Magoulas George E, Rigopoulos Andreas, Piperigkou Zoi, Gialeli Chrysostomi, Karamanos Nikos K, Takis Panteleimon G, Troganis Anastassios N, Chrissanthopoulos Athanassios, Maroulis George, Papaioannou Dionissios
Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece.
Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece.
Bioorg Chem. 2016 Jun;66:132-44. doi: 10.1016/j.bioorg.2016.04.003. Epub 2016 Apr 23.
Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl3-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256μM and periods of treatment of 24, 48 and 72h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC50 64-70μM) for the MDA-MB-231 cell line after 24-48h of treatment, but they were more selective and much more potent (IC50 4-16μM) for the MCF-7 cells after 48h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72h of treatment (IC50 1-2μM), probably as the result of slow hydrolysis of their methyl ester functions.
合成了两种新的非对映体木脂素酰胺（4和5），它们是二聚体咖啡酸 - l - 多巴杂合物。合成过程包括通过FeCl₃介导的咖啡酸甲酯的酚氧化偶联反应，得到对映体混合物形式的反式二酯1a，对儿茶酚单元进行保护，区域选择性皂化，与适当保护的l - 多巴衍生物偶联，通过快速柱色谱法分离得到的两种非对映体，最后对儿茶酚单元进行整体化学选择性脱保护。评估了杂合物4和5以及相关化合物对两种具有不同转移潜能和雌激素受体状态的乳腺癌细胞系（MDA - MB - 231和MCF - 7）以及一种上皮性肺癌细胞系A - 549增殖的影响，浓度范围为1至256μM，处理时间为24、48和72小时。在处理24 - 48小时后，两种杂合物对MDA - MB - 231细胞系均显示出有趣且几乎等效的抗增殖活性（IC50为64 - 70μM），但在处理48小时后，它们对MCF - 7细胞更具选择性且活性更强（IC50为4 - 16μM）。在处理72小时后，观察到两种杂合物对两种乳腺癌细胞系的活性最高（IC50为1 - 2μM），这可能是由于它们甲酯功能缓慢水解的结果。
