Departamento de Química Farmacéutica, Facultad de Farmacia-CIETUS, Campus Unamuno, Universidad de Salamanca , 37007 Salamanca, Spain.
J Med Chem. 2012 Aug 9;55(15):6724-37. doi: 10.1021/jm2017573. Epub 2012 Jul 23.
Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7α (podo) or 7β (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7β-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7α-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series.
通过对鬼臼毒素酮和几种醛酮的还原交叉偶联，合成了几种在 C-7 位具有不同侧链和功能的鬼臼毒素频哪醇衍生物。这些化合物在 C-7 位具有羟化链，但保留了各自的羟基，具有 7α（podo）或 7β（epipodo）构型。除了频哪醇外，还制备了一些 C-7 亚甲基和 C-7 烷基衍生物。通过细胞周期阻滞和细胞微管破坏来评估对肿瘤细胞的细胞毒性，并通过微管蛋白聚合抑制和与秋水仙碱结合位点的测定来进行机制表征。epipodopinacol（7β-OH）系列的化合物在所有测定中表现出与鬼臼毒素相似的行为，并且被证明是最有效的抑制剂。值得注意的是，7α-异丙基-7-去氧鬼臼毒素（20），没有任何羟基功能，似乎是一种新型微管蛋白聚合抑制剂的有前途的先导化合物。实验结果与对每个系列的代表性化合物进行的建模和对接研究总体上一致。
