title: Medicinal chemistry and chemical biology of diketopiperazine-type antimicrotubule and vascular-disrupting agents.
abstract: 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 38 m, 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.
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences School of Pharmacy.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yamazaki-Nakamura
authors.forename: Fumika
authors.initials: F
authors.lastname: Yakushiji
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology; D054659:Diketopiperazines / Q000737:chemistry* / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D019920:Photoaffinity Labels / Q000737:chemistry / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001577:Benzophenones; D054659:Diketopiperazines; D019920:Photoaffinity Labels; D014404:Tubulin; D050257:Tubulin Modulators; C047723:benzophenone