Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique, Université Paul Sabatier, UMR CNRS 5068, 118 route de Narbonne, 31062 Toulouse Cédex 9, France.
Eur J Med Chem. 2012 Aug;54:626-36. doi: 10.1016/j.ejmech.2012.06.012. Epub 2012 Jun 21.
A series of pyrrolic analogs and two series of regioisomeric pyrazolic analogs of the marine alkaloids granulatimide and isogranulatimide were prepared. The synthesis of the two first ones was based on the condensation reaction of diversely 5-substituted 3-bromoindoles with pyrrole or pyrazole followed by addition of the intermediates on maleimide or dibromomaleimide, respectively, the so-obtained acyclic adducts being finally photocyclized to the desired analogs. Compounds of the last series were obtained by reacting different 5-substituted-indole-3-glyoxylates with N-Boc-pyrazole-3-acetamide and subsequent photochemical cyclization of the adducts. All the compounds were evaluated for their in vitro growth inhibitory properties toward eight cancer cell lines. Several compounds were also assayed for their ability to abrogate the G2-cell cycle checkpoint or to inhibit a panel of Ser/Thr kinases. Lastly, computer-assisted phase-contrast microscopy (quantitative videomicroscopy) revealed that the three most potent compounds (4a, 9a, 9e), with IC(50) growth inhibitory concentrations ranging between 10 and 20 μM, displayed cytostatic, not cytotoxic, anticancer effects.
一系列吡咯类似物和两种海洋生物碱 granulatimide 和 isogranulatimide 的区域异构吡唑类似物被制备。前两种的合成基于 5-取代的 3-溴吲哚与吡咯或吡唑的缩合反应，然后分别将中间体加成到马来酰亚胺或二溴马来酰亚胺上，所得的非环加合物最后光环化得到所需的类似物。最后一系列的化合物是通过不同的 5-取代-吲哚-3-乙醛酸酯与 N-Boc-吡唑-3-乙酰胺反应，并随后对加合物进行光化学环化得到的。所有化合物均针对八种癌细胞系的体外生长抑制特性进行了评估。一些化合物还被检测其是否能够废除 G2 细胞周期检查点或抑制一系列丝氨酸/苏氨酸激酶。最后，计算机辅助相差显微镜（定量视频显微镜）显示，三种最有效的化合物（4a、9a、9e），其 IC50 生长抑制浓度范围在 10 到 20 μM 之间，具有细胞抑制而不是细胞毒性的抗癌作用。
