Synthesis and structure-activity relationship studies of pyrazole-based heterocycles as antitumor agents.
Several 4-cyano-1,5-diphenylpyrazoles attached to different heterocyclic ring systems at position 3 were synthesized starting from ethyl 4-cyano-1,5-diphenyl-1H-pyrazole-3-carboxylate 1. The newly synthesized compounds were tested in vivo for their anti-estrogenic effects and evaluated in vitro for their cytotoxic properties against estrogen-dependent tumors. 3-(5-Mercapto-1,3,4-oxadiazole-2-yl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile 13 revealed the highest cytotoxic activity with a GI(50) value equal to 40 nM against the IGROVI ovarian tumor cell line. It also showed an anti-estrogen activity 1.6 more effective than the reference drug, in addition to a high tolerable dose. 3-(5-(Methylthio)-4-phenyl-4H-1,2,4-triazol-3-yl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile 7 was found to have the highest anti-estrogenic activity, while 1,5-diphenyl-3-[5-(phenylamino)-1,3,4-thiadiazol-2-yl]-1H-pyrazole-4-carbonitrile 11 showed the lowest activity. The oral LD(50) values revealed that most of the tested compounds are relatively nontoxic.
Farag
Ahmad M
AM
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt. afarag49@yahoo.com
Mayhoub
Abdelrahman S
AS
Eldebss
Taha M A
TM
Amr
Abdel-Galil E
AG
Ali
Korany A K
KA
Abdel-Hafez
Naglaa A
NA
Abdulla
Mohamed M
MM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007928:Lethal Dose 50; D000077289:Letrozole; D008297:Male; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology
D000970:Antineoplastic Agents; D020847:Estrogen Receptor Modulators; D006571:Heterocyclic Compounds; D009570:Nitriles; D011720:Pyrazoles; D014230:Triazoles; D000077289:Letrozole