Almansour Abdulrahman I, Kumar Raju Suresh, Beevi Farzana, Shirazi Amir Nasrolahi, Osman Hasnah, Ismail Rusli, Choon Tan Soo, Sullivan Brian, McCaffrey Kellen, Nahhas Alaa, Parang Keykavous, Ali Mohamed Ashraf
Department of Chemistry, College of Science, King Saud University, P.O.Box 2455, Riyadh 11451, Saudi Arabia.
New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan-301030, India.
Molecules. 2014 Jul 10;19(7):10033-55. doi: 10.3390/molecules190710033.
A number of novel spiro-pyrrolidines/pyrrolizines derivatives were synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones 2a-n. Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N-methylglycine (sarcosine), phenylglycine, or proline. All compounds (50 μM) were evaluated for their antiproliferative activity against human breast carcinoma (MDA-MB-231), leukemia lymphoblastic (CCRF-CEM), and ovarian carcinoma (SK-OV-3) cells. N-α-Phenyl substituted spiro-pyrrolidine derivatives (5a-n) showed higher antiproliferative activity in MDA-MB-231 than other cancer cell lines. Among spiro-pyrrolizines 6a-n, a number of derivatives including 6a-c and 6i-m showed a comparable activity with doxorubicin in all three cell lines. Among all compounds in three classes, 6a, 6b, and 6m, were found to be the most potent derivatives showing 64%, 87%, and 74% antiproliferative activity in MDA-MB-231, SK-OV-3, and CCRF-CEM cells, respectively. Compound 6b showed an IC50 value of 3.6 mM in CCRF-CEM cells. These data suggest the potential antiproliferative activity of spiro-pyrrolidines/pyrrolizines.
通过甲亚胺叶立德与3,5-双[（E）-芳基亚甲基]四氢-4（1H）-吡啶酮2a-n的[3+2]环加成反应，合成了一系列新型螺-吡咯烷/吡咯嗪衍生物。甲亚胺叶立德由1H-吲哚-2,3-二酮（异吲哚酮，3）与N-甲基甘氨酸（肌氨酸）、苯甘氨酸或脯氨酸反应原位生成。评估了所有化合物（50μM）对人乳腺癌（MDA-MB-231）、淋巴细胞白血病（CCRF-CEM）和卵巢癌（SK-OV-3）细胞的抗增殖活性。N-α-苯基取代的螺-吡咯烷衍生物（5a-n）在MDA-MB-231中显示出比其他癌细胞系更高的抗增殖活性。在螺-吡咯嗪6a-n中，包括6a-c和6i-m在内的许多衍生物在所有三种细胞系中都显示出与阿霉素相当的活性。在三类所有化合物中，发现6a、6b和6m是最有效的衍生物，在MDA-MB-231、SK-OV-3和CCRF-CEM细胞中分别显示出64%、87%和74%的抗增殖活性。化合物6b在CCRF-CEM细胞中的IC50值为3.6 mM。这些数据表明螺-吡咯烷/吡咯嗪具有潜在的抗增殖活性。
