Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents
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- Hayashi Yoshio
- Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences School of Pharmacy
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- Yamazaki-Nakamura Yuri
- Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences School of Pharmacy
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- Yakushiji Fumika
- Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences School of Pharmacy
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Certain antimicrotubule agents displaying colchicine-like tubulin-depolymerizing activity can act as both cytotoxic and vascular-disrupting agents (VDAs). VDAs constitute a new class of anticancer drugs and are currently in clinical trials. We have developed a VDA clinical candidate (phase II) diketopiperazine (DKP)-type antimicrotubule agent called plinabulin (7) derived from the natural DKP phenylahistin (5), which displays colchicine-like tubulin-depolymerizing activity. To develop more potent antimicrotubule DKP derivatives, we performed an intensive structure–activity relationship study examining the phenyl group of compound 7. This study identified more potent DKP derivatives (2,5-difluoro derivatives [29] and benzophenone derivatives [36]) with vascular-disrupting activities. The benzophenone moiety of compound 36 was further modified to yield the most potent cytotoxic derivative yet discovered, the 4-fluorobenzophenone derivative 38m, which inhibited the growth of HT-29 cells in vitro at subnanomolar levels. As both VDAs and cytotoxic agents, these potent DKP derivatives are valuable second-generation drug candidates. The chemical biology of plinabulin was examined by designing and synthesizing biotin-tagged photoaffinity probes 40–42 that could be used to indicate the binding mode of compound 7 with tubulin. A tubulin photoaffinity labeling study suggested that compound 7 binds at the interface between the α- and β-tubulins near the colchicine-binding site and not inside the colchicine-binding cavity. A water-soluble prodrug of the poorly water-soluble 7 was next designed in an effort to improve the pharmacokinetics and chemotherapeutic indices. The lead compound 56 revealed high water solubility and a half-life profile appropriate for an injected drug.
収録刊行物
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- CHEMICAL & PHARMACEUTICAL BULLETIN
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CHEMICAL & PHARMACEUTICAL BULLETIN 61 (9), 889-901, 2013
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390001204177999104
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- NII論文ID
- 130003360830
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- NII書誌ID
- AA00602100
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- COI
- 1:STN:280:DC%2BC3sbksFCntw%3D%3D
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- ISSN
- 13475223
- 00092363
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- NDL書誌ID
- 024791683
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- PubMed
- 23995353
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- 使用不可