Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt.
Eur J Med Chem. 2010 Dec;45(12):5887-98. doi: 10.1016/j.ejmech.2010.09.054. Epub 2010 Oct 1.
The versatile hitherto unreported 3-[(E)-3-(dimethylamino)acryloyl]-1,5-diphenyl-1H-pyrazole-4-carbonitrile (3) was prepared via the reaction of 3-acetyl-1,5-diphenyl-1H-pyrazole-4-carbonitrile (1) with dimethylformamid-dimethylacetal (DMF-DMA). The latter product and 3-((E)-3-morpholin-4-yl-acryloyl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile (4) underwent regioselective 1,3-dipolar cycloaddition with nitrilimines to afford the corresponding pyrazole derivatives. In vivo anti-estrogenic activity and acute toxicity after single oral dose of the newly synthesized compounds were evaluated. In vitro disease-oriented primary antitumor screening utilizing 14 cell lines of breast and ovarian tumor subpanels has been also carried out. All tested compounds showed anti-estrogenic properties equipotent or superior to the reference drug, letrozole. 3-[3-(4-Cyano-1,5-diphenyl-1H-pyrazole-3-yl)-1-(4-methylphenyl)-1H-pyrazole-4-carbonyl]-1,5-diphenyl-1H-pyrazole-4-carbonitrile (27c) and 3-(3-acetyl-1-phenyl-1H-pyrazole-4-carbonyl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile (8a) showed a significant cytotoxic activity in a nanomolar range against certain types of breast and ovarian tumors with tolerable toxicity.
尚未报道的多功能 3-[(E)-3-(二甲氨基)丙烯酰基]-1,5-二苯基-1H-吡唑-4-甲腈（3）是通过 3-乙酰基-1,5-二苯基-1H-吡唑-4-甲腈（1）与二甲基甲酰胺-二甲缩醛（DMF-DMA）反应制备的。后一种产物和 3-((E)-3-吗啉-4-基-丙烯酰基)-1,5-二苯基-1H-吡唑-4-甲腈（4）与亚硝酮进行区域选择性 1,3-偶极环加成反应，得到相应的吡唑衍生物。新合成化合物的体内抗雌激素活性和单次口服后的急性毒性进行了评价。还利用乳腺癌和卵巢肿瘤亚面板的 14 个细胞系进行了针对疾病的体外初步抗肿瘤筛选。所有测试的化合物均显示出与参考药物来曲唑相当或更强的抗雌激素特性。3-[3-(4-氰基-1,5-二苯基-1H-吡唑-3-基)-1-(4-甲基苯基)-1H-吡唑-4-羰基]-1,5-二苯基-1H-吡唑-4-甲腈（27c）和 3-(3-乙酰基-1-苯基-1H-吡唑-4-羰基)-1,5-二苯基-1H-吡唑-4-甲腈（8a）在纳摩尔范围内对某些类型的乳腺癌和卵巢肿瘤具有显著的细胞毒性活性，且毒性可接受。
