2. Academic Validation
  3. Development of a new benzophenone-diketopiperazine-type potent antimicrotubule agent possessing a 2-pyridine structure

Development of a new benzophenone-diketopiperazine-type potent antimicrotubule agent possessing a 2-pyridine structure

  • ACS Med Chem Lett. 2014 Jul 23;5(10):1094-8. doi: 10.1021/ml5001883.
Yoshiki Hayashi 1,  Haruka Takeno 1,  Takumi Chinen 2,  Kyohei Muguruma 1,  Kohei Okuyama 3,  Akihiro Taguchi 1,  Kentaro Takayama 1,  Fumika Yakushiji 1,  Masahiko Miura 4,  Takeo Usui 2,  Yoshio Hayashi 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
  • 2 Graduate School of Life and Environmental Sciences, University of Tsukuba , Tsukuba, Ibaraki 305-8572, Japan.
  • 3 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.
  • 4 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.
PMID: 25313318 DOI: 10.1021/ml5001883
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.

Keywords

Cyclic dipeptide; anticancer; antimicrotubule agent; diketopiperazine.

Figures
Products