Barakat Assem, Islam Mohammad Shahidul, Ghawas Hussien Mansur, Al-Majid Abdullah Mohammed, El-Senduny Fardous F, Badria Farid A, Elshaier Yaseen A M M, Ghabbour Hazem A
Department of Chemistry, College of Science, King Saud University P. O. Box 2455 Riyadh 11451 Saudi Arabia
Department of Chemistry, Faculty of Science, Alexandria University P.O. Box 426, Ibrahimia Alexandria 21321 Egypt.
RSC Adv. 2018 Apr 17;8(26):14335-14346. doi: 10.1039/c8ra02358a.
Spirooxindole is a promising chemo therapeutic agent. Possible targets include cancers of the liver, prostate, lung, stomach, colon, and breast. Here, we demonstrate a one-pot three-component reaction a [3 + 2] cycloaddition/ring contraction sequence of a dipolarophile (activated alkene) with -generated azomethine ylide (1,3-dipoles) without the use of any catalyst. The reaction provides efficient access to synthetically useful and biologically important spirooxindoles in high yield (69-94%) with high diastereoselectivity. The synthesized compounds were subjected to cytotoxicity evaluation using colorectal cancer (HCT-116), hepatocellular carcinoma (HepG2), and prostate cancer (PC-3) cells. Compounds 4i, 4j, and 4k showed potent cytotoxic activity and high selectivity against HCT-116 cells when compared to cisplatin. Meanwhile compound 4d retained high cytotoxic activity and selectivity against HepG2 and PC-3 cells in comparison to cisplatin. The mechanism of compound 4d was further studied using phosphodiesterase 1 enzyme and showed 74.2% inhibitory activity. A possible binding mode for compound 4d to PDE-1 was investigated by molecular modeling using OpenEye software. Pose predictions for the active compounds were demonstrated by ROCS alignments. Compound 4d has a special geometry and differs from other active compounds.
螺环氧化吲哚是一种很有前景的化疗药物。可能的靶点包括肝癌、前列腺癌、肺癌、胃癌、结肠癌和乳腺癌。在此，我们展示了一种一锅三组分反应——亲偶极体（活化烯烃）与生成的甲亚胺叶立德（1,3 - 偶极体）的[3 + 2]环加成/环收缩序列，无需使用任何催化剂。该反应能以高产率（69 - 94%）和高非对映选择性高效合成具有合成用途和生物学重要性的螺环氧化吲哚。对合成的化合物使用结直肠癌（HCT - 116）、肝癌（HepG2）和前列腺癌（PC - 3）细胞进行细胞毒性评估。与顺铂相比，化合物4i、4j和4k对HCT - 116细胞表现出强效细胞毒性活性和高选择性。同时，与顺铂相比，化合物4d对HepG2和PC - 3细胞保留了高细胞毒性活性和选择性。使用磷酸二酯酶1对化合物4d的作用机制进行了进一步研究，结果显示其具有74.2%的抑制活性。使用OpenEye软件通过分子建模研究了化合物4d与PDE - 1的可能结合模式。通过ROCS比对展示了活性化合物的构象预测。化合物4d具有特殊的几何结构，与其他活性化合物不同。
