Pharmaceutical Chemistry Department, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia.
Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Anticancer Agents Med Chem. 2018;18(15):2124-2130. doi: 10.2174/1871520618666180409155520.
For further exploration of the promising pyrrolizine scaffold and in continuation of our previous work, that proved the potential anticancer activity of the hit compound I, a new series of pyrrolizines 2-5 and 7-9 were designed and synthesized.
Structures of the new compounds were confirmed by IR, H-NMR, C-NMR and elemental analysis. Antitumor activity for the prepared compounds against human breast adenocarcinoma (MCF-7), liver (HEPG2) and colon (HCT116) cancer cell lines was evaluated using SRB assay method.
Compounds 2, 3 and 5 were the most potent on colon cancer cells, their IC values were less than 5 µM. Compounds 2, 3 and 8 were the most potent on liver cancer cells, their IC values were less than 10 µM. As for MCF7, compounds 2, 7, 8 and 9 were the most active with IC values less than 10 µM. We can conclude that combining pyrrolizine scaffold with urea gave abroad spectrum anticancer agent 2 against the three tested cell lines. Micronucleus assays showed that compounds 2, 3, 8 are mutagenic and can induce apoptosis. In addition, caspase-3 activation was evaluated and compound 2 showed increase in the level of caspase-3 (9 folds) followed by 3 (8.28 folds) then 8 (7.89 folds).
The obtained results encourage considering these three compounds as novel anticancer prototypes.
为了进一步探索有前途的吡咯里嗪支架，并延续我们之前的工作，证明了命中化合物 I 的潜在抗癌活性，我们设计并合成了一系列新的吡咯里嗪 2-5 和 7-9。
通过 IR、H-NMR、C-NMR 和元素分析确认新化合物的结构。采用 SRB 法评价了所制备的化合物对人乳腺癌（MCF-7）、肝癌（HEPG2）和结肠癌（HCT116）癌细胞系的抗肿瘤活性。
化合物 2、3 和 5 对结肠癌细胞的活性最强，其 IC 值小于 5µM。化合物 2、3 和 8 对肝癌细胞的活性最强，其 IC 值小于 10µM。对于 MCF7，化合物 2、7、8 和 9 的活性最强，IC 值小于 10µM。我们可以得出结论，将吡咯里嗪支架与脲结合可以得到广谱抗癌剂 2，对三种测试的细胞系均具有活性。微核试验表明，化合物 2、3、8 具有诱变作用，可诱导细胞凋亡。此外，还评估了 caspase-3 的激活，结果表明化合物 2 使 caspase-3 的水平增加了 9 倍，3 增加了 8.28 倍，8 增加了 7.89 倍。
获得的结果鼓励将这三种化合物视为新型抗癌原型。
