Synthesis and mechanism of action of novel pyrimidinyl pyrazole derivatives possessing antiproliferative activity.
Pyrimidinyl pyrazole derivatives 1-4, prepared as a new scaffold of an anti-tumor agent, showed antiproliferative activity against human lung cancer cell lines and inhibited tubulin polymerization. Furthermore, it was found that compound 2 bound at the colchicine site on tubulin, but the tubulin binding pattern was different from that of colchicine. Here, we describe the synthesis of the derivatives and the differences of the action mechanism on tubulin polymerization inhibition between compound 2 and colchicine.
Ohki
Hitoshi
H
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co. Ltd., 16-13, Kita-kasai 1-chome, Edogawa-ku, 134, Tokyo, Japan. okihi10g@daiichipharm.co.jp
Hirotani
Kenji
K
Naito
Hiroyuki
H
Ohsuki
Satoru
S
Minami
Megumi
M
Ejima
Akio
A
Koiso
Yukiko
Y
Hashimoto
Yuichi
Y
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007202:Indicators and Reagents; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008870:Microtubules / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D014404:Tubulin / Q000187:drug effects; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D011720:Pyrazoles; D011743:Pyrimidines; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine