Design and synthesis of 4-acetoxypentanamide derivatives of spliceostatin A and their biological evaluation towards prostate cancer treatment

  • Bioorg Med Chem Lett. 2023 Jul 15:91:129333. doi: 10.1016/j.bmcl.2023.129333.
Satoru Hirabayashi  1 ,  Yuko Tsuyuguchi  1 ,  Yue Li  2 ,  Noriko Ohta  2 ,  Yusuke Yoshikawa  1 ,  Bangzhong Lin  1 ,  Megumi Fumimoto  1 ,  Kazuto Nunomura  1 ,  Takeyuki Suzuki  3 ,  Junichi Haruta  1 ,  Keisuke Nimura  4 ,  Mitsuhiro Arisawa  5
Affiliations
  • 1. Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan.
  • 2. Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, Yamada-oka 2-2, Suita, Osaka 565-0871, Japan.
  • 3. Comprehensive Analysis Center, Sanken, Osaka University, Mihogaoka 8-1, Ibaraki, Osaka 567-0047, Japan.
  • 4. Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, Yamada-oka 2-2, Suita, Osaka 565-0871, Japan; Gunma University Initiative for Advanced Research, Gunma University, Showa-machi 3-39-22, Maebashi, Gunma 371-8511, Japan.
  • 5. Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan. Electronic address: [email protected].
PMID: 37207846 DOI: 10.1016/j.bmcl.2023.129333
Abstract

We designed and synthesized novel 4-acetoxypentanamide derivatives of spliceostatin A, whose 4-acetoxypentenamide moiety is reduced (7), isomerized (8), or substituted with methyl at the α-position (9). The results of biological evaluation against AR-V7 and the docking analysis of each derivative suggest that the geometry of the 4-acetoxypentenamide moiety of spliceostatin A is important for its biological activity.

Keywords
Michael acceptor; Prostate cancer; Spliceostatin A; Splicing variant.