The Configuration-Dependent Anti-Leukemic Effect of Manoalide Stereoisomers: Reignite Research Interest in these Sponge-Derived Sesterterpenoids

Kuei Hung Lai, Bo Rong Peng, Yu Ming Hsu, Mohamed El-Shazly, Ying Chi Du, Mei Chin Lu, Jui Hsin Su, Yi Chang Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Manoalide was studied as a potential anti-inflammatory agent for the last forty years and more than 200 publications and 180 patents were reported on this compound. However, the configurations at positions 24 and 25 and configuration-dependent bioactivity were not yet studied. In the current report, ten manoalide-like sesterterpenoids were isolated from Luffariella sp. (1–10). These stereoisomers were identified and separated for the first time since 1980 and their configurations at positions 24 and 25 were determined by analyzing their spectroscopic spectra. The configuration-dependent anti-proliferative activity of manoalide derivatives was examined by evaluating their effect on four leukemic cancer cell lines (Molt 4, K562, Sup-T1, and U937). The 24R,25S-isomers exhibited the most potent activity (IC50 0.50–7.67 μM). The anti-proliferative mechanism of action of 24R,25S-manoalide (7) was further studied on Molt 4 cells. Compound 7 exhibited apoptotic activity on Molt 4 cells through the disruption of mitochondrial membrane potential (MMP) and the generation of intracellular reactive oxygen species (ROS). It also inhibited the activity of human topoisomerase I and II. The apoptotic-inducing effect of 7 was further supported by the in vivo experiment by suppressing the volume of xenograft tumor growth (66.11%) compared with the control.

Original languageEnglish
Article number105150
JournalBioorganic Chemistry
Volume114
DOIs
Publication statusPublished - Sep 2021

Keywords

  • Configuration-dependent anti-proliferative activity
  • Leukemia, Molt 4 cells
  • Manoalide stereoisomers

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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