Departamento de Quimica Farmaceutica, Facultad de Farmacia, Campus Miguel de Unamuno, Universidad de Salamanca, E-37007 Salamanca, Spain.
J Med Chem. 2010 Feb 11;53(3):983-93. doi: 10.1021/jm901373w.
Several series of nonlactonic podophyllic aldehyde analogues were prepared and evaluated against several human tumor cell lines. They had different combinations of aldehyde, imine, amine, ester, and amide functions at C-9 and C-9' of the cyclolignan skeleton. All the compounds synthesized showed cytotoxicity levels in the microM range and below. Within the new series tested, compounds having an aldehyde or imine at C-9 and an ester at C-9' were the most potent, with GI(50) values in the nM range, some of them being several times more potent against HT-29 and A-549 carcinoma than against MB-231 melanoma cells. Cell cycle studies and analysis of the microtubule-disrupting capacity have demonstrated the existence of two different mechanisms of cell death induction for compounds with closely related structures.
我们合成了一系列非内酯型鬼臼毒素类似物，并对其进行了活性测试，评估它们对多种人类肿瘤细胞系的抑制效果。这些类似物在环木脂素骨架的 C-9 和 C-9'位上具有不同的醛基、亚胺基、氨基、酯基和酰胺基组合。所有合成的化合物均表现出在微摩尔范围内的细胞毒性。在所测试的新系列中，在 C-9 位具有醛基或亚胺基且在 C-9'位具有酯基的化合物活性最强，其 GI(50) 值在纳摩尔范围内，其中一些化合物对 HT-29 和 A-549 癌细胞的活性比对 MB-231 黑色素瘤细胞的活性高几倍。细胞周期研究和微管破坏能力分析表明，对于结构密切相关的化合物，存在两种不同的细胞死亡诱导机制。
