Design, synthesis and structure-activity relationship study of novel pyrazole-based heterocycles as potential antitumor agents.
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.
Farag
Ahmad M
AM
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt. afarag49@yahoo.com
Ali
Korany A K
KA
El-Debss
Taha M A
TM
Mayhoub
Abdelrahman S
AS
Amr
Abdel-Galil E
AG
Abdel-Hafez
Naglaa A
NA
Abdulla
Mohamed M
MM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects
D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D011720:Pyrazoles; C031280:pyrazole