一种新颖的含呋喃酮骨架苦参碱衍生物合成及体外抗癌活性初步评价（英文）

Synthesis of Novel Matrine Derivatives Containing Furanone Skeleton and Preliminary Evaluation of Their Anticancer Activity in Vitro

以苦参碱为原料,在氢氧化钠的碱性溶液中使苦参碱的内酰胺水解得到苦参酸钠,将制得的苦参酸钠溶于醇,再与反应过的氯化亚砜醇溶液反应得到相应苦参酸酯.以互为药效基团的5-烷氧基-3,4-二溴-2(5H)-呋喃酮和苦参酸酯合成含呋喃酮骨架的苦参碱衍生物,并以四甲基偶氮唑盐比色法(MTT法)初步研究了目标化合物对人肝癌细胞株SMMC-7721的细胞毒活性,以苦参碱、长春新碱(VCR)和阿糖胞苷(ARA)作对阳性对照药物.初步研究结果表明,目标化合物能够显著抑制人肝癌细胞增殖、诱导其凋亡,其中5-甲氧基-3,4-二溴-2(5H)-呋喃酮和苦参酸薄荷酯(5a)的抑制活性最佳,给药24 h IC_(50)为0.0004μmol/L,优于一线抗肝癌药物长春新碱(0.1284μmol/L)、阿糖胞苷(0.4578μmol/L)及母体化合物苦参碱(0.9018μmol/L).

Sophora acid sodium was synthesized from matrine, where the lactam unit was saponificated in the presence of aqueous sodium hydroxide. Then, esterfication of the sodium salt with methanol and ethanol produced the corresponding esters in 60%～83% yields. Subsequently, the two pharmacophores, matrine esters and 5-alkoxy-3,4-dibromo-2（5 H）-furan ketones were combined through a C—N coupling reaction, producing a series of novel matrine derivatives with good yields. The antitumor activities of the matrine derivatives against human hepatoma SMMC-7721 cell lines were evaluated using the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT） method. The test results showed that the matrine derivatives can effectly inhibit proliferation of liver cancer cells, and the compound methyl 3-（2-（（S）-4-bromo-2-（（（1 S,2 R,5 S）-2-isopropyl-5-methylcyclohexyl）oxy）-5-oxo-2,5-dihydrofuran-3-yl）dodecahydropyrido[3,2,1-ij][1,6]naphthyridin-1-yl）propanoate（5 a） possessed stronger inhibitory activity against SMMC-7721 cell lines with the IC50 value of 0.0004 μmol/L at 24 h, showing markedly higher inhibitory activity in vitro than cytosine arabinoside（0.4578 μmol/L）, vincristine（0.1284μmol/L） and the parent compound matrine（0.9018 μmol/L）.