title: Synthesis and biological evaluation of novel pyrazole derivatives with anticancer activity.
abstract: We synthesized thirty-six novel pyrazole derivatives and studied their antiproliferative activity in human ovarian adenocarcinoma A2780 cells, human lung carcinoma A549 cells, and murine P388 leukemia cells. Four of these substances were selected because of their higher antiproliferative activity and further analyses showed that they were all able to induce apoptosis, although to a different extent. The expression of p53 and p21(waf1), which induce apoptosis and cell cycle arrest, was evaluated by western blot analysis in cells treated with compound 12d. The analysis of the cell cycle showed that all the selected compounds cause a partial G2/M block and the formation of polyploid cells. Furthermore, the four selected compounds were tested for their interaction with the microtubular cytoskeletal system by docking analysis, tubulin polymerization assay and immunofluorescence staining, demonstrating that the compound 12d, unlike the other active derivatives, was able to significantly bind dimers of α- and β-tubulin, probably causing a molecular distortion resulting in the disassembly of microtubules.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, V.le Benedetto XV 3, 16132 Genova, Italy. balbi@unige.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Balbi
authors.forename: Maria
authors.initials: M
authors.lastname: Anzaldi
authors.forename: Chiara
authors.initials: C
authors.lastname: Macciò
authors.forename: Cinzia
authors.initials: C
authors.lastname: Aiello
authors.forename: Mauro
authors.initials: M
authors.lastname: Mazzei
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gangemi
authors.forename: Patrizio
authors.initials: P
authors.lastname: Castagnola
authors.forename: Mariangela
authors.initials: M
authors.lastname: Miele
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Viale
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007211:Indoles; D011720:Pyrazoles; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C007293:DAPI