A novel tamoxifen derivative, ridaifen-F, is a nonpeptidic small-molecule proteasome inhibitor

作者：Hasegawa Makoto^*; Yasuda Yukari; Tanaka Makoto; Nakata Kenya; Umeda Eri; Wang Yanwen; Watanabe Chihiro; Uetake Shoko; Kunoh Tatsuki; Shionyu Masafumi; Sasaki Ryuzo; Shiina Isamu; Mizukami Tamio

来源：European Journal of Medicinal Chemistry, 2014, 71: 290-305.

DOI：10.1016/j.ejmech.2013.11.009

• Proteasome inhibitors
• Tamoxifen derivatives
• Structure-activity relationship (SAR)
• Docking studies

In a survey of nonpeptide noncovalent inhibitors of the human 20S proteasome, we found that a novel tamoxifen derivative, RID-F (compound 6), inhibits all three protease activities of the proteasome at submicromolar levels. Structure activity relationship studies revealed that a RID-F analog (RID-F-S*4, compound 25) is the smallest derivative compound capable of inhibiting proteasome activity, with a potency similar to that of RID-F. Kinetic analyses of the inhibition mode and competition experiments involving biotin-belactosin A (a proteasome inhibitor) binding indicated that the RID-F derivatives interact with the protease subunits in a different manner. Culturing of human cells with these compounds resulted in accumulation of ubiquitinated proteins and induction of apoptosis. Thus, the RID-F derivatives may be useful lead chemicals for the generation of a new class of proteasome inhibitors.

• 出版日期2014-1