of furanones 13a-e.