Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents

作者：Torikai Kohei^*; Koga Rintaro; Liu Xiaohui; Umehara Kaoru; Kitano Tatsuya; Watanabe Kenji; Oishi Tohru; Noguchi Hiroshi; Shimohigashi Yasuyuki

来源：Bioorganic & Medicinal Chemistry, 2017, 25(20): 5216-5237.

DOI：10.1016/j.bmc.2017.07.067

• Estrogenic
• Anti-estrogenic
• Benzoacridines
• Antiproliferation
• Diversity-oriented synthesis
• Estrogen receptor alpha (ER alpha)
• Estrogen receptor beta (ER beta)
• Estrogen-related receptor gamma (ERR gamma)

Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor alpha (ER alpha) and ER beta (IC50 < mu M), while binding to the estrogen-related receptor gamma (ERR gamma), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).

• 出版日期2017-10-15