Design, synthesis and structure-activity relationship study of novel pyrazole-based heterocycles as potential antitumor agents

作者：Farag Ahmad M^*; Ali Korany A K; El Debss Taha M A; Mayhoub Abdelrahman S; Amr Abdel Galil E; Abdel Hafez Naglaa A; Abdulla Mohamed M

来源：European Journal of Medicinal Chemistry, 2010, 45(12): 5887-5898.

DOI：10.1016/j.ejmech.2010.09.054

• Anti-estrogenic activity
• Antitumor
• Cytotoxic activity
• Nitrilimines
• 1,3-Dipolar cycloaddition
• 1,5-Diphenylpyrazoles
• Pyrazolo[3,4-d]pyridazins
• Structure-activity relationship (SAR)

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-carbony1]-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.

• 出版日期2010-12