Molecular design, chemical synthesis, and biological evaluation of agents that selectively photo-degrade the transcription factor estrogen receptor-[small alpha]

• Published in: Organic & biomolecular chemistry 2011-01, Vol.9 (18), p.6357-6366
• Main Authors: Tsumura, Kana, Suzuki, Akane, Tsuzuki, Takeo, Tanimoto, Shuho, Kaneko, Hajime, Matsumura, Shuichi, Imoto, Masaya, Umezawa, Kazuo, Takahashi, Daisuke, Toshima, Kazunobu
• Format: Article
• Language: English
• Subjects: Breast cancer
• ISSN: 1477-0520
• DOI: 10.1039/C1OB05629H

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-[small alpha] (ER-[small alpha]) agonist (hybrid 2) and a 2-phenylquinoline-ER-[small alpha] antagonist (hybrid 3) containing estradiol and 4-hydroxytamoxifen moieties, respectively. These 2-phenylquinoline hybrids effectively and selectively photo-degraded the target transcription factor, ER-[small alpha], 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-[small alpha] for growth. In addition, 2-phenylquinoline-estradiol hybrid 2 functioned as an agonist of ER-[small alpha] 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-[small alpha]. 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-[small alpha], and upon photo-irradiation significantly inhibited cell growth due to the dual antagonist effect of the 4-hydroxytamoxifen moiety and photo-degradation of ER-[small alpha].