title: Molecular design, chemical synthesis, and biological evaluation of agents that selectively photo-degrade the transcription factor estrogen receptor-α.
abstract: 2-Phenylquinoline (1) degraded proteins under photo-irradiation with long-wavelength UV light without additives and under neutral conditions. We designed and synthesized a 2-phenylquinoline-estrogen receptor-α (ER-α) agonist (hybrid 2) and a 2-phenylquinoline-ER-α antagonist (hybrid 3) containing estradiol and 4-hydroxytamoxifen moieties, respectively. These 2-phenylquinoline hybrids effectively and selectively photo-degraded the target transcription factor, ER-α, which has a high affinity for estradiol and 4-hydroxytamoxifen. Target-selective photo-degradation was examined in both glass vessels and MCF-7 breast cancer cells, which are dependent upon ER-α for growth. In addition, 2-phenylquinoline-estradiol hybrid 2 functioned as an agonist of ER-α and promoted growth of MCF-7 in the absence of photo-irradiation, while it inhibited the growth of MCF-7 cells upon photo-irradiation due to the photo-degradation of ER-α. In contrast, 2-phenylquinoline-4-hydroxytamoxifen hybrid 3 inhibited growth of MCF-7 cells in the absence of photo-irradiation due to the antagonist effect of the 4-hydroxytamoxifen moiety against ER-α, and upon photo-irradiation significantly inhibited cell growth due to the dual antagonist effect of the 4-hydroxytamoxifen moiety and photo-degradation of ER-α.
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Kohoku-ku, Yokohama, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Tsumura
authors.forename: Akane
authors.initials: A
authors.lastname: Suzuki
authors.forename: Takeo
authors.initials: T
authors.lastname: Tsuzuki
authors.forename: Shuho
authors.initials: S
authors.lastname: Tanimoto
authors.forename: Hajime
authors.initials: H
authors.lastname: Kaneko
authors.forename: Shuichi
authors.initials: S
authors.lastname: Matsumura
authors.forename: Masaya
authors.initials: M
authors.lastname: Imoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takahashi
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Toshima
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D010782:Photolysis; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: C541577:2-phenylquinoline; D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D011804:Quinolines; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol