title: Synthesis and in vitro antitumor activity of new 4,5-dihydropyrazole derivatives.
abstract: A series of 3,5-diaryl-4,5-dihydropyrazole regioisomers, and their 1-acetylated derivatives, bearing a 3,4,5-trimethoxyphenyl moiety combined with a variety of substituted phenyl rings, was synthesized and evaluated for antitumor activity. Results of the in vitro assay against a non-small cell lung carcinoma cell line (NCI-H460) showed several compounds to be endowed with cytotoxicity in micromolar to sub-micromolar range, depending on substitution pattern and position of aryl rings on 4,5-dihydropyrazole core. Potent and selective activity was also observed in the NCI 60 human cancer cell line panel. 5-(3,4,5-Trimethoxyphenyl)pyrazolines 31 and 39 were found to possess potent antiproliferative activity against SR and MDA-MB-435, with GI(50) inhibitory values in nanomolar range. Structure-activity relationships revealed that introduction of a (hydroxy)acetyl group at N-1 of inactive 5-(3,4,5-trimethoxyphenyl)pyrazolines, results in a clear in vitro activating effect. Compound 31 (IC(50)=5.16 microM) showed inhibition of tubulin polymerization comparable to that of CA-4 (IC(50)=4.92 microM).
authors.affiliation: Dipartimento di Tossicologia, Sezione di Chimica Farmaceutica, Università degli Studi di Cagliari, via Ospedale 72, Cagliari I-09124, Italy. ccongiu@unica.it
authors.forename: Cenzo
authors.initials: C
authors.lastname: Congiu
authors.forename: Valentina
authors.initials: V
authors.lastname: Onnis
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.forename: Massimo
authors.initials: M
authors.lastname: Castorina
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D050257:Tubulin Modulators