title: Development of a new benzophenone-diketopiperazine-type potent antimicrotubule agent possessing a 2-pyridine structure.
abstract: A new benzophenone-diketopiperazine-type potent antimicrotubule agent was developed by modifying the structure of the clinical candidate plinabulin (1). Although the right-hand imidazole ring with a branched alkyl chain at the 5-position in 1 was critical for the potency of the antimicrotubule activity, we successfully substituted this moiety with a simpler 2-pyridyl structure by converting the left-hand ring from a phenyl to a benzophenone structure without decreasing the potency. The resultant compound 6b (KPU-300) exhibited a potent cytotoxicity, with an IC50 value of 7.0 nM against HT-29 cells, by strongly binding to tubulin (K d = 1.3 μM) and inducing microtubule depolymerization.
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Takeno
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba , Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Chinen
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Muguruma
authors.affiliation: Section of Oral Radiation Oncology, Department of Oral Health Science, and Section of Maxillofacial Surgery, Department of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University , Bunkyo-ku, Tokyo 113-8549, Japan ; Section of Oral Radiation Oncology, Department of Oral Health Science, and Section of Maxillofacial Surgery, Department of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University , Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Okuyama
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Fumika
authors.initials: F
authors.lastname: Yakushiji
authors.affiliation: Section of Oral Radiation Oncology, Department of Oral Health Science, and Section of Maxillofacial Surgery, Department of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University , Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Miura
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba , Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
keywords: Cyclic dipeptide; anticancer; antimicrotubule agent; diketopiperazine