title: Synthesis, cytotoxicity, and inhibitory effects on tubulin polymerization of a new 3-heterocyclo substituted 2-styrylquinazolinones.
abstract: In order to study the influence of 3-substitution on the cytotoxic activity of 2-styrylquinazolinones, new 6-chloro-2-styryl-3-(heteroaryl)-4(3H)-quinazolinones were synthesized by refluxing equimolar amounts of 6-chloro-2-methyl-3-(heteroaryl)-4(3H)-quinazolinones and benzaldehyde in glacial acetic acid. At 1 microg ml(-1) concentration, almost all 2-styrylquinazolinones showed some cytotoxic activity against the L1210 and K562 leukemia cell lines. However, only 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone inhibited the growth of these cells by over 50%. This last compound was also the only member of the series that inhibited tubulin polymerization, with an IC(50) value of 5.8 versus 3.2 microM for colchicine. It was also examined for effects on the growth of human MCF7 breast carcinoma cells and Burkitt lymphoma CA46 cells, which had IC(50) values of 0.34 and 1.0 microM, respectively. At 10 microM 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone induced G2/M arrest (66%) in Burkitt cells, with a mitotic index of 20%. At 3.4 microM, it caused disruption of the cellular microtubule system of the MCF7 cells. Both these cellular effects are consistent with its mechanism of action resulting from its inhibitory effect on tubulin assembly.
authors.affiliation: Dipartimento di Chimica e Tecnologie Farmaceutiche, Università di Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Demetrio
authors.initials: D
authors.lastname: Raffa
authors.forename: Michael C
authors.initials: MC
authors.lastname: Edler
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Daidone
authors.forename: Benedetta
authors.initials: B
authors.lastname: Maggio
authors.forename: Mourad
authors.initials: M
authors.lastname: Merikech
authors.forename: Mourad
authors.initials: M
authors.lastname: Merickech
authors.forename: Salvatore
authors.initials: S
authors.lastname: Plescia
authors.forename: Domenico
authors.initials: D
authors.lastname: Schillaci
authors.forename: Ruoli
authors.initials: R
authors.lastname: Bai
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D015394:Molecular Structure; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D011799:Quinazolines / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D011108:Polymers; D011799:Quinazolines; D014404:Tubulin; D050257:Tubulin Modulators