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: arisaw@phs.osaka-u.ac.jp.

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.

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