Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez-Canal University, Ismailia, 41522, Egypt.
Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt.
J Photochem Photobiol B. 2018 Mar;180:98-108. doi: 10.1016/j.jphotobiol.2018.01.026. Epub 2018 Jan 31.
Owing to their structural novelty and inherent three-dimensionality, spiro scaffolds have been shown indisputable promise as chemopreventive agents. A new series of heterocycles containing spirooxindole and pyrrolidine rings were synthesized by the 1,3-dipolar cycloaddition of an azomethine ylide, which was generated in situ by the condensation of a secondary amino acid (l‑proline) and dicarbonyl compounds (isatin), with dipolarophiles. This method is simple and provides diverse and biologically interesting products. The new series of compounds with a high degree of stereo- and regioselectivity were evaluated against breast cancer cell lines (MCF-7) and leukemia (K562). Among them, compound 4g was identified as the most potent with IC values of 15.49 ± 0.04 μM, against breast cancer cell lines (MCF-7) compared to standard drug 5-Fu (IC = 78.28 ± 0.2 μM) and compound 4i IC values of 13.38 ± 0.14 μM against leukemia (K562) compared to standard drug 5-fluorouracil (5-FU) (IC = 38.58 ± 0.02). The selective apoptotic effects of 4g were investigated against MCF-12 normal mammary cell and the cytotoxicity of 4g was not associated with any induction of necrosis compared to untreated cells. Molecular docking studies were investigated. From the docking data, these compounds could be act as small molecules that inhibit the MDM2-p53 interaction.
由于其结构新颖性和固有三维性，螺环支架作为化学预防剂具有不可否认的前景。通过亚胺叶立德的 1,3-偶极环加成反应，合成了一系列新的含螺吲哚和吡咯烷环的杂环化合物，亚胺叶立德是由氨基酸（l-脯氨酸）和二羰基化合物（靛红）的缩合原位生成的，与偶极子反应。该方法简单，提供了多样化且具有生物意义的产物。用高立体和区域选择性合成的新系列化合物对乳腺癌细胞系（MCF-7）和白血病（K562）进行了评价。其中，化合物 4g 被鉴定为最有效的化合物，其对乳腺癌细胞系（MCF-7）的 IC 值为 15.49 ± 0.04 μM，与标准药物 5-氟尿嘧啶（IC = 78.28 ± 0.2 μM）相比，化合物 4i 对白血病（K562）的 IC 值为 13.38 ± 0.14 μM，与标准药物 5-氟尿嘧啶（5-FU）相比（IC = 38.58 ± 0.02）。研究了 4g 对 MCF-12 正常乳腺细胞的选择性凋亡作用，与未处理细胞相比，4g 的细胞毒性与任何诱导坏死无关。进行了分子对接研究。从对接数据来看，这些化合物可以作为抑制 MDM2-p53 相互作用的小分子。
