title: Antiproliferative activity and mechanism of action of DZ-3358, a novel pyrimidinyl pyrazole derivative.
abstract: The novel pyrimidinyl pyrazole derivative, 1-[5-methyl-1-(2-pyrimidinyl) -4-pyrazolyl]-3-[4-(3-chlorophenyl)-1-piperazinyl]-1-trans-propene hydrochloride (DZ-3358), was found through random screening to exhibit anti-proliferative activity against human and murine cancer cell lines. DZ-3358 induced the mitotic arrest of P388 murine leukemia cells at 0.4 microgram/ml in a time-dependent manner, and inhibited porcine tubulin polymerization. Furthermore, using immunofluorescence techniques, we observed microtubule formation in NUGC-3 human gastric cancer cells treated with DZ-3358. Microtubule formation was disordered, similar to that which occurred when such cells were treated with colchicine. These findings suggest that the mechanism of the anti-proliferative effect of DZ-3358 is the inhibition of mitosis due to the blocking of tubulin polymerization. The differential pattern of growth inhibitory concentrations of DZ-3358 against a series of cancer cell lines was compared with that of colchicine and vincristine, and no correlation was found with the pattern of these two drugs. DZ-3358 may be useful as a new type of tubulin inhibitor and anti-cancer drug.
authors.affiliation: New Product Research Laboratories IV, Daiichi Pharmaceutical Co., Ltd, Tokyo, Japan. iwahaqca@daiichipharm.co.jp
authors.forename: M
authors.initials: M
authors.lastname: Iwahana
authors.forename: Y
authors.initials: Y
authors.lastname: Ochi
authors.forename: A
authors.initials: A
authors.lastname: Ejima
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D003078:Colchicine / Q000633:toxicity; D003110:Colonic Neoplasms; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020014:K562 Cells; D007938:Leukemia; D007941:Leukemia P388; D008175:Lung Neoplasms; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000473:pathology; D010051:Ovarian Neoplasms; D011720:Pyrazoles / Q000633:toxicity; D011743:Pyrimidines / Q000633:toxicity; D013274:Stomach Neoplasms; D014404:Tubulin / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; C408507:DZ 3358; D011720:Pyrazoles; D011743:Pyrimidines; D014404:Tubulin; D014750:Vincristine; D003078:Colchicine