Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università Degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università Degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
Eur J Med Chem. 2018 Oct 5;158:236-246. doi: 10.1016/j.ejmech.2018.09.017. Epub 2018 Sep 7.
Pyrrolizinones represent an interesting class of compounds with varied degrees of structural complexity and pharmacological activity. Among these, 9H-pyrido[2,3-b]pyrrolizin-9-one, tripentone analogs, recently reported by us, showed significant antiproliferative activity against human tumor cell lines, inducing apoptosis and not affecting viability of Caco-2 differentiated in normal intestinal-like cells. Considering their interesting biological activity, their 5H-pyrido[3,2-b]pyrrolizin-5-one analogs were efficiently synthesized in good to excellent yields (61-91%). All tripentone derivatives were tested to assess their cytotoxicity against two human tumor cell lines, HCT-116 (human colorectal carcinoma) and MCF-7 (human breast cancer). The most active derivatives, with IC ranging from 0.11 to 16.11 μM, did not affect viability of Caco-2 differentiated in normal intestinal-like cells, suggesting tumor cells as the main target of their cytotoxic action. The same compounds, further investigated, showed that they did not exert necrotic effects, while induced a clear shift of viable cells towards early apoptosis confining the cells in the mitotic phases.
吡咯里嗪酮类化合物是一类具有不同程度结构复杂性和药理活性的化合物，其中，9H-吡啶并[2,3-b]吡咯嗪-9-酮、我们最近报道的三戊酮类似物具有显著的抗人类肿瘤细胞系增殖活性，诱导细胞凋亡，不影响正常肠样细胞分化的 Caco-2 细胞活力。鉴于它们的有趣的生物活性，其 5H-吡啶并[3,2-b]吡咯嗪-5-酮类似物以良好至优异的收率（61-91%）高效合成。所有的三戊酮衍生物都被测试以评估它们对两种人类肿瘤细胞系 HCT-116（人结肠直肠癌细胞）和 MCF-7（人乳腺癌细胞）的细胞毒性。最活跃的衍生物，IC 范围为 0.11-16.11μM，不影响正常肠样细胞分化的 Caco-2 细胞活力，表明肿瘤细胞是其细胞毒性作用的主要靶标。进一步研究的相同化合物表明，它们不会产生坏死作用，而是诱导活细胞向早期凋亡明显转移，将细胞局限在有丝分裂阶段。
